ORIC Pharmaceuticals Inc Stock

All right. Good morning, everyone. My name is Frank Tang, and I'm with the Investment Banking division at Morgan Stanley. Thank you all for joining us today for the Fireside Chat with ORIC Pharmaceuticals. I'm joined here today with -- by the CEO, Jacob Chacko; and CFO, Dom Piscitellic. Great. Thank you both for joining us today.

To start off, for those in the audience that are not familiar with ORIC, could you guys give us an overview of where the company sits today, your lead programs and your priorities now that you crossed into late-stage development?

Sure. Happy to, Frank, and thanks for having us. So ORIC Pharmaceuticals, ORIC stands for Overcoming Resistance in Cancer. In a nutshell, that's the mission of the company. We are today focused on executing across 2 late-stage development programs. So rinzimetostat, which is a PRC2 inhibitor that's being developed in prostate cancer in combination with 2 of the big 3 androgen receptor inhibitors in prostate cancer.

That has just started its first Phase III study, a study called Himalayas-1, which is in the castration-resistant prostate cancer setting in patients who are post-abiraterone. I'm sure we'll talk a lot about that today. And then our second program, enozertinib, which is a brain-penetrant TKI for lung cancer, which is being developed in 2 different populations within the EGFR family of mutations, so EGFR exon 20 and then separately EGFR atypical mutations.

That's a program that will have a pretty substantial data update coming up not too far from now at ESMO in Madrid in about a month's time. And if all goes according to plan there, and if we continue to show a best-in-class profile for that program, we would anticipate starting the first Phase III study next year in 2027. So a lot going on at the company and extremely well funded, but let's get into your specific questions.

Yes. I'd like to start by going a little bit deeper into rinzimetostat. What are your expectations for Pfizer's upcoming MEVPRO-1 readout, particularly in light of their announcement that top-line data is now expected in Q4 of this year?

Yes. So probably the most common question we get in meetings these days is about Pfizer's data and what's the expectations for MEVPRO-1. I always hesitate to comment on expectations for another company's program. So maybe what I'll just leave it at is, I think we and others on the street have been doing a statistical events analysis around Pfizer's MEVPRO-1 study.

That's the first of 3 Phase III studies that Pfizer is undertaking with the same mechanism. So Pfizer's got a drug mevrometostat, which is a PRC2 inhibitor, which they're combining with the third of the AR inhibitors. So I mentioned that we're combining our drug with 2 of the 3 big AR inhibitors. Pfizer is combining their drug with enzalutamide, which is their AR inhibitor that they acquired from Medivation.

They've got MEVPRO-1, 2, and 3, and MEVPRO-1 and 2 are in the CRPC setting, MEVPRO-3 is in the CSPC setting. But MEVPRO-1 is the one that Pfizer recently on their Q2 earnings call, narrowed the guidance for the top-line readout to Q4 of this year. I think that the analysis that we and others on the street are doing essentially suggests that, that probably bodes well for the trial results.

The fact that the top line would be coming in Q4 probably means that the treatment arm is doing well and that the events are -- have been accruing on the control arm. And so I think folks are now kind of reading statistically a decent chance that, that trial will be positive. Obviously, the later, the better in terms of that positivity.

But I think most importantly, Frank, is that almost any statistical analysis you can do on the event accrual into that trial would suggest that a readout in Q4 pretty much takes off the table a huge miss in the trial. Meaning that as you start to think about scenarios for how that trial might play out, whether that's a huge win ranging all the way down to a small win, a small miss or a huge miss, you basically have taken a huge miss off the table at this point and kind of narrowed the range of outcomes for them. But beyond that, I'll leave it to Pfizer to comment on expectations.

Okay. That's super helpful. So your -- I guess, how do you see any of that impacting you in terms of the types of readouts, right? So the extreme outcomes are kind of gone, but it could be a clear positive or an edge case scenario? How do you view those outcomes?

Yes. So if I just take those 4 scenarios, again, that any trial could have, which is a huge win, a small win, a small miss or a huge miss. The fact that you've kind of taken huge miss off the table, at least statistically speaking, should be a good thing because a huge miss obviously would call into question the mechanism of action itself.

I think for all the statistical and event reasons that we've talked about, it seems highly unlikely that a huge miss is on the table at this point. I think even beyond that, just taking a huge step back and looking at the half a dozen or so data points that at this point Pfizer has shown in various single-arm settings, as well as a randomized controlled trial of their own in a Phase II setting.

And then 2 different Phase I data sets that ORIC has now presented. Another drug also had some positive data at ASCO GU. I think across half a dozen different data points, the mechanism does truly seem to be additive. So when you add a PRC2 inhibitor with an androgen receptor inhibitor, you get pretty profound synergy. So taking that big miss scenario off the table is quite helpful because I think the other 3 possibilities, which would be anywhere from a big win down to a narrow miss, would be, frankly, good for us.

And what I mean by that is, mechanistically, we've already seen evidence that this works. There's always edge case scenarios that can take place. If Pfizer has safety issues that pop up on the treatment arm, if that leads to dose reductions and therefore, lower dose intensity that the patients receive, that obviously could compromise the therapeutic effect of their regimen.

I mentioned that they're combining their PRC2 inhibitor with enzalutamide, which is their AR inhibitor. Enzalutamide is a well-known CYP inducer, meaning it pushes down the exposure of drugs that you try to combine with it. And so they're having to dose higher with their mevrometostat in order to get back to the right exposures that can always insert some level of uncertainty into a trial.

They're also taking a relatively -- it's a new regimen actually that they're using in the Phase III, which is dosing in a fed state as opposed to the randomized data where they were dosing in a fasted state. Now they've shown data that suggests that they're able to exposure match between those 2 doses and regimens. But anything can happen in a Phase III. So there's a whole variety of reasons that could lead to an edge case scenario.

But of course, everything that I just rattled off is very specific to their drug, to their regimen. Would not read through to rinzimetostat, our drug. The key point that lets Dominic and I and the rest of the company sleep well at night as we think about these various scenarios and even an edge case sort of near miss for them is that rinzimetostat on a like-for-like basis is just a better drug than mevrometostat.

If you look at just drug development 101, look at the pharmacokinetics of the 2 drugs, mevrometostat has done a lot better for patients in this space than other PRC2 inhibitors have come before. Part of the reason is because it has a better half-life than the other PRC2 inhibitors that have come before. Those PRC2 inhibitors, the first-generation compounds had a half-life of about 1 to 2 hours.

A lot of them had what's known as CYP auto-induction, where they would rev up the CYP enzymes and then themselves be metabolized by the CYP enzymes and you would see things like dose-dependent decreases in exposure. So mevrometostat, to Pfizer's credit, has been able to solve some of those issues. They don't seem to have CYP auto-induction. They have a relatively longer half-life than the first-generation compound. Their half-life looks to be about 4 to 5 hours.

What I love about rinzimetostat is it's taking that and then taking it to the next level. And what I mean by that is we acquired this program from Mirati. The chemists at Mirati did a phenomenal job of coming up with a best-in-class drug profile for the compound. With rinzimetostat, we don't have CYP auto-induction. And importantly, we have a 20-hour clinical half-life.

So that 20-hour clinical half-life means that we can dose relatively low doses of the drug once per day. So our Phase III dose is 400 milligrams once daily. And that's obviously a fraction of the dose that Pfizer is using with mevrometostat, which they are dosing 875 milligrams twice daily. And so at the end of the day, that means that we don't run into the same level or ought not to run into the same level of Cmax-driven toxicity that Pfizer is going to see with their regimen that they themselves have said that they see with their regimen.

And so that list of factors that I just rattled off to you that could lead to an edge case near miss scenario for them don't apply in the same way to rinzimetostat. On top of that, you have to look at the other part of the combination regimen. So the 3 androgen receptor inhibitors, which are enzalutamide from Pfizer, apalutamide from J&J. And then darolutamide from Bayer, have done phenomenally well for patients with prostate cancer.

They have transformed the care of prostate cancer patients. So those 3 drugs collectively do over $13 billion globally in sales. And that is a clear indicator of just how much unmet need those drugs have met for those patients in prostate cancer. When you go survey the physicians and understand the profile of those drugs, what you will hear in every conversation you have is that the efficacy of those 3 drugs is the same.

What is different is that enzalutamide, which was first to market, is a little worse tolerated, has a little worse tox that people worry about than apalutamide, which was the second drug that came to market. And then darolutamide from Bayer, which is the one that we're combining with, is the best tolerated of the 3 drugs. And darolutamide is also not a CYP inducer, whereas enzalutamide and apalutamide are CYP inducers.

And so by bettering each component of the combination regimen, we feel very strongly that we just have a better regimen overall than what Pfizer has. And so essentially, anything they can do, we can do at least as good, if not better, is kind of the mantra. And so in any of the scenarios you talked about, it would be fantastic for us.

Great. I mean you mentioned a lot about the differentiation, but just maybe to cap it off, how do you expect the primary differentiation to be driven? Is it efficacy, safety or both?

Yes. I mean I think the thing that I can confidently underwrite just based on the pharmacokinetics is a safety differentiation. And so again, with a 4- or 5-hour half-life and having to dose the drug 2 times per day, I mean, you know exactly what the PK curve looks like for Pfizer, which is they're going to have 2 very large peaks and then 2 troughs in the course of a day.

And so in order to cover the target, the required amount of target coverage you need over a 24-hour period, they do have to give relatively high doses of the drug. And so the issue with that, and this is not me saying it, Pfizer said this at ASCO GU back in 2025, is that they do see Cmax-driven toxicity. So when you have those 2 peaks, you're getting to a Cmax that does lead to an accentuation of the toxicity.

So on-target toxicity for PRC2 inhibitors should be hematological toxicity and then a variety of different GI toxicities. And Pfizer sees those as do we, of course, because if you're hitting the target, you should see those toxicities. But of course, they see it at a greater frequency and a greater intensity than what we see. And so that ought to be at a minimum base case, the difference is that we'll have better safety than what they'll end up having.

And assuming that both drugs can cover target for 24 hours. I know that we are covering target for 24 hours. I don't know that Pfizer is because they haven't shown those data yet. I just have to assume that they are. But assuming that both drugs are covering target for 24 hours, efficacy should essentially come out about the same between the 2 regimens, but safety obviously would come out quite different.

Now everything I just said applies to the castration-resistant prostate cancer settings where you're hoping to see patients stay on drug for anywhere from 9 months to upwards of a year or more. And you can manage some level of toxicity in that setting. And clearly, Pfizer was able to do that. You see the randomized Phase II data that they presented last year, which were quite phenomenal in terms of the PFS that they showed, but had a fair bit of toxicity.

You can obviously manage some level of toxicity in the castration-resistant prostate cancer setting. The real question comes when you move to the CSPC setting. So Pfizer's third Phase III study, MEVPRO-3 and certainly a population that we would want to study as well in a future Phase III study of our own, castration-sensitive prostate cancer, you expect patients to stay on drug for 4-plus years.

And certainly, with a treatment like this, you would expect even longer than that. And that's a setting in which the room for error, the margin for error of having too much toxicity is going to be quite thin. And that's an area where you very well could see a safety advantage bleed through into an efficacy advantage. And so what I mean by that is if we end up with a better, clearly differentiated safety profile versus the Pfizer combination regimen in the CSPC setting that actually could yield better long-term durability as well because patients are more willing to stay on drug for the number of years that you would expect in the CSPC setting.

It's a thorough overview of differentiation. I appreciate that. You've initiated Himalayas-1, your first Phase III in castration-resistant. Could you walk us through the design, including the key similarities and differences versus the MEVPRO-1 trial?

The design of Himalayas-1, our first Phase III study is very, very similar to the design of MEVPRO-1. Both are being studied in the castration-resistant prostate cancer setting. The inclusion/exclusion criteria for both studies is, again, quite similar, which is patients have all progressed on abiraterone, and up to 1 prior line of chemotherapy is allowed for those patients to have experienced as well.

And so it's very clean in terms of like-for-like patient populations. One thing -- one small difference that we've done in terms of just trial design, and this is just to kind of narrow the unexpected surprises possibility is, obviously, for Pfizer, for us, the control arm is a physician's choice, either an ARPI switch or chemotherapy. And that's the same for both.

Now one thing that we've done in our trial is just cap the physician's choice to no more than 60% of either one of those things, meaning that at the end of the day, you'll have between 40% to 60% of the patients will have received an AR switch and between 40% to 60% of patients will have received chemotherapy in the control arm. I don't believe that Pfizer has put a cap in their study.

That's really the only significant difference between the 2 in terms of trial design. Otherwise, their size is the same, which is 600 patients, roughly 300 patients in the treatment arm, 300 in the control arm. And the trial design, stats, timelines, everything else is quite similar, which is you'd expect about 6.75 months of PFS in the control arm.

That's a blend of the expected PFS of an AR inhibitor switch versus chemotherapy in the control arm. And then you'd expect about 10-plus months in the treatment arm. So -- and all of that is solving for a 0.66 hazard ratio on PFS powered at 95%. So it's a very, very similar trial stats as well.

Great. What are your plans for other trials outside of post-abiraterone CRPC?

Yes. So internally at ORIC, aside from trial execution in Himalayas-1, the other topic du jour is what comes next. So planning for success, what will Himalayas-2 look like? What will Himalayas-3 look like in the prostate cancer space? And then there's certainly -- we don't have time for it today, but there's a lot of places you would develop a PRC2 inhibitor even outside prostate cancer that is also on our radar.

But within -- staying within prostate cancer, probably the 2 next most favorite populations for us, one would be castration-resistant prostate cancer, but in the post-AR inhibitor setting. So as you think about the class of drugs called ARPIs, it's really the 3 big AR inhibitors as well as a drug called abiraterone, which is also widely prescribed to prostate cancer patients today.

And so obviously, MEVPRO-1, Pfizer's trial and Himalayas-1, our trial are looking to address half of the prescriptions of ARPIs today, which is post-abiraterone CRPC, but the other half are the 3 big AR inhibitors. And so what do you do for patients who are -- who have progressed on an AR inhibitor. And so that would be a trial that could be of high interest to us.

Now Pfizer and we have both shown pretty strong Phase I data that suggests a very strong treatment effect in that setting. At least until today, Pfizer has not announced a Phase III study in that setting. So that would obviously be an area that would be of high interest to us is to pursue a trial in the CRPC setting post-androgen receptor inhibitor.

But also where MEVPRO-3 is. So castration-sensitive prostate cancer is also high on our list. So like Pfizer, we also have every intention of going earlier line. And as large as castration-resistant prostate cancer is in the 2 different indications I talked about, and we can certainly provide some of the sizing around that, castration-sensitive prostate cancer is multiples larger than even that population. And so that would also be high interest to us.

Got it.

Either way, whichever one we choose, we're hoping to get the next Himalayas study -- Himalayas-2 started next year.

Yes. You've guided to rinzimetostat program having a program update expected later this year or in the second half of this year. Can you preview what that is expected to cover?

Yes, I'll take that one, Frank. So what we do every year, we give our guidance back in January of each year, so it's kind of our guide, excuse me, for the milestones for the year. And back then, we did say that we'd have intentionally said we have a program update in the second half of this year.

So that program update could be one of many things. That could be an update on the Himalayas-1 study on how we're doing with that program on that study. The second thing could be a potential -- second Phase III study for prostate cancer that we're pursuing or it could be some data updates. So a little bit of TBD on what that will include.

Got it. Okay. Maybe this might be a little bit of a switchback, but could you walk us through the commercial opportunities and dynamics if both mevrometostat and rinzimetostat ultimately reach the market? What factors do you think will help or help drive physician choice between the 2 agents?

Yes, so I think as we think about the commercial opportunity, this is prostate cancer, this is a very large commercial opportunity. And maybe I'll walk through kind of the studies or the areas of focus that Jacob highlighted. The first one obviously is the post-abiraterone patient population. This is where we're studying the first study, the Himalayas-1. So there you've got about 17,000 patients in the U.S. We think that's about a $3.5 billion total just in the market in the U.S. Globally we think it's doubled, so it's about $7 billion globally. The second one is the post-AR inhibitor. That's around 20,000 patients in the U.S. again that's about a $3.5 billion total addressable market in the U.S. and about $7 billion globally. And then if you move into the early stage, obviously you have higher patient populations and longer durability.

So that is probably greater than $10 billion commercial opportunity. So again, this is a huge commercial opportunity in prostate cancer. Where we kind of really think we've differentiated so far based on the data that we've shown earlier this year is really on the safety front. And again, Jacob kind of alluded to this, but if you look at both the frequency and the severity of adverse events were significantly better than Pfizer, and that really does translate into market share and kind of see it with the analog that Jacob referred to with darolutamide, which came 7 years after and darolutamide is taking a significant number of share. And then we've done our own independent market research and assuming equivalent efficacy but just differentiation on the safety front, we should own the large majority of the PRC2 class overall. So obviously we think just on safety, that should translate into a market leader in the PRC2 class share.

It's a great opportunity. Maybe switching gears to your other lead asset, Enozertinib, what's your development strategy there, including the treatment setting and regimens that you guys are pursuing?

Yes, so Enozertinib is a drug that is almost as advanced as Rinzimetostat. We're developing in lung cancer in two different patient populations within the EGFR family of mutations, I'll call it. So EGFR exon 20 and then separately EGFR atypical mutations. So we're right now studying Enozertinib. We've already studied Enozertinib in pretreated populations in both of those settings. But right now the focus is almost exclusively, in fact exclusively, on the first-line setting, the front-line setting, so treatment-naive patients with one of those two types of mutations. We presented a lot of data on both of those populations last year in December at ESMO Asia. That was a mix across different lines of settings, but now, as I said, we're focused entirely on the front line.

And within there, you know, the interesting thing, Frank, is that both of those populations are, you know, first of all, taking a step back. So non-small cell lung cancer have these various driver mutations that end up leading to, you pretty atypical lung cancers for patients, where you see patients who are young, never smokers, but they're genetically driven tumors. And so this is an area that has now been, thankfully we've made a lot of progress, other companies have made progress on mutations like ALK and ROS and RET and classical EGFR mutations. The interesting thing about EGFR exon 20 and then separately EGFR atypical mutations are, those are two sets of mutations where to date there has not been either approved or late stage therapies that have shown really profound CNS activity.

And you might ask why does CNS activity matter for a lung cancer drug. The reason is because of the high prevalence of metastases to the brain in these patient populations. And so in the front-line setting in either of these populations, about 35% of patients will present with brain metastases at baseline. So before they've ever been treated, 35% have brain metastases at baseline. That is actually under-calling the percentage. And what I mean by that is there's certainly a large portion or percentage of patients who have what are known as micro-metastases, which are brain metastases that have come from their lung into their brain that are just too small to see on traditional imaging. And so the true number is even north of 35% of the patients who present with brain metastases or who have them. And then the brain is often the first site of progression for patients as well. And so that's why it's so important, and it has become dogma amongst lung cancer physicians that for patients with any of these driver mutations, you want the drug to be brain penetrant.

If you look across the various driver mutations in lung cancer, whether that's ALK or ROS or classical EGFR mutations, the best-in-class drug is always, without exception, a brain penetrant drug. And the reason for that is that the non-brain penetrant drugs can't handle those brain metastases, they can't prevent the brain metastases, and so you end up getting artificially lower progression-free survival in those patients because you're essentially pulling in the PFS of the patients who present with brain metastases.

And so the overall PFS gets pulled in as well for those drugs. So If you look at Alectinib or Osimertinib, these drugs have done incredibly well for patients. What is special about them is that their brain penetrance has led to a profile where there is essentially no difference in the progression-free survival in the patients with versus without brain metastases. What struck us was the lack of a brain penetrant compound in these two spaces. And so that's what got us excited about developing Enozertinib in both of these populations. We have already shown actually pretty compelling activity, pretty compelling evidence of the CNS activity of the regimen in both populations. And then, obviously, we've got an update in a month's time on our atypical front-line population where we will hopefully make the case that this is the best-in-class molecule in that space.

Yes. I mean, on that point, could you remind us what you expect to show in this update at ESMO, I'm assuming you were referring to, and then what were the relevant benchmarks?

Yes, so we'll have a poster at ESMO on the atypical, each of our atypical patient population. We'll have 20 to 25 patients' worth of data. So we show there is systemic response, CNS response, safety tolerability, and some form of durability, most likely a swimmer plot given the maturity of the data. When we look across the competitive landscape and the benchmark, and we really look at it through three different lenses, one is systemic response, one is CNS response, and lastly is safety and tolerability. If you look at the competitors, the systemic response rates are somewhere in the low to mid-60s.

What's really interesting is when you look at the CNS response rate. And what I mean by that, you see a significant drop off in the CNS response rates from the systemic. So some of these guys have a systemic response rate of call mid-60s but their CNS response rates is in the low-40s. If you truly have a good CNS active drug, you shouldn't see that daylight between the systemic response rate and the CNS response rate. So hopefully we exceed one of those benchmarks and then we at least meet some of the others. The other thing I'd want to focus on is safety and tolerability. Now with these agents you're going to have some on-target toxicities, but the other thing you're seeing with some of these other agents is off-target toxicities, which is not something you'd want with these type of agents. And you see things like QTc prolongation, elevated liver enzymes, and anemia.

So we think this is, there's definitely room for improvement. As Jacob alluded to before, the data that we saw with the CNS activity back at ESMO Asia last year was really encouraging. So hopefully we can exceed at least one of those benchmarks I spoke about and be at least as good on the other.

For the EGFR exon 20 What will determine whether you move into a Phase III and how whether you pursue a mono or combination approach? And how would you think about the upcoming competitor updates and impacting that potential decision?

So we've taken a very pragmatic approach on what to do with the EGFR exon 20 space in particular, given the reality is it is somewhat of a crowded space and there's continuous data coming out from competitors. We expect one additional data to come out from one of the competitors in the coming months as well. We do think that's an interesting space as well. We think the market opportunity there, again, is pretty significant as well. So we will have an update in the second half of this year. What we're doing there is we're studying it in three different ways. We're studying it both as a monotherapy in combination with chemo and in combination with amivantamab. So in order for us to move forward into a Phase III program, we really need to have a differentiated profile. So obviously we're looking at the benchmarks that are out there today, but as well as the ones we expect in the later part of this year.

So if we're differentiated, we'd move forward into a Phase III study next year. If we're not differentiated, we'd probably look to partner the program.

So at the end of the day, Frank, we have to be best-in-class in order to move forward into the Phase III setting for either of these populations. And obviously the benchmarks are, you know, or the benchmark competitors are somewhat overlapping but not totally overlapping between the two. So it's an independent decision that we make as to whether we advance neither of these populations, one population or two, into a subsequent Phase III study or studies.

I guess given those decisions and given the differentiation we've now talked about, how would you characterize the commercial opportunity that you expect for?

Yeah. So these are smaller than prostate. I agree with that, but I do not agree with people think this is a small patient population. These are both blockbuster opportunities, both the EGFR exon 20 and the atypical. When you look at the EGFR exon 20, there's about 4,000 patients in the U.S. So if you do the back-of-the-envelope math, that's over a $1 billion TAM in the U.S. alone. And if you jump over to the EGFR atypical, that's around 6,000 patients. It is a larger patient population. And we estimate that to be a total addressable market of about $2.5 billion in the U.S. alone. Again, if you look at the targeted space, you look at a best-in-class molecule, that best-in-class molecule should capture the large majority of that market share.

So we're really interested in this space. We're really excited about the data that we showed at ESMO Asia. And again, we'll have an update a lot of part of this year.

That's great. We're looking forward to it. Moving on to the corporate side, could you give us an overview of your cash balance and runway? You ended the quarter with roughly $388 million guided to runway of second half of 2028. Does that cover the potential Phase III for Enozertinib as well?

Yes, so we're in a very good position from, well capitalized from a cash position. We have $388 million at the end of Q2. As you said, we've got a runway into the second half of 2028, and that does assume both the Phase III study for Rinzimetostat Himalayas-1 that's included in that cash runway, And it also assumes we're starting a Phase III study for Enozertinib in the first half of next year. So that is a fully burdened cash number. And again, that's cash runway into the second half of 2028. And the reason that's really important is based on our timeline of starting the Himalayas-1 study, we would expect our top-line data from that Phase III study in the first half of 2028, so our cash runway is past that top-line data readout for that Phase III study.

Got it. That's great. Now, a final question from me is, with two potentially best-in-class assets, how do you think about the strategy of building and as these programs continue to mature versus partnering?

We think very carefully about it. It's a topic that's top of mind for us. We know the value of the two programs. If we truly hit this best-in-class profile for even one of the programs, but let alone two of them, building something of incredible importance here for cancer patients. And so, Dominic and I and the rest of the team, you know, we're not dogmatic about what the potential path forward is. We're always evaluating opportunities. And really it's just about maximizing the reach of both programs in terms of the development strategy that we would want to undertake. For the lung cancer program, it's relatively more straightforward in terms of the types of trials you might run in one or both populations. Certainly In prostate cancer, you know, I alluded to it earlier, Frank, there's a broad development program you can undertake in just prostate cancer with Rinzimetostat, but even beyond prostate cancer, there's a number of areas that the preclinical evidence would suggest that program, a PRC2 inhibitor, ought to be studied. And so there's combinations with KRAS inhibitors in either colon cancer or lung cancer, there's combinations with ER directed agents in breast cancer, there's a whole host of other areas where we may want to develop Rinzimetostat.

So That could be one that lends itself more easily, more readily to a larger partnership at some point, whenever is that right time. But we're, you know, right now, heads down, focused on execution for the two programs. We will always, continue to think actively about what's the right way to broaden the development strategy for each of the programs. But beyond that, no other specifics I can offer.

Thank you. That's something investors are obviously keeping a keen eye on. Well, thank you both for joining us, and we look forward to the next conversation.

Thank you for having us.

Great. Good morning, everyone. Thanks for joining us here at the Goldman Sachs Global Healthcare Conference. And good morning on our second day of event for everyone who's joining us online as well. And we're thrilled to have the team from ORIC here this morning, and we'll just get right into it.

Maybe to start, there was some news last week, not from you guys, but from Fulcrum, which was an update that has obviously been top of mind given the mechanism of action overlap. Maybe you could speak to the Fulcrum update on pociredir and any potential implications for your program in prostate cancer rinzimetostat.

Yes. Firstly, thanks for having us here at the conference. So it's a great conference. We're just talking about the long flight across the country. So at a high level, last week, Fulcrum announced the discontinuation of their PRC2 inhibitor, which they were studying in sickle cell disease. If you read the press release, the press release kind of states that the FDA's position was really based on 3 things. One is the risk-benefit profile for sickle cell disease, which is obviously very different than it is for oncology. Two was the previously disclosed malignancies they saw in their preclinical tox work. And third was the ongoing secondary malignancies that tazemetostat is seeing in various indications as well.

So obviously, that was -- people think that's a read-through to us. When we take a look at this, we think the implications are limited when we look at rinzimetostat. And again, that's really for 3 reasons. One is that we've dosed over 100 patients, both as a monotherapy and in combination with AR inhibitors. We have not seen any instances of secondary malignancies. Based on the preclinical work we've done, which is a 4-week tox and a 13-week tox in 2 species, which is a requirement for oncology, which is different from non-oncology. We have not seen any signs of malignancies as well. And third, I think most importantly is, as I said before, the risk profile for prostate cancer is very different than sickle cell disease. So that's, I think, first and foremost, when you think about any drug, it does come down to the risk-benefit profile, taking into consideration therapeutic area, taking into consideration the overall patient population as well.

We also went on to say that over the last 6 months, obviously, we've had a number of interactions with the FDA as we imminently look to start our Phase III study. And there's been no change to our base case plan. Now as you can imagine, with the news on tazemetostat, which I think happened in the first quarter, secondary malignancies was a topic that came up as well, but there was no delay or anything in our timing. And lastly, last week, we did announce that we have completed the end of Phase I meeting.

The 3 objectives of that meeting were first was to finalize the protocol. The second was to confirm the dose selection that we picked for the Phase III study, which is 400 mg once a day of rinzimetostat in combination with darolutamide. And third was to determine any other prerequisites that were required for the initiation of the Phase III study. So we did announce last week that the protocol is finalized, the dose is confirmed and there's nothing else kind of precluding us from starting that Phase III study. So we expect to start that study imminently.

At the end of the day, I think our view is this all comes down to the risk-benefit profile of the drug. Even if you look at some of the prostate cancer drugs today like docetaxel, some of the PARP inhibitors some of the radioligands, there is some small percentage of patients that see these secondary malignancies. So again, it all just comes down to the risk-benefit profile, which, again, oncology is very, very different than sickle cell disease.

Great. So maybe we can talk about a more relevant comp within the prostate cancer context, which is mevrometostat. And could you just speak to like the mechanism of action differences and distinctions between rinzi and mevro?

Yes. So going way back, I think PRC2 inhibitors in general have been studied in prostate cancer for a number of years. I think the #1 issue has been the first-generation PRC2 inhibitors have been plagued with poor drug properties, poor in-vivo potency, very, very short half-lives, call it, 1 to 2 hours. And some of these also had CYP auto induction where you actually saw a decrease in exposure with repeat dosing. We think mevrometostat call it a second-gen PRC2 inhibitor. We think they've improved on a number of those. They've got good in vivo potency. They've increased the clinical half-life from about 1.5 to call it, 5 hours. And they don't appear to have the CYP auto-induction issue. And as you can see, that has translated into a pretty profound benefit based on the randomized data they presented at ASCO GU in 2025.

What we bring to the table, I think, is we continue to have good in vivo efficacy. We have a clinical half-life of 20 hours. And we think that could be a key differentiator for us because with these epigenetic modifiers, what you want to do is cover Cmin for 20, 24 hours, and we're able to do that with that. Now Pfizer's half-life being 5, 6 hours does require BID dosing. So you do have this kind of peak to trough. And our view, and I think Pfizer's view as well is that a lot of the on-target toxicities is Cmax driven. So we're able to prevent that with the once-a-day dosing.

Great. You started to allude to this, but as you think about that differentiation, how would you expect to show up in like clinical benefit? And what maybe tie that into what you've actually seen in the clinical data you put today?

Yes. That's a great segue. And I think what we expect that to see is in the safety side of things. And I think we have seen that. As you know, we had a pretty comprehensive Q1 update. The Q1 update was really -- the objective of the Q1 update was really threefold, is one to select the patient population that we're going to study the first Phase III and select the dose of rinzimetostat that we're going to move forward with. And thirdly, to determine which AR inhibitor we're going to pick for the first Phase III study.

As you know, we're studying both with apalutamide and with darolutamide. We did that. We selected a dose of 400 mg of rinzimetostat, and we've decided to go with darolutamide for the first Phase III study. So if you look at that data update, I think, first and foremost, the efficacy that we've shown primarily on the PFS because that's ultimately the regulatory endpoint. It's highly competitive to what rinzimetostat has shown compared to mevrometostat. If you look at the landmark analysis at 5 months and we look at 5 months because the average follow-up we had -- the median follow-up, I should say, was 5 months. We had a landmark analysis of about 84%, which is right on top of what Pfizer showed at 5 months, both at the ASCO GU data in 2025, I think it was about 80% and then ASCO GU 2026 showed about 84%.

So the differentiation really comes on the safety side. So we were able to show that competitive -- highly competitive efficacy with a differentiated safety profile. So if you look at the adverse events and safety events us versus Pfizer, you can see both in the frequency and the severity of events were significantly less. If you look at Grade 3 treatment-related adverse events, we had mid-single digits. I think depending on which data set you look at, the 875 BID in the Fed or the 1250 in the fasted state, they had somewhere in the mid-30s to high 40s.

So we think safety at the end of the day will win out here, obviously, dealing with older men that are on therapy for an extended period of time. So I think that's the key differentiator so far what we've shown. Now could that translate into longer PFS longer term? We'll have to run that out to see what that looks like.

Great. One of the things that's come up in our conversations kind of subsequent to the data was just like nonspecific discontinuations in the Phase I trial. Maybe you could just contextualize that for us. and help us think about what you guys saw in your early Phase I update relative to apples-to-apples comparison versus mevro or other prostate cancer trials?

Yes, I think that's a good question. That's something that we've gotten a lot of questions about since our last data update. I think a couple of things. We addressed that in a few ways. I think, one, what we saw in our study is no different than what you typically see in other Phase I studies for prostate cancer. Just to remind people, it is a Phase I study, the primary endpoint is safety and PK. It's not an efficacy endpoint. I think that's kind of one.

When you look at other Phase I studies in prostate cancer, there's been many that's been reported recently, including mevrometostat and some of the other T cell engagers and other things like that. It's very common that you have early kind of non-related discontinuations. So I think that's kind of one. In these early Phase I studies, you don't always have perfect clarity on exactly why there are discontinuations, short of something definitive like a safety or an adverse event. And so patients can discontinue for a variety of reasons. Often, it's attributed to something like withdrawing consent or physician's decision.

What's a little bit unique in prostate cancer studies, you also have the phenomenon of increasing PSA. And so often patients can come off the study, especially in a Phase I study where the endpoint safety can come off early, not for radiographic progression, but just to move on to other studies or other therapies. And so that's something that you typically see in Phase I studies with prostate cancer, even though the prostate cancer guidelines discourage that, they encourage you to stay on treatment until radiographic progression, which is a key kind of regulatory endpoint.

As we move forward, thinking about a Phase III study, a lot of times that resolves itself usually because the primary endpoint is something efficacy in the case of mevrometostat it's radiographic progression-free survival or overall survival. Patients, physicians are often blinded to PSA response to not have any bias in the study. And so you see that as kind of typical in the way the progression of clinical studies for prostate cancer trials are conducted.

You've guided to providing another update from the program later this year. And maybe you could just talk about the scope of update that you're going to provide? What kind of things should we be expecting there?

Yes. So we provided updated guidance in January of each year, which we do on a regular basis. And at that time, we specifically intentionally called it a program update to give us full optionality or flexibility on what we provide there. So that could be a number of things. That could be just an update on where we are with the first Phase III study, which we refer to as Himalayas-1.

It could be our thoughts on a second Phase III study in prostate cancer, could be potentially a third -- another study outside of prostate cancer or it could be some additional data update as well. Now obviously, we're expecting the MEVPRO-1 data update as well. So it could also be some color on the results of that study and anything we learned from that study as well. So that's kind of broad. Obviously, we'll provide additional details at a later point.

Within that range of things you just said, one of them is data in the post ARPI population. And so what do you think you need to have to be able to provide a robust update such that it would be worth sharing in the second half of the year in terms of patient numbers, et cetera?

Yes. Specifically on the post-AR inhibitor population, I think, one, we're obviously excited by the data we've shown so far. I think when you look at radiographic progression-free survival, it looks fairly consistent to what we've seen in the post-abiraterone setting. I think you asked a good question, what do we need to see to kind of move that one forward. I think, one, we want to see a little bit more patients responding the same way that we have in our initial bolus of data. And then two, I think a little bit longer duration is what we want to see.

And so again, as Dominic said, similar to the post-abiraterone patients, we had a median follow-up of about 5 months. And so the 5-month PFS actually stands out pretty well compared to other therapies in the space at that landmark. So I think we want to see a few more months of duration to see if that holds. And I think that we will get pretty excited by that moving forward since there is a significant unmet need there.

And remind us what the benchmarks are for rPFS 5 months?

Yes. It's relatively similar to the post-abiraterone setting and that you see a lot of patients, either 1 in clinical studies or 2 in the real world getting AR switch. And so this would be the opposite. So instead of patients having received abiraterone and getting an AR inhibitor, this is kind of the vice versa. They're getting an ARPI, so the AR switch would be abiraterone. And in that setting, there's been some recent Phase III studies that reported data. You typically see an rPFS of about 3 months. And so the AR switching is typically shorter as patients do worse, having seen an AR inhibitor switching to abiraterone. So I think that's one.

Chemotherapy is about the same, so about 7 to 8 months. That is a 5-month landmark PFS in the 60%, whereas we're tracking about 85%. And I think the other interesting benchmark there, it is a relatively small data set. It's a population that Pfizer has not been focused on with mevrometostat, but they did report Phase I data in one of their earlier updates a couple of years ago in that setting. And there, they showed a 5-month landmark PFS in the high 60s. And so again, there's some separation there. Again, it's small data sets to compare, but I think what we're seeing so far is very encouraging.

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You covered it.

You got it. All right. Okay. Let's talk about the registrational study Himalayas-1. Maybe first speak to the dose selection at 400 mg. And are you confident kind of with that selection? And it sounds like you've had these regulatory conversations that you've satisfied any sort of Project Optimus or other requirements?

Yes. I think on -- I think we disclosed this on the Q1 update. We did complete an extensive exposure response analysis across a number of different measures, looking at the correlation to exposure to both the efficacy and safety. And the key takeaway there is that from an efficacy standpoint, there was no statistical difference in the dose on the safety there was. So that was a key driver. So this is actually the ideal scenario for Project Optimus, right? You want to maintain the efficacy without pushing the dose too much from a safety standpoint.

And as you pointed out, we did complete the end of Phase I study and the FDA was satisfied with the completion and the way we approach Project Optimus. So 400 is our dose going forward. We feel good about it. And we'll have data probably in early 2028 from the Phase III study.

One of the key strategic questions you answered with the update earlier this year was the decision on combination agent of darolutamide. Maybe you could talk about the advantages you saw partnering in that direction, both with respect to the drug and Bayer as a partner.

Yes. I think at the end of the day, we think both apalutamide and darolutamide are both great drugs. I think what we've said to date, there's really been no drastic difference between the 2 agents combining with apalutamide or with darolutamide. I think at the end of the day, and we know this, right, we know enzalutamide and apalutamide are CYP inducers. And when you're combining it with our drug as well as mevrometostat, you have this kind of CYP interaction of CYP DDI, which decreases the dose or the exposure, I should say, of our drug and mevrometostat as well, which requires you to increase the dose. And I think that's why Pfizer is required to push their dose as well.

So that's a big difference, I think, when you look at the difference between going with darolutamide and apalutamide. Again, we think they're both great drugs. We just think from a differentiation standpoint, this further differentiates us from Pfizer in the first Phase III study. Now to be clear, the decision to proceed with the first Phase III study, darolutamide does not preclude us from using a different AR inhibitor in the second Phase III study in prostate cancer that we choose to go. So I think that was the key driver. They're both great drugs. And then if you ask a number of KOLs, I think they stack rank the 3R inhibitors, they'd say the cleanest from an efficacy standpoint, I think most people would say they're generally the same.

I think from a safety standpoint, first, they'd say darolutamide is the safest drug of the 3. And if you look at some of the darolutamide, just kind of rehash history here, but enzalutamide was launched back in 2012. Apalutamide came 6, 7 years late in 2018 and darolutamide came a year after that. And darolutamide is a run rate, call it, $3 billion, $3.5 billion, and they're growing at 50% to 60%. So they're kind of one of the leaders in the space, and they're growing exponentially there. So I think that's another factor we think about. Obviously, we want to hitch your wagon to is the key driver there. And the further differentiation on safety here, we think the better it is for us for this indication.

Great. So you mentioned that you've reached FDA. I guess what can you share about the parameters in the registrational program that you're going to start here in the near term?

Yes. So I think obviously, we don't go into intimate detail on our FDA interactions. But at a high level, the study design is a 600-patient study, 300 in the treatment arm, 300 in the control arm. The dose we selected, as we said, is 400 of rinzimetostat plus the approved dose of darolutamide. The control arm will be a physician's choice of AR inhibitor or docetaxel. And again, the primary endpoint will be radiographic PFS. Now we're expecting to start that study imminently. We think it will take about 15, 16 months to enroll that study, and we could have top line data as early as early 2028.

Okay. What would you expect the mix of docetaxel versus AR inhibitor to be based on real-world utilization trends?

Yes. I think generally speaking, we'd say the range is close to 50-50, maybe it's 40-60 on the extremes. But depending on which KOL you speak to, there's definitely a preference that each KOL has on what they like to do and some of that may be regional or their experience with the drug as well. So I think, yes, I think that's generally the rule. Now if you look at Pfizer, I think they're generally assuming -- it appears there they're kind of assuming a similar split between AR inhibitor and docetaxel as well.

Right. All right. That's a great transition to MEVPRO-1 data, which is away from you all technically, but is a big catalyst for the cost this year. Maybe just remind us briefly of the trial design relative to the Phase III that you guys are taking forward.

Yes. To be honest with you, we've obviously done our own independent work around our stats and our trial design. And it is very similar to MEVPRO-1. And just to remind everybody that, again, it's 600 patients, they're using 875 BID in the fed state of mevrometostat plus the approved dose of enzalutamide versus the control arm, which again is physician's choice between docetaxel and enzalutamide. That study is powered to show a hazard ratio, I think, about 0.66 or 6.5. They're assuming the control arm does 6.75. And if you do rough math, it appears they're assuming around 6 months for enzalutamide and about, call it, 7-ish months for docetaxel.

So if you assume a 50-50 split between the 2 agents, you get to this blend of 6.75 in the control arm. For the treatment arm, they're assuming 10.2. And as you know, they showed about 14 months at ASCO GU in 2025 in their randomized data set and the more recent update at ASCO GU 2026, they showed about 14 months. So they're assuming some level of degradation. So we think that study is well powered. We think that study has a good chance of being positive as well.

It's pretty common to assume some level of degradation from early studies into later studies in oncology. But I guess, how would you guys think about that level of 14 months to 10 months in transition from a smaller study to later-stage trial?

Yes. I think generally speaking, I'd say that's maybe a little bit on the conservative side based on -- we've seen multiple data sets that they presented where they've confirmed the 14 months. But again, we think it's an appropriately powered study. And even if you're able to show 10 months, I think 10 months in that setting is a big win for the class for Pfizer and then direct read through to us. I mean if you look at other agents in the space, Pluvicto, for example, in a pre-chemo patient population is probably close to 10 months. So this -- as you guys know, in this study design, you're looking at metastatic CRPC patients. These are patients that had failed abiraterone, and they could have seen up to 1 round of chemo as well. So in theory, these are more heavily pretreated patients than the Pluvicto pre-chemo patient population.

I think the other maybe small point to mention as well as side effects using improved dosing regimen and formulation in their Phase III. So they are switching from the 1250 BID in a fasted state into the 875 fed. And I think the data they've shown on that, obviously, one, way more tolerable than their original regimen that they used in their Phase II randomized. And then two, the data they presented earlier this year at ASCO GU, the efficacy seems like it's tracking a little bit better as well. The PSA response is a little bit better. The PFS hasn't been reached yet. And so there's actually potential for that it could exceed. In their earlier Phase I study, they also showed 17.1 months.

And I think as Dominic said, I think we believe if it is a positive study, that should be very commercially relevant when you look at the benchmarks. There are not many therapies in prostate cancer that have beaten the chemotherapy control arm. So I think that's one really interesting thing that, that is the standard to actually beat. And so if they are able to do that, that would be fairly significant. The only other benchmark out there is Pluvicto that is doing very successful, competing well against docetaxel that has an rPFS about 9 months. And so we think if Pfizer can post results in the 10 months is kind of what they're assuming with an oral therapy that's relatively generally well tolerated, we think that would be very successful for the program and the class.

Great. Is there anything that you might take into consideration on seeing your data that could inform Phase III kind of at the margin in your own design?

That may be difficult. Obviously, we don't know when the MEVPRO-1 data will be released. I think the guidance is mid-'26 or second half '26, which basically means the rest of the year. I mean we're early June, so we don't know when that's coming. As I said before, we're imminently starting the Phase III study. So it may be highly unlikely that we'd be able to kind of read into that.

The other thing I'd say is that Pfizer typically will present top line data, just telling you the study is positive and maybe very little color around that. So we won't know the details about that as well. So I mean, realistically, it may be very difficult to kind of see what -- get any color on what they've disclosed other than whether the study hits or not.

Okay. Maybe you could just talk about like a world in which, obviously, your base case is that it succeeds on efficacy and it looks reasonable from a profile perspective. Is there a world in which the trial disappoints but you guys still feel confident in rinzimetostat? And what would that look like?

Yes. We kind of think about it in 4 buckets. One is there's a big win where they just kind of knock it out of the park. Two is where they barely win. Three is where they barely miss and 4 is where they really totally dismissed, which I'd say 4, based on the data that we've seen based on the powering of their Phase III study, we think is kind of off the table. In the middle 2, I think it's interesting because we really would need to understand why they barely made it or why they barely missed.

Again, we think the key differentiator for us to date based on the data that we presented really comes in the form of safety, right? Better safety, you get better compliance, you maybe get longer duration as well. So I think that's the key part. Now again, when Pfizer presents that detailed information, we'll be telling. They obviously have 3 studies ongoing with MEVPRO 1, 2 and 3. So we'll have to just see obviously what they present when they give the top line data update.

Okay. Maybe you could talk about the market opportunity in this first indication that you selected? And could you provide like a high-level view of what you think the opportunity is there?

Yes. So we -- I mean, I think, one, just to start off, we think it's a very significant commercial opportunity. Again, we're kind of going into patients that have previously failed an ARPI, specifically abiraterone. One thing to point out, if you look at the kind of prescriptions in the U.S., abiraterone right now is tracking about 50% of prescriptions in the ARPI market. So there's very significant abiraterone use in the U.S. global as well. And so we think there are a lot of patients that have failed abiraterone, roughly half the market. And I think there's pretty good statistics out there that kind of cite 35,000 to 40,000 metastatic prostate cancer patients. A majority of them have had seen a prior ARPI, potentially up to half of those would have seen abiraterone is their ARPI of choice.

And again, one of the benefits with the PRC2 inhibitor, what we're starting to see with our data and the mevrometostat data is you have the potential for really long duration of therapy with mevrometostat in the randomized Phase II, a 14.3-month PFS. If you kind of add those numbers together using kind of typical pricing for an ARPI, you can easily get to a $3.5-plus billion, a year opportunity just in the U.S., just in the post abiraterone setting. Again, if we were to move forward in a post AR inhibitor setting, that would be essentially about the same market size, again, just in the U.S. alone. So it's a very substantial market opportunity with a very significant unmet need.

Yes. And again, it sounds like your expectation is you'd share this market. So how do you think about kind of share?

Yes. And again, as Matt said, like we think the TAM is $3.5 billion in the U.S. if you just do some rough math based on number of patients and duration and using some average price. When you look at the ex U.S. market, if you look at prostate cancer, it's probably 90% or 100% of the U.S. market. So overall, we think worldwide, that could be close to a $7 billion opportunity. I think when we think of market share, I kind of look at it 2 ways. One is you have the perfect analogy with darolutamide, right? You have a drug that came out 7 years after enzalutamide. The only difference is really on the safety front, and that's doing $3.5 billion, and that's growing 50% per year.

I think the other thing is we've done -- actually, Matt and our Head of Commercial have kind of done an independent market research with the party. And based on that market research, if you just kind of put the profiles of our drug versus mevro and the only differentiation is safety, we should share. So safety does matter here is the point, and we think that could be a huge differentiator, especially as you kind of move up into early lines of therapy like castrate-sensitive prostate cancer, where patients are not on drug for months, but they're on drugs for 4 years or so.

Great. Maybe we can pivot for the last couple of minutes here to the EGFR program. It's specifically designed for potency against exon 20 and atypical mutations in that drug is ORIC-114. And I know there's a new name, but it easier for me to say. So let's start with how the agent is theoretically differentiated versus the range of other EGFR programs.

Sure. Yes, we call it enozertinib is kind of the new name. So yes, preclinically, the molecule, I think a couple of things was designed specifically for exon 20. So prospectively screened and designed for that. I think that's one differentiator. That is not true for most of the EGFR exon 20 inhibitors today. And then two, also prospectively designed to be brain penetrant. And so we thought that, that is a key feature preclinically that was missing in the marketplace. I think there's been a number of companies, a number of therapies that have been going after EGFR exon 20 for a while. We always felt the landscape was missing like a truly good brain-penetrant drug, which is extremely relevant in lung cancer.

As you see from studies and other prevalence reports that at least 1/3 of patients will actually present with baseline brain mets at diagnosis or the time they enter clinical studies and a majority of them will actually progress with brain lesions over the course of their therapy. And so what we've seen with other targeted therapies for the other oncogenic drivers is that you really need a brain-penetrant drug to be very successful, to have very long duration of therapy. And so we think that, that is kind of the key differentiator.

That was early preclinical data and how it's designed. We have presented clinical data now where we're actually seeing that. And so those were the things that we really wanted to see in the clinic. And so I think, one, that we look at the potency and selectivity, which is what it was designed for, and we're actually seeing that in the clinic. From a safety perspective, some EGFR kind of toxicities where we've seen none of the off-targets that other therapies have, such as cardiotoxicity and QTc prolongation, CPK elevations, liver enzyme elevations, things like that. We haven't seen any of that. So I think that's one very good.

Two, we're enrolling an extremely heavily pretreated patient population. We're allowing extremely broad enrollment criteria for CNS criteria. And so one of the distinguishing features is that we allow patients to come into our study with so-called active brain metastases. And so they do not have to have been treated. They can come with full active CNS metastases. That's very different from other studies that will restrict patients from having brain metastases at all. Some studies allow it, but they have to be treated with things like radiation. And so that's kind of key.

And what we have seen from our early data, we're actually seeing really dramatic responses in those patients. And so we think Again, that is the differentiating feature that we have presented so far. We think that, that will translate into kind of long duration of therapy that has the potential to do that. And so we're excited to kind of continue to update folks with the progress of that program.

Great. You did share an update in December and you, I think, anticipate sharing another update kind of midyear this year. Maybe you could talk about the data to date and the scope of the update we could expect.

Sure. I can cover the data, and then I think Dom can kind of point you to what to expect going forward. So I think a couple of the things that we've shared is we are really prioritizing first-line patients. And so we initially started enrolling patients that were previously treated. Now we're really focused on the first-line patients, both in the EGFR exon 20 side and the atypical side. what we've seen just from a high level so far, I think the efficacy in terms of initial ORR seems to be as good, if not better, than what other therapies have reported in both in terms of EGFR exon 20 and atypicals. The safety profile as well looks as good or better than anything else. And so I think we feel extremely excited by that.

And then I think the one thing that is extremely differentiated is what we've seen on the CNS side. So again, in both of those patient populations, that's the first-line EGFR exon 20 and the atypicals, we enrolled patients with active CNS mets. Patients had measurable CNS mets. And in both of those populations, we had 100% CNS ORR in those patients with measurable disease. That has been something that has not been reported yet. And so we think, again, that one speaks to the differentiation and I think leaves us hopeful that we'll see a long-term duration of benefit there.

Other companies that have reported data, especially in the exon 20 side, most of them actually do not see a benefit in patients with CNS metastases, which is why a lot of times, those are excluded from clinical studies. And so we're seeing activity in patients that aren't even allowed to be enrolled in other studies. We saw a couple of updates at ASCO. There's a company, Dizal reported data with sunvozertinib. They had extremely restrictive CNS criteria. But when you look at the data, they actually had no benefit in patients that actually had CNS metastases even though they were required to be treated. And so that was kind of the third study. We've seen that with others as well is that there's just no benefit with some of the other therapies out there. Patients have any sort of history with CNS disease.

And I'll take the second part. So we have a pretty comprehensive update in the second half of the year. This will be at the 80 mg dose, which is kind of the recommended dose we're going forward with. So in first-line EGFR exon 20 as a monotherapy, we have 20 to 25 patients worth of data. In first-line EGFR atypical, we'll have another 20 to 25 patients of data, and then we'll have about 20 patients or so in exon 20 first line with combination with amivantamab as well.

So it's a pretty comprehensive update you'd expect to see there is obviously systemic response rate, CNS response rate, safety, tolerability and a look on durability as well. When we think about the benchmarks in each of those respective areas, we think more or less it's at 60% plus from a systemic response rate.

Maybe briefly, you could touch on what you see as the market opportunity or the size of the market in this population, particularly given the competitive landscape?

Sure. Yes. I think when we think about this space, it's a smaller opportunity in terms of patients wise than prostate cancer, but there is the potential for really long duration of treatment. What's been pretty well characterized is both of the EGFR populations we're targeting. Exon 20, people typically cite about 2%, maybe a little bit higher of lung cancer, and that will get you several thousand patients in the U.S., about 4,000 patients. The atypical side seems to be a little bit bigger. I think it's commonly cited about 3% of lung cancer. And so again, that will get you kind of another 6,000 patients. So with about 10,000 patients, the potential for long duration of therapy, typical drug pricing, you can easily get to multibillion dollars just in the U.S. for both of those is a TAM.

The one thing that's a little bit different with targeted therapies in our view is you really want to have a best-in-class therapy. It is rare that you see markets kind of split evenly in targeted therapies. So again, we want to have a best-in-class profile. If that is true, that's a very substantial commercial opportunity for both of those populations we're targeting. Again, if you add both of them together, it's about 5% of lung cancer. That is kind of in the ballpark of an ALK market. And we've seen that market in the U.S. is about -- or globally is about $4 billion to $5 billion split between kind of the 2 leading therapies there.

Okay. Maybe in our final minute here, you could talk about cash runway and the clinical activities that are embedded in that guidance.

Yes. So we ended the first quarter with $420 million in cash and investments. That gives us cash runway into the second half of 2028. That does assume, obviously, the Phase III study for rinzimetostat, Himalayas-1 that we're starting imminently. That also assumes us starting a Phase III study for enozertinib in early 2027. So that's fully burdened in there.

I think the other key takeaway, as I said before, we're expecting top line data from the first Phase III study with rinzi in early 2028. So we've got cash runway well past that going into the second half of 2028. So we feel we're well capitalized at this point in time.

Beautiful. Well, it's great having you. Thanks for the conversation today, and thanks to everyone who joined us. And with that, we can turn it off.

Thanks.

Thank you. Great.

Good day, and thank you for standing by. Welcome to the ORIC Pharma Update Conference Call. [Operator Instructions]. Please be advised that today's conference is

being recorded. I would now like to hand the conference over to your speaker today, Dominic Piscitelli. Please go ahead, sir.

Welcome to the ORIC Pharmaceuticals rinzumetostat dose optimization data update call. Earlier today, we issued a press release highlighting new clinical data and details for our first Phase III trial. We have prerecorded our prepared remarks, after which we will host a live Q&A session. A replay of the webcast, along with the accompanying slides will be available on the Investor Relations section of our website for 90 days.

Before we begin, during this call, we will be making forward-looking statements, including forward-looking statements based on our current expectations and projections about future events. Our actual results may differ materially from those indicated by such forward-looking statements. For a description of risk factors, please refer to our recent filings with the SEC. ORIC specifically disclaims any obligation to update any forward-looking statements.

Now turning to Slide 3. During today's call, we'll discuss rinzimetostat's preclinical differentiation, clinical data supporting selection of the recommended Phase III dose design of rinzimetostat's first Phase III trial and an overview of its commercial potential, followed by Q&A.

Joining me on the call today, we have Jacob Chacko, CEO; Lori Friedman, CFO; Pratik Multani, CMO; Matt Panuwat, CEO; and Keith Louis, Senior's Vice President, Commercial and Medical Affairs.

Now let me turn the call over to Jacob.

Turning to Slide 5. At ORIC Pharmaceuticals, our late-stage pipeline is centered on 2 potentially best-in-class programs, each targeting large commercial opportunities. The first is rinzimetostat, a PRC2 inhibitor being developed for prostate cancer in collaboration with our partners at Bayer and Johnson & Johnson.

The second is enozertinib, a brain-penetrant EGFR inhibitor being developed for non-small cell lung cancer also in collaboration with Johnson & Johnson. Today's presentation will be focused on rinzimetostat and specifically the dose optimization data that supports our selection of a Phase III dose and the path forward into our first Phase III registrational trial, IMBAS1.

Turning to Slide 6. Let me take a moment to frame the key takeaways from today's data update before we walk through the details. First, PRC2 inhibitors have demonstrated significant clinical benefit in metastatic CRPC with far longer radiographic progression-free survival than approved and emerging therapies in this setting.

Second, rinzimetostat is a next-generation PRC2 inhibitor that was rationally designed to have best-in-class drug properties, including superior potency and a 20-hour clinical half-life that provides strong target coverage and pharmacokinetics that successfully minimize Cmax-related toxicity. Third, we have selected rinzimetostat 400 milligrams once daily in combination with darolutamide as our recommended Phase III dose, or RP 3D for this first Phase III trial.

This dose demonstrated a highly competitive emerging efficacy profile as measured by early landmark radiographic PFS, PSA response and ctDNA reduction, while also demonstrating a highly differentiated safety profile with significantly lower frequency and severity of adverse events compared to competitor regimens. Finally, we expect to immediately initiate our first Phase III trial, which will be called HIMALAYAS 1 in post abiraterone metastatic CRPC, a population that is a $3.5 billion total addressable market annually in the U.S. and has a lack of oral well-tolerated therapies. We are simultaneously evaluating multiple additional potential registrational trials with the intent of starting our second Phase III trial in 2027.

Now turning to Slide 7. To appreciate the opportunity ahead for its it's helpful to first understand the competitive landscape in post ARPI metastatic CRPC. Currently available therapies in this setting, including enzalutamide, docetaxel, cabazitaxel, and [ levicto ] have demonstrated median RPFS ranging from roughly 6 to 9 months and often come with meaningful associated toxicity and administration challenges.

By contrast, rinzimetostat meets Pfizer's PRC2 inhibitor in combination with an AR inhibitor has demonstrated impressive median RPFS in the range of approximately 12 to 14 months, which is far longer than these other therapies. Given the alternative, even a double-digit RPFS would be a game changer for patients in this setting, especially considering that the PRC2 regimen is an all oral therapy. However, the mevrometostat regimen carries with it meaningful toxicity challenges.

As we will discuss shortly in the slides ahead, our early data for rinzimetostat in combination with darolutamide is tracking quite favorably relative to the MEBro-PFS benchmarks while also offering a substantially cleaner safety profile.

Turning to Slide 8. This slide provides a snapshot of the key efficacy and safety data for rinzimetostat at 400 milligrams once daily in combination with darolutamide in the far right column and places it side-by-side with 2 key comparators. Enzalutamide monotherapy in the far left column and the combination of mevro with enzalutamide in the middle column.

Starting with efficacy. The early RPFS landmark data for [ vinci ] plus darolutamide is highly competitive. As 3, 4 and 5 months, our combination achieved landmark RPFS percentages that are essentially identical to the mevro combination and far higher than those of AR inhibitor monotherapy.

For that matter, the rinzimetostat landmark RPFS percentages outperformed those of the various alternative therapies listed on the prior page like pluvicto and chemotherapy as well. What is even more remarkable though is that rinzi's strong efficacy is accompanied by an exquisitely clean safety profile.

The safety profile for our 400-milligram dose in combination with darolutamide is markedly cleaner than what has been reported in the mevro regimen with pluvicto or with chemotherapy. The most common treatment-related adverse events for the rinzi daro combination are fatigue, diarrhea and nausea, all of which occur at relatively low rates and critically, all are grade 1 or 2. Treatment modifications of any kind were exceedingly rare. The contrast versus our competitor safety profile and versus other alternatives in this space is stark.

Finally, turning to Slide 9. I want to briefly review the magnitude of the opportunity that lies before us. In prostate cancer alone, we estimate that rinzimetostat has the potential to reach approximately 70,000 patients in the U.S. annually across 3 distinct indications. The initial target population post abiraterone metastatic CRPC is today roughly a $3.5 billion annual total addressable market in the U.S. alone, with additional prostate populations like post AR inhibitor metastatic CRPC and metastatic castration-sensitive prostate cancer, the opportunity grows substantially, with the metastatic CSPC setting alone being a potential market of greater than $10 billion annually in the U.S.

Beyond prostate cancer, we also see meaningful future development opportunities for Rinse in other settings, including non-small cell lung cancer, colorectal cancer and breast cancer, where the biology of PRC2 inhibition may similarly enable combination strategies with various approved and investigational therapies.

With that, let me hand the call over to Lori to walk through the preclinical rationale for rinzi before Pratik walks us through the clinical data. Lori?

Thanks, Jacob. It's my pleasure to talk about PRC2 and our excitement for developing rinzimetostat in prostate cancer. Turning to Slide 11. PRC2 has been a target of interest for many years. However, the first-generation inhibitors such as CPI-1205 and tazemetostat had multiple shortcomings as shown in the left side of the table.

mevrometostat, a second-generation inhibitor addressed some of these issues including cell potency and SIP auto induction, yet fall short in other drug properties such as solubility and half-life. Rinzimetostat shows improvement in all categories, including drug properties that result in a 20-hour half-life in the clinic, thus, rinzi has potential as a best-in-class PRC2 inhibitor that addresses all the limitations of earlier generation inhibitors.

On Slide 12 are 2 examples of preclinical in vitro data demonstrating the superior potency of rinzimetostat to first-generation PRC2 inhibitors. In these dose-ranging studies, AR-positive prostate cancer cell lines were treated head-to-head with 4 different drugs and assay for effects on cell growth and viability. The cell potency for first-generation inhibitors shown in black and dark blue curves are right shifted due to their weaker potencies. Rinzimetostat demonstrates comparable potency to mevrometostat in prostate cancer cell lines and superiority to the first-generation PRC2 inhibitors.

The graphic on Slide 13 summarizes how therapeutically targeting PRC2 reverses the evolution of prostate cancer. As prostate cancers are treated with hormone blockade or with AR targeted agents, they evolve to evade these therapies. Going from left to right, the illustration shows prostate tumors progressing from castration sensitive to insensitive and from AR dependent to AR independent. Epigenetic reprogramming is the mechanism by which prostate cancer cells transition to change their cell state to escape therapeutic pressure.

PRC2 inhibition can reverse this process and even prevent the transition. So that prostate cancer cells regain and maintain their luminal cell state and their dependency on AR. This mechanistic rationale supports the combination of PRC2 inhibitors with AR inhibitors and suggest that the therapeutic potential of rinzimetostat in prostate cancer will be maximized in combination with AR inhibitors.

On Slide 14 is an example of preclinical data supporting the mechanistic rationale, where PRC2 inhibition with rinzimetostat sensitizes prostate cancers to AR inhibition through epigenetic reprogramming, in the 2 experiments shown here with the CRPC model on the left and the CSPC model on the right, prostate cancers were treated with either rinzimetostat or the vehicle control and tumors were then assessed for transcriptional changes using RNA sequencing. 2 consistent changes were observed, a significant increase in AR signaling and a significant increase in luminal cell state markers. These transcriptional shifts result in the prostate tumors having an increased dependency on the androgen receptor.

Slide 15 shows how rinzimetostat further controls epigenetic reprogramming at the level of chromatin modifications in experiments using ATAX sequencing. These volcano plots depict transcription factor sites on chromogen that are either significantly opened, shown in orange or significantly closed shown in blue.

On the prior slide, I showed how luminal and AR transcriptional signatures were increased following rinzi treatment. In these experiments, we also see that important transcription factor sites are closed. And notably, these closed sites are known to drive lineages statement in prostate cancer, such as [ 1 CAT II and FOXA1 AR ] half sites. Visibility of rinzimetostat to reduce accessibility to lineage escape factors means that rinzi has the potential to prevent resistance from arising. And again, like the prior slide, we see the same mechanism in both CRPC and CSPC models.

Moving forward to in vivo efficacy on Slide 16. On the left is an example of a study where castration-resistant prostate cancer xenograft were treated with darolutamide with and without PRC2 inhibitor. The combination of rinzimetostat with darolutamide impressively improved progression-free survival in this castration-resistant setting. On the right is a similar study. Only this time, the combination was assessed in castration-sensitive prostate cancer xenograft. Once again, adding rinzimetostat to darolutamide increase the progression-free survival. Thus, rinzimetostat has been shown to combine with AR inhibition in prostate cancer xenograph to improve survival in both CRPC and CSPC studies. And importantly, with rinzimetostat's improved drug properties, it stands out as the potential best-in-class PRC2 inhibitor. We're excited to see rinzi's progress in the clinic, as Pratik will tell you about.

Thank you, Lori. Turning to Slide 18. It's my pleasure to provide an update of the dose optimization data from our Phase Ib trial of rinzimetostat and the extensive work we've done to select the recommended Phase III dose to take into our first registrational trial.

This trial is a multicenter study being conducted in 4 countries in patients with metastatic prostate cancer. Initially, we explored rinsimetostat as a single agent at doses ranging from 100 milligrams to 900 milligrams once daily. These data established rinzi's strong pharmaceutical properties, including dose proportional exposure, no evidence of SIP auto induction and a 20-hour clinical half-life allowing once-daily dosing. We also demonstrated robust target engagement at doses as low as 200 milligrams and a well-tolerated safety profile with a single agent maximal tolerated dose of 800 milligrams giving us a wide therapeutic window and making rinzi is highly suitable for drug combination.

Collectively, these properties differentiated rinzimetostat from other PRC2 inhibitors, and positioned it as a potential best-in-class molecule. We then proceeded to combination dose finding conducted in parallel with both darolutamide and apalutamide and have previously presented data from this experience last year.

After determining the candidate RP 3Ds for each AR inhibitor combination, we then embarked upon comprehensive dose optimization randomizing patients to receive 1 of the 2 RP 3Ds selected for each AR inhibitor, respectively. This dose optimization was conducted in 2 separate patient populations with metastatic prostate cancer. One in patients who have previously received abiraterone and the other in patients who had previously received a second-generation androgen receptor inhibitor, namely apalutamide enzalutamide or darolutamide.

Today's update will focus on our dose optimization work with rinzimetostat in combination with darolutamide in the post abiraterone patient population. Before I get into the new dose optimization clinical data, turning to Slide 19, I wanted to spend a minute talking about the pharmacokinetics and pharmacodynamic results that underpin our decision-making around optimal dose and RP 3D selection.

On the left of this slide is a PK plot of rinzimetostat over 24 hours for the 2 doses selected for dose optimization with darolutamide. 400 milligrams and 600 milligrams once daily. You can see that both blue curves peak at 4 hours with a gradual decay over 24 hours demonstrating rinses 20-hour half-life and well-behaved pharmacokinetics. Superimposed on these 2 curves in shades of gray are the single agent PK curves for the same doses of rinzimetostat highlighting the lack of drug-drug interaction between rinzi and daro. The

2 dotted red lines superimposed on this PK plot represent target minimum concentrations from our preclinical work. The key point here is that both doses cover the target exposure for the full 24 hours. On the right, we have pharmacodynamic data, looking at the level of H3K27 trimethylation levels in PBMCs both as a single agent or in combination with darolutamide, we maximize the PD signal in this readout at both 400 and 600 milligrams. And from our single agent work, you can see that we even cover the target at 200 milligrams.

So these data collectively support our choice to take 2 dose levels into dose optimization that were both predicted to be efficacious. Turning to Slide 20 and our clinical data. You can see the demographics and baseline characteristics of the patients treated with rinzimetostat at 400 and 600 in combination with darolutamide in patients with mCRPC post abiraterone.

Overall, these patients were more heavily pretreated than those from recent competitor data sets. The median baseline PSA was 26 for the 400-milligram dose and 12 for the 600-milligram dose. While the median baseline PSA of 12 is comparable to what's been seen in other MCRPC data sets, the median of 26 in the 400-milligram group is considerably higher. In terms of treatment history, patients at both doses had a median of 2 prior therapies, not counting ADT. They all had received prior abiraterone with many receiving prior docetaxel as well as additional therapies such as immune therapy, radium-223 or PARP inhibitors.

This prior treatment history makes our population more heavily pretreated than the disclosed mebrometostat experience which only allowed prior abiraterone and up to one prior chemotherapy and no other therapies. Finally, tables like these conventionally show median age in the first row with little comment. But I think it's important to point out that the median age here is in most studies in metastatic prostate cancer was 70 years overall, meaning that this is a more fragile elderly population with less tolerance for drug-related toxicity.

Slide 21 shows the safety profile of rinzimetostat at 400 and 600 milligrams in combination with darolutamide. You can clearly see that almost all adverse events are either grade 1 or 2. In fact, across all 33 patients at both dose levels, there was only 1 grade 3 event. There were also no grade 4 or 5 treatment-related adverse events at either dose. The most frequent adverse events include fatigue, which can be attributed not only to rinzimetostat, but also the AR inhibitor darolutamide and to the patient's cancer itself.

Next on the list are GI-related toxicities, diarrhea and nausea. These side effects can be particularly troublesome if they are chronic, even at grade 2 in severity because they can significantly impact a patient's quality of life. They'll note that at the 400-milligram dose, most of these events were Grade 1, whereas it's 600 milligrams, there was a generally higher rate of grade 2 events. This safety trend can be seen more clearly on Slide 22, where we pull back and include 39 additional patients from the post AR inhibitor dose optimization cohorts.

The overall safety experience here is larger with 37 patients at the 400-milligram dose level and 35 patients at the 600-milligram dose level. Again, there are a few grade 3 events overall but there remains a trend towards fewer grade 2 versus grade 1 adverse events at the 400-milligram dose level versus 600, especially with the important potential quality of life toxicities of diarrhea and nausea.

In keeping with this observation, the rate of diarrhea at 400 is also just about half the rate at 60, 19% versus 37%, respectively. Nausea is also lower at 400 milligrams and entirely grade 1 compared with 600 milligrams. From a safety perspective, both those levels appear to be well tolerated. However, for a drug where long-term dosing is expected for months and even years, minimizing the incidence of even grade 2 events can be critical to patient adherence.

For the treatment to work, patients need to stay on therapy and the need to maintain that therapy without frequent interruptions for toxicity since interruptions can lead to loss of target coverage and compromise efficacy. Furthermore, these factors become even more critical if you intend to move the drug earlier in the course of disease, for example, into the CSPC setting, where we are planning future potential Phase III trials.

Turning to Slide 23. We have additional safety data, specifically various types of treatment modification events, rates of dose interruptions, dose reductions and treatment discontinuations presented for both the post abiraterone population and the broader post ARPI population. The general trends that we just saw with the adverse event tables are also evident here.

Both the 400 and 600-milligram dose groups have event rates that are lower than competitor regimens, but the 400-milligram remains more favorable than the 600 milligrams with lower rates of treatment modifications across the board.

With that in mind, let's turn to Slide 24, which outlines the work we did to satisfy the requirements of FDA's Project Optimus and formally select the rinzimetostat recommended Phase III dose in combination with darolutamide. To do this, we performed an extensive set of exposure response analysis that look for correlations between drug exposure and a range of measures of both safety and efficacy. Drug exposure was quantified multiple ways. We looked at Semen the lowest concentration over 24 hours. We looked at Cmax, which is the highest concentration, and we looked at AUC a measure of overall exposure, including accounting for individual patient dose modifications.

Safety measures we examined included the rate of grade 2 or higher adverse events, grade 3 or higher events or serious adverse events. We also look for correlations between exposure and specific subsets of adverse events of interest such as gastrointestinal or hematologic toxicities. And finally, we look at the relationship between exposure and rates of treatment modifications.

On the efficacy side, we looked at correlations with radiographic progression-free survival with PSA reduction, both categorically as a response rate and as a continuous variable. We also looked at reduction in ctDNA, and a pharmacodynamic readouts such as changes in H3K27 trimethylation. Overall, this in-depth analysis showed that both 400 and 600 milligrams provided comparable efficacy. There was substantial overlap and exposure distributions between responders and nonresponders on any measure of efficacy, including progression-free survival without statistical significance.

Thus, the 600-milligram dose was statistically comparable to and not superior to the 400-milligram dose. In terms of safety, however, the ER analysis showed statistically significant relationships between exposure and clinically meaningful toxicities as well as statistically significant correlations between higher exposures and higher rates of treatment modifications.

Thus, on the basis of safety, the 400-milligram dose was clearly favored over the 600-milligram dose. Overall, the conclusions from this ER analysis were unambiguous with no advantage in efficacy at the higher dose but a clear statistically significant advantage in safety at 400 milligrams. Therefore, the definitive conclusion from this work is that 400 milligrams is the preferred RP 3D for rinzimetostat in combination with darolutamide. With 400 milligrams selected as our recommended Phase II dose of rinzimetostat in combination with darolutamide.

Let's now take a look at its efficacy profile over the next few slides, beginning on Slide 26. We would hope to replicate this efficacy profile in the upcoming Phase III trial, which if we do, would yield a therapy that is more effective and yet safer than options currently available to these patients today. In fact, we may even be able to improve upon this profile given the more heavily pretreated nature of the patients we treated in dose optimization versus those we would be enrolling in our upcoming Phase III trial.

On this slide, we have a PSA waterfall plot of the best percentage change in PSA from baseline for the 15 patients with mCRPC post abiraterone, who had a PSA measurement by the data cutoff. You can see strong clinical activity with a 47% unconfirmed and 33% confirmed PSA 50 response rate. Multiple of these patients remain on treatment, offering the potential for further deepening of responses.

Slide 27 depicts a waterfall of the best percentage change in circulating tumor DNA fraction and shows a similar impressive molecular response. 71% of patients had a 50% ctDNA reduction and 29% had a 90% reduction. To put this into context, this 71% rate of reductions is meaningfully higher than what was seen with enzalutamide in the Ambassador 250 study, for example.

Of note, these rinzimetostat ctDNA responses were seen across a variety of AR alterations, including point mutations, AR amplifications as well as the wild-type setting. These impressive data are important, especially given the established strong correlation between ctDNA reduction and long-term durability.

Finally, Slide 28 depicts the time on treatment swimmer plot for the 18 patients in dose optimization at the 400-milligram dose. The plot depicts which patients have had radiographic progression events and their timing as well as which patients remain on study. On the left, along the y-axis, we have listed the prior treatment history outside of ADT for each of the patients as well. Follow-up is still early, but with a median follow-up of 4.9 months, you can see in the embedded table on the right, the landmark radiographic progression-free survival at 3 time points where we have reliable data 3, 4 and 5 months.

At 3 months, an impressive 93% of patients remain progression-free which has been 84% at the 4- and 5-month landmarks, meaningfully higher than what you would expect from an ARPI switch alone. With further follow-up, we will be able to extend our estimate of long-term durability. But at this early stage, we are excited by the durability that we're seeing.

Now to put all these data that I presented into context, Slide 29 compares the safety profile that we have developed for rinzimetostat 400 milligrams in combination with darolutamide versus the disclosed safety profile for best both at 1,250 milligrams BID fasted and their more recent data at 875 milligrams BID Fed. We can't do a complete comparison because for rinzimetostat we only know the adverse events that occurred with a 20% or higher incident.

You can see that the adverse event profile of rinzimetostat stacks up very well against the mevrometostat results. regardless of whether you're looking at the fasted or fed mevro regimen. Specifically, for all the adverse events disclosed for mevrometostat, the incidents with rinzimetostat is lower in each case with the one exception of a slightly higher overall rate of fatigue versus the mevro 875 bed regimen. But even here, there are no grade 3 events with Rinse while there are with mevro. In addition, there are a number of adverse events reported with mevro that we don't see to any appreciable degree with rinzi, such as alopecia, neutropenia, thrombocytopenia or vomiting.

Slide 30 extends these safety observations summarizing the rate of grade 3 adverse events, serious related adverse events, dose reductions and treatment discontinuations for rinzi with darolutamide versus mevro with enzalutamide. You can see that across all of these tolerability metrics, the 400-milligram rinzimetostat dose in combination with darolutamide demonstrated a clearly differentiated safety profile from both mevrometastat plus enzalutamide dosing regimens with a lower rate of Grade 3 adverse events no serious related adverse events, no dose reductions and few discontinuations. This differentiated profile, we feel is highly compatible with long-term dosing and sustained patient adherence.

Slide 31 summarizes the important elements of safety and efficacy from the rinzimetostat data with a benchmark comparison to the same results for the mevrometostat combination, both with their fasted and fed regimens as well as enzalutamide single agent. But before I walk through this, I wanted to again point out that our study was conducted in patients who are more heavily pretreated than in the Mero studies, and they had a higher baseline PSA, 26 for the rinzi patient population compared with 15.5% and 16.7% for the 2 mevro groups.

Now in terms of radiographic progression-free survival, we have less follow-up than the mevrometostat patients approximately 5 months median follow-up compared with 9 to 11 plus months for mevro. But for the RPFS landmarks that are available for comparison at 3, 4 and 5 months, the rinzimetostat data are nearly identical to the mevro data and superior to the enzalutamide single-agent data.

In terms of safety, on the other hand, any way you look at it by the rate of grade 3 adverse events or the rate of dose reductions or discontinuations, rinzimetostat appears to be markedly safer than the competitor benchmark. Overall, we feel very good about the safety and efficacy profile we have developed for rinzimetostat at the 400-milligram dose in combination with darolutamide, a profile that positions it well for success as we now move to Phase III development.

Turning to Slide 33. With this strong rinzimetostat profile in hand and having selected the RP 3D of 400 milligrams in combination with darolutamide, I'm excited to unveil our first Phase III trial, which we are calling Himalayas-1. You can see the design of Himalayas-1 here. This study will be conducted in patients with metastatic castration-resistant prostate cancer who have previously been treated with abiraterone and have had up to 1 prior chemotherapy in the CSPC setting. Patients will be randomized 1:1 between a combination of rinzimetostat and darolutamide versus physician's choice of an AR inhibitor or chemotherapy. The primary endpoint of the study will be radiographic progression-free survival with overall survival as a key secondary endpoint.

We are far along in study startup activities, having selected over 250 sites in over 20 countries in North America, South America, Europe and across Asia Pacific. And to help us in the conduct of this study, turning to Slide 34, we have engaged many of the world's leading experts in the treatment of prostate cancer as members of the Himalayas-1 steering committee. The Committee Chair is Matthew Smith of Massachusetts General Hospital and the Vice Chair is Karim [ Pozzi ] of Gustavo. Additional members include Johan de Bono of the Royal [ Marsden ], Arun Azad of Peter Mac. Elizabeth Heat of the Mayo Clinic, Joaquin Matteo of [ ValdeBran ]; Rahul Agarwal of UCSF and [ Wasim Abita ] of Memorial Sloan Kettering. Basically a who's who of international thought leaders in the field of new therapies for prostate cancer.

With the expertise of our steering committee and the partnership with many GU oncologists and urologists around the world, we have agreed to participate in our trial. We have strong momentum to initiate Himalayas-1 in the first half of this year.

Now turning to Slide 35. As a final step to our regimen selection, one that is required by FDA, we are conducting a food effect study. We did look at food effect of rinzimetostat as a single agent and didn't see a significant impact of dosing with food on rinzi exposure. We're now repeating this with the rinzi-daro combination. And so far, we are not seeing a significant food effect here either. Of note, the early data in the food effect cohort continues to look good on efficacy and safety.

In the first 5 patients in this cohort who are evaluable for PSA response, we have observed to confirm PSA 90 as well as 2 confirmed PSA 50 and all safety events noted thus far are grade 1 with 1 Grade 2 related event. This obviously gives us further confidence in our choice of the 400-milligram dose for Phase III development.

Finally, on Slide 36, while we are hyper focused on near-term initiation and execution of our Himalayas-1 Phase III trial, we are simultaneously exploring additional indications in which we may conduct future Phase III studies. Earlier in the presentation, Lori presented compelling preclinical data suggesting that the therapeutic benefit of a PRC2 inhibitor may translate to the CSPC setting.

In addition, as I stated earlier, with our ongoing Phase Ib trial, we are currently generating clinical data looking at rinzimetostat with darolutamide in the post AR inhibitor mCRPC patient population.

Here on this slide, we have a preliminary look at the time on treatment swimmer plot in these post AR inhibitor patients at the 400-milligram RP 3D dose. Follow-up is still early with a median of 4.8 months, but the 3, 4 and 5 month landmarks are very encouraging with 93% progression-free at 3 months going to 85% at 4 and 5 months and 8 of these 19 patients are still on treatment. This performance is particularly striking, given that an AR inhibitor alone after a prior AR inhibitor would be expected to give a PFS of 2 to 3 months at best. These data leave little out in our minds as to the potential of rinzimetostat more broadly in patients with prostate cancer.

Now let me hand it over to Keith, who will outline rinzi's commercial potential. Keith?

Thanks, Pratik. Turning to Slide 38. As Pratik highlighted earlier, based on the highly differentiated rinzimetostat RP 3D efficacy and safety profile, we are excited about the upcoming initiation of Himalayas-1 in post abiraterone MCRPC.

From a commercial perspective, the next logical question is how large is that market? And the answer to that question is driven by the widespread use of abiraterone both in the U.S. and globally that makes it by far the world's most prescribed ARPI. As the first ARPI approved by the FDA for prostate cancer, abiraterone remains the leading ARPI, accounting for approximately half of new ARPI prescriptions annually as evidenced by real-world clinical trial and prescription data.

Turning to Slide 39. This is how we think about the total addressable market in post abiraterone and CRPC. In the U.S., we estimate that the annual incidence of MCRPC patients previously treated with abiraterone is approximately 17,000, then based on mevrometastat Phase II combination data, we estimate a treatment duration of about 14 months. Finally, factoring in the current day pricing of advanced prostate cancer therapies, we arrived at an addressable market in the U.S. of over $3.5 billion and a total global addressable market of around $7 billion for this first indication alone.

As Jacob and Pratik noted earlier, PRC2 inhibitors have demonstrated significant clinical benefit in MCRPC with far longer radiographic PFS than approved and emerging therapies in this setting. Rinzimetostat, albeit early, thus far is tracking to the same long durability. But importantly, rinzi is already well on its way to establishing a highly differentiated safety profile that would stand in a class of its own.

And so as we model out future share scenarios, we are really looking at 2 potential future cases, both of which assume that rinzi continues to demonstrate a best-in-disease safety profile. In a minimal case, rinzi achieves equivalent efficacy to other PRC2 inhibitors, which, as stated earlier, is far longer than other currently available therapeutic alternatives. And in a scenario more akin to our base case, rinzi is able to achieve differentiated efficacy as well. Obviously, either case results in substantial rinzimetostat share of the $7 billion post abiraterone MCRPC market.

Turning to Slide 40. To pressure test the minimal case where rinzi maintains its highly differentiated safety advantage, but achieved only equivalent efficacy to other PRC2 inhibitors, we conducted independent market research with U.S.-based academic and community urologists and oncologists. The physicians assess blinded target product profiles of rinzimetostat noted in the research as product-wide, in combination with darolutamide against a competitor PRC2 inhibitor noted as product Z in combination with enzalutamide in post-abirateron MCRPC.

The TPPs reflected similar efficacy but a more favorable safety profile for the rinzi plus daro combination that was similar to the 400-milligram safety profile Pratik shared earlier in his presentation. The key insight from our research was that physicians indicated they would describe the blinded rinzimetostat profile, 80% share of the PRC2 class, reinforcing the notion that a differentiated best-in-disease safety profile alone can drive prescribing decisions and significant market share, especially considering the demographics of this patient population. This prescribed preference is reflected in multiple quotes throughout the research where prescribers expressed strong preference for product wide based on the safety benefit alone.

Turning now to Slide 41. I want to revisit the commercial potential that Jacob spoke to earlier in the presentation. In the U.S., our initial launch indication in post abiraterone MCRPC represents approximately 17,000 patients per year alone, with a total addressable market of greater than $3.5 billion annually. With additional development potential in prostate populations like post AR inhibitor MCRPC where we showed promising early landmark PFS data in metastatic castration-sensitive prostate cancer, where Lori showed strong preclinical data, the commercial opportunity grows significantly with the MCSPC indication alone representing a potential market of greater than $10 billion just in the U.S.

Beyond prostate cancer, we also see multiple future development opportunities for rinzimetostat in other tumor settings where PRC2 inhibition combined with various approved and investigational therapies may address various unmet medical needs.

I'll now hand it back over to Jacob to discuss next steps and close out our session. Jacob?

Thank you, Keith. We'll wrap up our prepared remarks on Slide 43. We continue to be excited about the development prospects for both our clinical programs and their emerging best-in-class profiles. Within prostate cancer, we believe the dose optimization data presented today build a strong case that rinzimetostat in combination with darolutamide in our upcoming Himalayas-1 registrational trial has the potential to yield profound benefit for patients in a market that is large, but woefully underserved today by oral well-tolerated therapies.

Before we begin Q&A, I'd like to thank our investigators as well as the entire ORIC team who worked diligently to tackle our mission on behalf of patients. And most importantly, I want to thank our patients and their families who we hope to help overcome resistance in cancer.

With that, let's open it up for Q&A.

[Operator Instructions]. Our first question comes from the line of Anupam Rama with JP Morgan.

Thanks so much for the comprehensive update and congrats on the update. So based on physician feedback, we previously laid out these win scenarios, right, which -- what it would take to -- that was sort of a best-in-class profile, and it was really driven by safety differentiation alone.

Today, in your update, you repeatedly talked about a best in disease profile. What gives you confidence that rinzimetostat profile is tracking to a best-in-disease profile that can be replicated in later-stage studies? That's the first question. And the second one is, can you give us any color on any FDA feedback you got on the Phase III study? And how this impacts your start time for the Phase III.

Okay. Sorry, I don't know what happened with the audio on -- thanks for your question. I'll do your first question and then I'll ask Pratik our CMO to cover your second question. Short answer is we're super excited about the profile that we're seeing from rinzimetostat right now, frankly, in combination with either of the AR inhibitors, but right now, we're focused on the rinzimetostat plus daro update. As the programs advance and now we're months away from initiation of the first Phase III trial, we're seeing an emerging profile in that post ARPI metastatic CRPC setting that is highly differentiated for not only mevrometostat, but all the other alternatives that a patient in that space could have today available to them.

So the only other PRC2 inhibitor, as you know, that's currently in prostate Phase III trials is Mevro,and they've shown RPFS from a randomized trial that's substantially better than all the available standard of care therapies for these patients. We laid that out early in the deck with rinzi, while we don't yet have a mature RPFS number, the landmark PFS rate, obviously, are tracking nicely. They're essentially identical to those from mevro. And that's despite, as Pratik said, our population be more heavily pretreated and with a meaningfully higher baseline PSA. So, obviously, intuitively, you can draw a strong correlation between Landmark, RPFS and eventual mature RPFS performance. And again, Slide 7 in our deck shows exactly that across a whole variety of treatments in first-line metastatic CRPC.

So we believe that means that rinzi is tracking to have the same kind of durability, if not better than Mero. And hopefully, that gets better once we get to a like-for-like population with mevro in a Phase III study. But on top of that, this is what's really important to note Anupam is mevro stellar RPFS comes with a tox profile that obviously leaves significant room for improvement with high rates of GI and heme tox as well as things like [ viscusi ] and alopecia. So far, the safety profile of rinse looks markedly better than that.

And for that matter, it looks -- the safety profile looks better than what you see with pluvicto, chemo, T cell engagers, you name it. So if this profile continues to hold into the Himalayas-1 trial, it would set up rinzi to have a combined efficacy and safety profile that's obviously head and shoulders above any of the mechanisms available to these patients today. So that's -- that's why we're so excited about the potential for rinzi and its potential to become a best in disease therapeutic option for these patients.

Now let me have Pratik cover your second question.

Sure. So happy to do so. So your second question was about FDA feedback in the Phase III. So we've had regular communication with the FDA, as you can imagine, all along as the program has progressed. I can't get into specifics, but we are planning an end of Phase I meeting in Q2 to get their final sign-off on the RP 3D selection, the 400 milligrams that we presented today as well as the final design of the Himalayas-1 protocol. There's also some other topics in terms of clinical pharmacology studies, et cetera, but we feel really good going into that end-of-phase meeting. And that should put us on the time line and take outline to start still in the first -- second quarter this year.

[Operator Instructions]. Our next question comes from the line of Prakhar Agrawal with Cantor.

I had a couple. So maybe just if you can expand on the baseline of the patient population in this readout compared to the Mero population. I think you entered at that during the prepared remarks and specifically as it relates to the implications on efficacy on PSA as well as PFS and secondly, CTDNA reductions that you have observed could you contextualize that as well, the 71% ctDNA molecular response out of that compared to some of the other prostate drugs?

Yes. Thanks, Prakhar. We'll have Pratik take your first question. And then Lori, our CFO, will take your second question.

Sure. Thanks. So I take I've already sort of hinted at. As a headline, I'd say that our patient population is more advanced has a higher baseline PSA and on media and then more prior therapies. So our post abiraterone 400-milligram dose group, the median baseline PSA was 26. This is meaningfully higher than the baseline for either of the mevrometastatic data sets. As you'll recall from the randomized experience with the 1250 BID-fasted regimen. They had 41 patients post abi in the median baseline PSA was 15.5%. And then their more recent update at ASCO GU last month with the 875 BID Fed regimen, the regimen they're taking into all of their Phase III there in 14 patients post abi, the median baseline PSA was 16.7.

So ours is meaningfully higher at 26 than theirs in the mid-teens. In terms of prior therapy, our data set includes patients who have had additional prior therapies beyond abi and possibly docetaxel. So the Mero data set on the other hand, was restricted to just prior abi and possibly docetaxel alone.

One other thing I would just point out is that in our study, we enrolled far more African-American patients. 30% of our patients in dose optimization were black or African American and as you probably know, prostate cancer is overrepresented in this population. And so I would say we did a good job of reflecting the real-world demographics of prostate cancer. Mevro just had 5% in the randomized data set, none in their more recent update. So as I said, our patient population is more advanced. It has a higher baseline PSA and more prior therapies.

Okay. For the second question, just doing a sound check. All right. So this question, Prakhar, you asked about ctDNA reductions and how to contextualize those given that we know rinzimetostat mechanism, of action is to enhance the luminal cell state and increase AR signaling. ctDNA reduction is even a better read-through of treatment effect on tumor burden than PSA. While we do see strong PSA responses, we're even more excited to evaluate the ctDNA reduction in clearance, which have been shown to associate with long-term PFS and overall survival, even more strongly than PSA.

In this dose optimization cohort of 400 mg of ready plus darolutamide, the molecular response rate is an impressive 71%. We have no way to compare this ctDNA response to Pfizer's mevrometastat, they've measured ctDNA reductions, but they haven't publicly released it. So to give context to rinzi's 71% molecular response, this result is superior to other active therapies in similar patient populations. For example, in the Ambassador 250 and conrad studies assessing AR inhibition and Radium-223, the molecular response rates were at 28% and 44%.

In treatment-naive metastatic CRPC populations that receive standard of care, the reported rates of molecular response range from 65% to 78%, making our ctDNA response of 71% in the pretreated population that much more notable. So I'm very pleased with this.

[Operator Instructions]. Our next question will come from the line of Brad Canino with Guggenheim.

It would be good to hear the key factors that led to the selection of darolutamide instead of apalutamide. And then you've shown some strong early durability with the landmark RPFS that you put in the slides, but can you also provide some additional color on what you saw or stuff like PSA kinetics or resist responses to help support that RPF as well.

Thanks, Brad. I'll take your first question on the choice of AR combo partner, and then Pratik will cover your second one. So obviously, we've generated a lot of data over the last several years with both -- and apa as combination regimens for rinzi. Both daro and apa are great drugs and great combo partners for rinzi. So I can't say enough good high compliments about both of those programs.

As we've commented many times in the past, we see similar efficacy and similar safety with both combo agents obviously, one big difference. It's not a surprise for folks is that apalutamide and for that matter, enzalutamide has the same factor going forward, which is their well characterized as -- inducers. And so they will push down the exposure of other drugs, most other drugs that are co-administered with them, just given how many drugs are metabolized by the -- times.

So mevrometostat is clearly going to experience that same DDI when they're dosed with apalutamide and while that type of DDI can be overcome through higher dosing, obviously, we're taking higher doses into our dose optimization with rinzimetostat with apalutamide and darolutamide, we chose for this first Phase III study to just go with a simpler path of no DTI. And so that's to combine it with darolutamide. And I should say, obviously, choosing darolutamide for this first Phase III study. We're quite excited about that, but it obviously doesn't preclude us from using apalutamide in subsequent Phase III studies.

And let me ask Pratik to take your second question.

Sure. So Yes. As we progress through the rinzi program to a later stage and as the data mature and more follow-up, the most important end point clearly is radiographic progression-free survival. It's the main regulatory end point for this patient population and it's going to be, as I said, the sole primary endpoint of Himalayas-1, overall survivals and implant secondary.

So we focus today's presentation on the landmark, RPFS through our median follow-up of 5 months since we don't yet fully have a mature PFS for the later time points. And as just to reprise some of what I presented, looking at the 5-month landmark in the post abi population, it's 84%, which is right on top of the mevrometastat data. And if you look at the same 5-month values for other approved agents for these patients, they range from 60% to 75%. So well south of what we're seeing in our patient population.

And then although near the end of my presentation, I also gave a preview of what we're seeing in the post AR inhibitor population with the rinzi-daro combination. And here, again, the 5-month landmark is -- of PFS is 85% where you'd expect the median to be something like 2 to 3 months only. So really much better than conventional therapy. So this gives us a lot of confidence both in terms of the activity, the mechanism and the dose that we picked to go forward into Phase III.

Now with respect to RECIST responses, yes, we definitely looked at additional points of correlation, but most of our patients have bone-only disease, as typical for this patient population. And so for the few patients that have soft tissue disease of those only subset have lesions large enough to be RECIST measurable. So that leaves us just a handful of patients with measurable at 400 milligrams. And we have 100% disease control rate in those patients, and we have seen confirmed RECIST responses at both 400 and 600. So we do see tumor shrinkage, but the low number of patients who are RECIST evaluable makes calculating an ORR not terribly informative.

In terms of PSA kinetics, PSA is actually kind of interesting with respect to the mechanism of PRC2 inhibition. If you go back when we were doing our preclinical work and the effect of PRC2 had on increasing AR signaling, one of the side effects of that is it can drive up PSA because it increases the expression of the gene for PSA. So we initially expected actually that PSA would go up. And that's basically what we saw in our single agent experience.

The PSA went up in all the patients. So we wondered actually what might happen when we combined with an AR inhibitor, whether PSA actually go down or would it even be uninterpretable. So we were glad to see the initial Pfizer data in their combination that the PSA could go down. And as you can see, we're seeing that in patients as well.

So the net effect of the combination regimen can drive down PSA, but it does take time to develop. In our experience, many patients, the reductions can happen over the first 2 or 3 cycles in 2 or 3 months, but we've seen further reductions out past 6 months and even 9 months. And so really because of the locations of looking at RECIST response, not a lot of patients and the limitations of PSA, given the PS2 mechanism, it's why we've actually looked hard at ct DNA, which is a direct -- a more direct measure of disease burden and can be evaluated for most patients. They're all evaluable for ctDNA except for a few exceptions. And so that ctDNA response has been correlated with long-term durability. And on this measure, our molecular response rates are higher than what's been reported for all the active agents this patient population.

[Operator Instructions]. Our next question will come from the line of Maurice Raycroft with Jefferies.

Congrats on the update. You mentioned that 400 mg and 600 mg doses had comparable efficacy. Is there any additional color you can provide on what you observed on efficacy at 600 mg and do you have an update to know for sure that there's no additional benefit on our RPFS with the 600 mg dose?

Yes, Pratik, you can handle that more. Thanks for the question.

Sure. So the objective of the presentation today was delayed the groundwork for our first Phase III study. So we wanted to identify the patient population, identify the AR inhibitor that we were going to combine with and then complete dose optimization and select the dose going forward. And so the bulk of the presentation was then focused on this RP dose selection and the regimen. And that selection, as you heard, is 400 milligrams once a day with darolutamide.

But we did do, as I went into a bit of detail in the presentation, what's called an ER analysis, an exposure response analysis. And with this -- through this analysis, we looked at a broad range of variables that captured exposure, a bunch of different ways, efficacy, a bunch of different ways and same for safety. And the bottom line for the efficacy analysis is that there was no statistical relationship between exposure and efficacy.

It's not really surprising because both of the doses that we took into dose optimization were above the minimum concentrations that we were projecting from a preclinical work. and pharmacodynamic signal that we were looking at maxed out, even at 200 milligrams. So the 4 and 6 were, in our minds, highly likely to be clinically active.

But anecdotally, if you look at any individual readout for the various efficacy measures that we looked at in some of them, the 400 was numerically higher than 600 and others, the 600 value is higher, but the confidence interval is overlapped. And so you can't draw a conclusion from any single comparison as to which dose would be better.

It's the ER analysis that really makes that assessment. But that wasn't the case with respect to safety. There, we saw a clear relationship between exposure and multiple measures of safety, adverse events, adverse events of interest, treatment modifications. And it shows up when you look at the side-by-side safety tables for 400 and 600, 600 has more toxicity, mostly Grade 2 or Grade 1, and it also has more dose modification.

So the bottom line was that there was no advantage in efficacy, but there was an additional toxicity burden with the 600, which is why we concluded the 400 would be the RP 3D. And frankly, that's kind of what FDA wants companies to do when we do these project optimist type of exercises is to move away from just assuming that higher is always better. So I think we have conclusive evidence to support the 400 milligram dose as the RP 3D, and we want to sort of look forward and plan for our first Phase III study and potentially others as well after that.

Got it. That's really helpful. And you're showing low rates of progression and low discontinuation rates. What are some of the other reasons for stopping drug as observed in your consumer plot data? Or how should we contextualize that?

Sure. So the events in a radiographic progression-free analysis that you capture as events are radiographic progression on imaging or death from any cause. So if patients are live in progression-free they're censored at their last visit or the last time they had imaging done. But patients can also be censored if the loss to follow-up or come off of treatment for other reasons other than progression. And these can be a variety of reasons like the patient withdraws consent because they don't like the study visits.

PSA progression where they may want to go on to another therapy even before they progress radiographically or tolerability issues, they don't like the side effects. Consumer plot, we do have some patients like this, and it's typical in prostate cancer trials. Actually, if you look at the Mero swimmer plot from ASCO GU, many of those patients are off treatment, but without a progression event defined 6 of their 14 are off for this reason. So it's not unexpected in this patient population in these kinds of studies.

[Operator Instructions]. Our next question will come from the line of Kelsey Goodwin with Piper Sandler.

Congrats on the update. Maybe first, question. For this combo data, maybe just remind us that this was the facet, I believe. And then in terms of this food effect cohort that you're running now, maybe just tell us what the purpose of that is did the FDA require it? Or are you doing that on your own? And then is that in response to Pfizer also running a food effect study dosing at the -- or looking at the higher dose fasted and then a lower dose wellhead? Maybe just some more color there would be helpful for us.

Thanks, Kelsey. Yes, Pratik can take that one.

Sure. So it's a good question. But before I answer that, let me provide some context and you were actually covering some of those points already. There's a couple of reasons to do food -- studies, as you said. So first, it's an FDA requirement. They want to know whether dosing with food with or without food affects the exposure of your drug. And if there's any meaningful effects of those changes in exposure on the safety and efficacy profile ideally, you wouldn't want to have a food effect. That would give you much more flexibility and a more convenient dosing regimen, the patient can take it however they want.

But if there's a true food effect, then you may have to revisit dose and stricter in terms of patient instructions on how to take the drug. But as you said, the other reason to look at the food effect is that it may improve the safety profile of the drug mostly GI toxicities like nausea or vomiting and diarrhea. And you might want to do this even if there's no meaningful food effect on drug exposure.

So if we start with our drug, rinzimetostat, so we're mostly conducting our food effect to satisfy the FDA requirement. And as I said during the presentation, so far, we don't see meaningful food effect, we looked at this initially as a single agent, and now we're doing this again in the combination with the rinzi-daro combination. And part of the reason is that since darolutamide is taken with food, we want to see if we can make sure that rinzi can just be taken at the same time, which will be more convenient for patients. And so, so far, we aren't seeing a the way a true food effect.

In terms of just the effect on safety so far in the first patients that we've treated on this little cohort, we've only seen Grade 1 treatment-related adverse events except for 1 grade 2 event of decreased appetite. So maybe there's some potential for incremental improvement in GI tox beyond the clean profile we have, but it may stay very much the same and then in terms of efficacy, you saw from the initial PSA data, it looks very consistent with our faster data, the early activity that we're seeing out of the 5 patients, we have 2 PSA 50 and 1 PSA 90, all of them are confirmed. So that's our story. Mevro missed that, the story is a bit different because it does seem to have a meaningful food effect. Since their faster dose of 1250 is if you do the math 44% higher than the Fed dose of 8.75, but you get to the same exposure in each of those instances because of the food.

So there is a meaningful food effect but I think they really chose the dosing with food to improve the GI tox. They had a nearly 80% regimen or rate of diarrhea with their fasted regimen and it dropped to just below 50 with dosing with food. But as you might notice, it doesn't affect the other adverse events like heme tox, which comparing the 1250 to the 8.75 million is about the same, if not maybe a little higher with the Fed regimen. So our reasons and Pfizer reasons for doing the food effect are actually pretty different.

Okay. Got it. And then maybe 1 follow-up. In terms of the second half program update that you guided to earlier this year, now that we have this first quarter data set out, I guess are you providing any more color on what that might look like?

I can take that one, Kelsey. No, not at the moment. I'd say we do have that second half program update, but right now, it's TBD in terms of what that additional -- what additional data, if any, we would plan to disclose during that update, we'll just -- we'll refine that thinking in the coming weeks and months and let you know.

[Operator Instructions]. Our next question comes from the line of Colleen Kusy Hussey with Baird.

A couple on safety for us. Can you just comment on any rate of cytopenias or alopecia that you're seeing? I believe that's something that we saw program? And then on the blood creatinine increases that you saw with -- can you just provide a little more color there? Do you think that's a drug effect of rinzi class effect? Any color there?

Thanks, Colleen. Appreciate you can take both of those.

Sure. So your first question was on the cytopenias or alopecia that Pfizer C. So in terms of cytopenias, we do see both neutropenia and thrombocytopenia, but at a low rate, less than 5% -- CCI inhibition as a class does lead to hematologic toxicity. And it was the dose livering toxicity in our single-agent dose escalation experience. But that only occurred when we pushed the dose up really high. We have a wide therapeutic index with a great sort of long half-life. So we don't have to deal with a high Cmax, and we were able to work within dose ranges that limit the cytopenia complication. And then in terms of alopecia, we've seen a grand total of 1 treatment-related alopecia event of Grade 1 at the 600-milligram dose. So we see maybe a smidgen of it.

And then in terms of the blood creatine increase. So our rate from the table we presented at the 400 is 16%, mostly grade 1 the increase in blood creatinine in older patients, most often is an indicator of dehydration. And if you look at the other adverse events that these patients are experiencing around the same time. You see these events track with some sort of concomitant or preceding GI adverse events like nausea or diarrhea, which leads to decreased oral intake and they get dehydrated and then the creatinine goes up. Good news is that it resolves easily with hydration and the creatinine rise reverses.

In terms of whether this is seen with mevrometostat, it's hard to say because in terms of the mevrometastat profile, we only have insight into the adverse event that they've disclosed in over 20% of patients. So we don't know what the adverse event profile looks in the short of 20% of patients. So they very well could be seeing it, but it just hasn't been disclosed.

[Operator Instructions]. Our next question comes from the line of Derek Archila with Wells Fargo.

This is Simone for Derek -- just 2 from us. One, will you have a drug supply agreement in place before initiating the Phase III. And two, can you walk us through expectations for timing of the Phase III top line data readout and what assumptions go into that?

Thanks, Simone. I'll take your first question on the drug supply agreement and then Pratik can cover your second one. So I think probably all I can say is this, we continue to have excellent working relationships with our partners at both Bayer and J&J. Obviously, we can't comment on the specifics of any ongoing confidential discussions. So it's probably best if I just leave it at that for now, and we'll provide a pick update at the appropriate time.

And I can answer the second one. So as we said in the call, we expect to start the first Phase III Himalayas-1 in the first half of this year. So depending on the exact timing of the study start, we'd expect top line data in late '27 or early '28. So that assumes a 16-month time to fully enroll the study. which would be actually a couple of months longer, a bit of a buffer than what we believe. Pfizer to enroll their mevro-1 study in the same patient population. And then you need to add some additional time for us to get to the necessary number of events for the final analysis. So that's kind of the general time frame.

[Operator Instructions]. Our next question will come from the line of Corinne Johnson with Goldman Sachs.

This is Eric on for Corinne Johnson. I have 2 questions. And first is, is there a corresponding Kaplan-Meier curve that you use to generate the landmark PFS analysis? And if so, any color would be helpful. And second, we're hearing anecdotes that abiraterone usage may be slowly decreasing. How do you reconcile that with the approximately 50% stable market share data you presented in one of the previous slides.

Yes. Great. Thanks, Eric. I'll ask Pratik to take your first question on the Kaplan-Meier curve and then our head of -- and Medical Affairs, Keith Louis, can take your second question on the much -- the rumored attrition of abiraterone.

Yes, sure. So on the Kaplan-Meier curve, so we have a median follow-up of just about 5 months. And so a Kaplan-Meier curve would be immature past that point. So that's why we focused on landmark analysis through the time point where we have our median follow-up. So with immediate follow-up of 4.9 months, that's why our landmark goes out to 5 months. But we have multiple patients approaching or beyond this median that are still ongoing. So the curve is going to be unstable past that point. And so you're not going to get a good read on the later time points.

But you can -- with the tumor plot and bit of graph paper and make -- what the draw out what the Kaplan-Meier curve is going to look like. I would just say that it's going to be unstable far less helpful beyond the immediate follow-up time points.

Yes. And then maybe to comment on the second question. This is Keith. Given that the abiraterone population is going to be the focus -- the [ post-return ] population be the focus of Mason we pressure tested our assumptions about market size from multiple different angles, both quantitatively and qualitatively. And so to develop our market assumptions, we've gathered numerous data points from real-world clinical trial and third-party prescription data, you saw some representative examples of those data in today's presentation. We then triangulate those data with our own market research efforts and then even further validate our insights by speaking with dozens of health care professionals and user professionals, not only in academic settings, but importantly, in community settings where about 80% of prostate cancer patients are treated in the real world.

We also spoke with a wide swath of both oncologists and urologists and we continue to hear from those conversations that there's a strong preference for abiraterone and its usage continues to be highly sticky which is why it's still by far the most prescribed ARPI and has maintained a relatively stable share of new ARPI prescriptions at around that 50% that I presented over the last 5 years, and the reason, I cited are given that it has widespread and long-standing physician experience with the drug, payer preference given that abi is generic, and evidence-based medicine report that starting abi first in the sequencing of RPIs results in longer durability than abi is sequenced later. And so based on all this, we feel really good about the market prospects for that patient population we're setting in Himalayas-1.

[Operator Instructions]. Our next question comes from the line of Yigal Nochomovitz with Citigroup.

Congrats on all the updates. Just a few things. So you mentioned, of course, there's the potential for another Phase III trial -- and I think, Jacob, you said what you've shown today doesn't preclude using apa next. But I guess the question is, is the preference still for daro for the second Phase III, say, in the post AR setting especially since you showed some of that post ARPI data already today. So that's the first one.

And then second, just with regard to the safety, of course, I appreciate the comments and the survey data you showed with the preference for 80% of the time for rinzi. My question was just with regard to exposure times and whether you had to do any normalization or adjustments for median follow-up, given it's obviously about half the amount for Renzi versus what you have for Mero? And then the last question is anything you can say with respect to other feedback from the prostate cancer KOL community, you noted some of the luminaries on the slide at the beginning of the presentation. Anything else that people are commenting on with regard to what you're showing today.

Thanks for the question, Yigal. Yes. I'll take your first one, and then I'll ask Pratik maybe to comment around your questions on safety and the investigator feedback. The we're generating great data. We've continued to generate great data with both of the combo partners, Yigal,both of the AR inhibitors, so darolutamide and apalutamide I would say even though the data that we flashed up today was all focused on the darolutamide combination, including in that sort of experimental population where we're signal-seeking, frankly, for the post-air inhibitor population, which might be a future Phase III study, all of that focused on darolutamide today.

But we don't have a preference for what we might do for that or third Phase III study as well. Obviously, for simplicity's sake, we chose to focus on darolutamide for this first Phase III study, but we're kind of keeping the door open on what we would use for future Phase III studies.

Maybe let me have Pratik take the other questions.

Yes. So in terms of the Kaplan-Meier comparisons, you're absolutely right. We have a different amount of follow-up. We have less follow-up than Pfizer does for their patients, which is why we stuck to the landmark analysis. So the 3, 4, 5 months with our median follow-up of just about 5 months, those comparisons, we think are fully valid because at that point, that curve is quite stable. It's when you get past the median follow-up that comparisons, I think, then become sort of tricky and not really tenable. So that's -- I think we stuck to that just to be strict in terms of where the curves are comparable versus where they're not. Not yet, more follow-up will push out that analysis. In terms of the...

I guess I was referring to more on the safety side, though, that would apply as well on the safety side of things in terms of looking at the rates of different as...

Yes. But the safety develops -- we don't have new safety events that sort of develop in the 5-, 6-month time frame. If they're going to develop toxicity, it happens in the first, if not the first, the second cycle. So I don't feel like the safety profile is going to worsen over time.

Yes, Yigal, the safety kind of is what it is. And one of the reasons why we and pulled back the curtain even a little bit more here on the safety side to show the full experience, not just the post abi, but even the post air inhibitor patients was to really bolster the end that you all were looking at to give everyone confidence that the profile that we're showing you for safety in that post abi population is, in fact, the safety profile for the drug because you obviously see the trends don't change when you look at the full post ARPI population. And then Pratik can just comment quickly on the investigator feedback.

Yes. So I mean, I think the long and short of it is our investigators are very excited to be part of this new study. You already cited, I think the most visible proof is that we've got a top flight steering committee with thought leaders from around the world. World top institutions are represented. But to be more specific, I think they are -- everybody is looking for an all-oral therapeutic option for these patients with MCRPC. There's a lot of -- even though it may not always be on the guidelines, there's so much ARPI switch because physicians and patients want to maximize their time on an oral regimen. And so this whole class PRC2 inhibition potential to have an all oral regimen that may be better, at least have a potential for a long PFS, I think, is very exciting.

And then just to distinguish between the 2 programs, I think the safety profile that we're seeing with our program has -- our current investigator is very excited, and they've signed on from the Phase I on to the Phase III for that very reason because I think that this drug is highly competitive to what's out there.

Our next question comes from the line of Corey Kasimov with Evercore ISI.

So curious if there's anything to read into the RPFS flattening from months 4 to 5? Is it just too small of an end to kind of extrapolate there. And then a follow-up is I'm curious, is there any reason that there are different cutoffs for the efficacy analysis, at least in the swimmer plot, which I think is like March 9 and then the safety data, which has a cutoff in January.

, Cory. I'll have Pratik take both of those.

Yes. So I mean, I think you already answered the first question, which is, yes, there's a few patient numbers. So it's just -- it remains flat, the curve remains flat over that interval. And in terms of the cutoff, yes, so what we -- the cutoff is really January 16, but then we extended the follow-up of those patients to the March date so that we could have more PFS to look at.

Basically, Corey, just trying to eke out as long of a landmark PFS as we could, just to give everyone confidence in how it's tracking.

[Operator Instructions]. Our next question comes from the line of Matthew Biegler with Opco.

I just wanted to ask about Descovy because it doesn't seem like you're seeing much, if any, of it. And it's been flagged by a lot of KOLs we talk to as a big tolerability issue with mevrometostat. So any idea kind of why the low rates? Because I always thought it was more of an on-target tox, but maybe it's just reflective of the lower doses that you're using here?

Thank you, Matt. I'll have Pratik take that.

Yes, sure. So we do see it at a low rate, again, probably like less than 5%. I think actually I wouldn't say that we're using a lower dose I just want to be careful about that. So Pfizer in their -- some of their presentations have correlated safety with a Cmax. And the Cmax is -- for their drug because it has a short half-life, they still have to give very high doses in order to get coverage above a minimum concentration over 24 hours.

So it's dosed BID with still even with food, 75 milligrams twice a day. So they're going to get big swings from peak to trough -- and that is potentially going to drive the toxicity. We have a lower dose. I mean it's a different molecule, but since we have a full 20-hour half-life we have a much lower swing between peak to trough. And so our Cmax, relatively speaking, doesn't go as high. And so we're able to essentially cover the target without necessarily incurring the safety liability from the Cmax.

And so I think that explains a lot of the issues that we don't see with heme tox in particular. We see less GI tox. And so I think that's that would be the explanation I have for those differences.

[Operator Instructions]. our last question will come from the line of David Nierengarten with Wedbush Securities.

I just had one on -- when you look at your side effect profile and discontinuations, the actual discontinuations appear pretty comparable to Mero across trials. I mean is that what we should be looking at? Or should we be really looking at the actual grade 3 adverse events? And if so, several of them from mevro just seem to be lab values versus diarrhea or nausea. And maybe you can just walk us through like what's what are you looking at and prioritizing what the doctors are in your survey work?

Thanks, David. Yes, Pratik will cover that, including -- we get a lot of just qualitative guidance from doctors. Obviously, who are familiar with both drugs and to give us some color in terms of what are the more problematic AEs for Mero. So Pasi can kind of highlight all of that.

Yes. I mean I think there's a range of treatment modifications. And you're right that the discontinuation rate is not terribly distinct. But I think where you also have to focus is treatment interruptions and dose reductions. Dose reductions because of toxicity often almost inevitably lead to some treatment interruption, you may be able to keep the patient on drug, but you're now lowering the dose, and I'm not sure if you have to lower from the mevro 875, how much coverage you're going to get. And so that patient is going to be either underdosed or uncovered if you're going to do a dose interruption for a period of time, yet they're not going to technically have a treatment discontinuation. And so that's where I think the safety profile distinction in terms of adverse events, the grade 3s, maybe they can get patients through grade 3 toxicity, but they've got to hold the dose or lower the dose and they haven't discontinued, but they're on a lower drug and have had meaningful treatment gaps. Whereas we have the potential with the safety profile to have a continuous dosing for a given patient because they don't incur toxicity that requires those kinds of modifications.

Thank you. This does conclude today's question-and-answer session. Ladies and gentlemen, this does conclude today's conference call. Thank you for participating, and you may now disconnect. Everyone, have a great day.

All right. Welcome back, everyone, to the next session of the first day of Citi's 2026 Virtual Oncology Leadership Summit. I'm Yigal Nochomovitz, Biotech Analyst here at Citi in New York. The next session is with ORIC. It's great to have the CEO and CFO here, Jacob Chacko, CEO; and Dominic Piscitelli, CFO.

Welcome to both of you. Thank you very much for doing this. For those listening, if you have questions for the company, just e-mail me, and I will relay over to Jacob and Dominic.

So welcome, gentlemen. It's been a busy year, obviously, for you and for us. Maybe to start out, Jacob, if you could just kind of give us the very high level, highest level overview of the company, and then we can move directly into some of the key questions related to your prostate cancer program.

Yes. Happy to do that. Thanks for having us here, Yigal. So ORIC stands for Overcoming Resistance In Cancer. In a nutshell, that's the mission of the company. So we're focused on small molecule drug development in primarily solid tumors, but most specifically, prostate cancer and lung cancer. That's obviously where our 2 lead programs are currently being developed. Both of those programs are in dose optimization right now. Both of those are headed towards Phase III studies with a lot of data that's been presented over the last 12 months, showing the best-in-class potential of both programs.

The most imminent Phase III is for our prostate program, which ORIC-944 now has a name, rinzimetostat. And so we anticipate starting a Phase III study with that program in the first half of this year. We're awaiting some more data from our lung program in the second half of this year, after which we would potentially start the first Phase III for our lung program, ORIC-114, which is known as enozertinib, probably in the first half next year.

So a lot on our plate, but really excited about where the company is at, both in terms of data and cash runway to execute on our Phase III aspirations.

Okay. Great. Well, obviously, you've got a pretty significant competitor in the race here with Pfizer, and you have a very important and different molecule, too. So maybe if you could just start by talking about what we've seen from Pfizer so far and how that sets you up for how you're going to play out your data this year and beyond.

Yes. We like to refer that fluky young upstart, Pfizer, a lot like ourselves. They've done a lot for the field in terms of derisking this mechanism, Yigal. So as we're talking specifically about PRC2 inhibition within prostate cancer, it's an area that's been studied a lot over the years. And the first-gen PRC2 inhibitors really ran suboptimal clinical experiments. The reason being that those drugs were suboptimal. They had very short half-lives on the order of 1 or 2 hours. They had -- a lot of them had what's known as SIP auto induction, where they would rev up the SIP enzymes that would then metabolize the drug. So in some of those cases, they would get dose-dependent decreases in exposure.

So in other words, there was a lot of reasons why those drugs did not work in the clinic despite a really wide swath of preclinical evidence that suggested that if you combine a PRC2 inhibitor with an AR inhibitor, you ought to get longer, more durable outcomes by virtue of keeping those prostate tumors in an AR-dependent state, which is where those AR inhibitors work best. So we're really thankful that Pfizer has really derisked the mechanism quite a bit. You referenced their randomized data set that they presented almost exactly a year ago this time at ASCO GU last year. And in that data set, what they showed was that in a CRPC population where all the patients were post abiraterone, so they had already been experienced with abiraterone and where one prior line of chemotherapy was allowed, those patients achieved a 14.3-month radiographic PFS, median radiographic PFS. And that's in the context of a control arm of enzalutamide alone, so an AR inhibitor alone that achieved exactly what you would expect in that population, which was about 6 months of radiographic PFS.

And so that 8-plus month benefit on PFS was profound. It's longer than any other mechanism that you have seen studied in that patient population. Obviously, people talk about how -- what good Pluvicto has done for patients across the prostate treatment paradigm. Pluvicto has been studied in very analogous populations and doesn't come close to the PFS that Pfizer was able to show. And so it explains why Pfizer was investing so heavily in their PRC2 program Mevrometostat, in combination with their AR inhibitor, enzalutamide. They've now got 3 different Phase III studies enrolling and underway with MEVPRO-1, their first study in that post-abiraterone population having finished enrollment, and we're going to get to see a readout from them later this year.

But it's really could be game changing if their Phase III results replicate what they were able to show in Phase II. And obviously, we think we've got a better drug than they do.

Okay. So tell us more about that. What are the properties of your molecule that may be differentiated that would give you optimism that you have at least a good profile, perhaps a better one as you start to do your Phase III work?

Yes. I mean if you go through and do the analysis of the drug side by side, and again, if you look at all the ways that the first-gen PRC2 inhibitors sort of fell short of an optimal target candidate profile, it was really in all different ways that they fell short. So they didn't have enough potency. They didn't have enough in vivo activity. They had poor half-life, as I mentioned earlier. A lot of them had these CYP autoinduction issues where essentially they got very bad PK properties. didn't even get to the right exposures that they needed to, to test the clinical experiment.

Now Pfizer seems to have solved a lot of it. Their drug, Mevrometostat has very good potency, very good in vivo activity. It looks like it's got a half-life of roughly 5 hours, so better than the first-gen compounds, but clearly something that can be approved upon and doesn't look like it's got CYP autoinduction. And so by virtue of those things, it seems to be getting enough exposure in these patients that they're able to get the kind of profound outcomes that I mentioned earlier.

Now in the case of rinzimetostat, our drug, which we acquired from Mirati back in 2020, the chemist of Mirati, they went about this in a very empirical fashion, Yigal. So they just -- they looked at the space. They decided none of the drugs in the space were achieving the right target candidate profile, and they set out trying to make a drug that was every bit as potent and had as good in vivo activity as what you've seen from Pfizer, but importantly, a much better half-life. And in this case, they developed a drug that has a 20-hour clinical half-life, does not have CYP autoinduction. And what that means is that it's consistent with once-a-day QD dosing, but the benefit we're talking about here is not just simply a convenience benefit of QD dosing versus BID dosing.

Really, what it is, is the ability to cover target for 24 hours with your Cmin without pushing Cmax high to get -- or too high to get Cmax-driven toxicity. And that's where our drug really seems to differentiate. So if you look at the data we presented last year, we had a couple of different data readouts from our dose exploration work. As folks know, we're working with the other 2 big AR inhibitors. So Pfizer's got their own AR inhibitor, enzalutamide, but the other 2 multi-blockbuster AR inhibitors are apalutamide from J&J and darolutamide from Bayer. We're supported by both companies in our dose exploration and dose optimization work in combo with both of those AR inhibitors.

And in the data that we showed last year, we showed PSA50s and PSA90s that were numerically better than Pfizer's. And obviously, we showed some pretty profound ctDNA. We don't know what Pfizer's clearance rate on ctDNA is. They haven't shown it, but we showed about a 59% clearance rate on ctDNA which as you benchmark that across various Phase III data sets, again, is a very profound number.

And then finally, on the safety side of things, which is where you really see the differentiation is clearly a differentiated profile for rinzimetostat in combination with either apalutamide or darolutamide as compared to what Pfizer showed you with their drug -- with their combo. And with the PRC2 inhibitor, you should really see 2 major classes of toxicity. You should see heme tox in the form of various penias and you should see GI Tox in the form of diarrhea, nausea, vomiting and sort of that general constellation of GI symptoms.

Now clearly, the name of the game here is to try to minimize how much of the frequency and the intensity of those types of toxicities that you see. And in what you saw from us last year, you saw a safety profile that while we see those classes of tox like Pfizer does, we see a lower frequency and a lower intensity of those things while also having, like I said, numerically better PSA50s and PSA90s. Now we don't yet have our own mature PFS number to quote, but really, the way this should work is that if you've got better activity in those early proxy forms of PSA50s and 90s and ctDNA and you have a better safety profile that ought to long term translate to a better PFS profile.

Okay. That is a very, very comprehensive description of the situation. So now you're going to have an update soon, I believe, in the first quarter. You've talked about it a bit, but maybe we can just review and maybe Dom can jump in and comment. What will we -- what are we going to be seeing there? I know you mentioned the PFS is not quite ready for prime time, but what would you show us in this update coming up?

Yes. So big picture, as you know, we wrapped up the dose escalation portion of the study in the latter part of last year and we selected the doses for the dose optimization. So the data that we'll get in Q1 will be from the dose optimization portion of the study.

What we're saying is going to be 20 to 25 patients worth of data. Now as you know, we're studying 2 different patient populations. We're testing the post-abi patients, but we're also testing the post-AR inhibitor patient population. So it will be from 1 of those 2 patient populations. And then as Jacob articulated, we're also doing 2 different combinations. We're doing combination with apalutamide from J&J and with darolutamide from Bayer. So it will be from 1 of those 2 patient populations, and it will be from 1 of those 2 combinations.

Now this is very intentional. The patient population and the regimen that we disclosed, that's kind of a preface for the Phase III study that we anticipate starting in the first half of 2026. And what we want to show here is, again, PSA50, PSA90, we want that to be consistent to what we've shown you guys previously in 2025. We want to show obviously the ctDNA data that Jacob referred to. Safety and tolerability, we want to be at least as good as what we've shown you previously as well. And the new piece of information will be an early look on durability. And as you said, we will not have a mature PFS, but we'll have an early look and durability. So think of a landmark analysis at 3 months or 4 months, that's what we'll kind of show to kind of make sure there's nothing -- no surprises in the data and that things are trending in the right direction from a durability standpoint.

Okay. So just so everyone is clear. So we're going to see either it's going to be a post-abi group or it's going to be a post-AR. And then within that, you're going to show us -- if you do the post-AR, it will be either apa or daro.

Yes. Whichever patient population we'll show you, we'll show you one of the AR inhibitors. So you do apa or daro. That's correct.

Okay. And then -- so it's -- but it's not going to be both post-abi and post-AR. It's what you're going to pick.

That's correct.

Yes. It will basically, Yigal be a -- it will essentially be a laying the groundwork for the first Phase III study that we intend to start in the first half of this year.

Right. Okay. No, it makes sense. I just want to make sure everyone understands that. And then what -- tell us without revealing what it is because I mean, I guess you're close to the decision, but what are the factors that go into the decision in terms of what you want to see like apa versus daro, as you pointed out, is 2 different pharma partners so presumably that obviously has relevance, but there's also the drug-drug interaction aspects, there's dosing and so forth. So just tell us in broad terms like how you think about the decision.

Yes. In broad terms, I think it's -- we're very lucky to be in a position where both AR inhibitor drugs and both partners are great. And so what we talked about in the data last year was that we don't see any differences in the efficacy or the safety profile of the 2 drug -- the 2 combinations in our hand.

Look, there's differences, obviously, on the nuances of each drug and the way they're dosed. One is dosed twice a day, the other one is dosed once a day. One has a food effect, the other one doesn't have a food effect. There's some tolerability differences between the 2 regimens. If you really force rank kind of which of the 2 drugs -- which of the 3 AR inhibitors are the most tolerable, I think the good news is most physicians would tell you that darolutamide and apalutamide are both better tolerated than enzalutamide. And so in a lot of ways, Yigal, it really comes down to we'd be fine with either one of those as our go-forward combo partner for the first Phase III study.

And one thing we've emphasized throughout the course of our development of this program is the first Phase III study will choose one of those drugs to be our combo partner of choice. We'll keep an open mind as to whether we stick with that drug for future Phase III studies or whether we choose the other one to get experience with both of them. So there's reasons why we might choose one or the other. I think more fundamentally on just the dosing of 944, I think really the only difference is we use a lower dose of 944 when we dose with darolutamide than we do when we dose with apalutamide. And the reason for that is pretty self-explanatory for folks that have been following us for a while, which is that apalutamide and for that matter, enzalutamide, Pfizer's drug are both well-known CYP inducers. And what that means is that they will push down the exposure of many drugs you combine with them because so many drugs are metabolized by the CYP enzymes. And that's the case for 944. That's the case for Pfizer's drug, Mevrometostat.

And so we are testing higher doses of 944 in our dose optimization with apalutamide than we are with darolutamide. So that's the only really meaningful difference between the 2 regimens right now in terms of which one we -- in terms of the experience with the 2 drugs. We have our own choice internally that we've made. Obviously, we'll make that clear when we do the Q1 update.

Okay. But regardless, as you pointed out at the beginning, with the longer half-life and ability to have a better target coverage over the 24 hours and lower Cmax, even if you did go with like an apa for just hypothetically, you would -- you're in a good place because you've got that benefit on the PK.

That's right. There's -- the beauty here, Yigal, is with the combination regimen, we actually have the ability to double down on the differentiation versus Pfizer. And what I mean by that is for all the reasons I articulated earlier, we believe that our PRC2 inhibitor has a better profile and is a better PRC2 inhibitor than Pfizer's. And at the same time, we think that we have the option between darolutamide and apalutamide, either one of those is a better AR inhibitor than enzalutamide, Pfizer's AR inhibitor. And that's not to take anything away from enzalutamide. That was the first to market. It's done phenomenally for patients. But again, if you ask clinicians to rank order the efficacy of those 3 AR inhibitors as single agents, they'll tell you they're all the same efficacy. If you ask them to rank order the tolerability of those 3 AR inhibitors, every clinician is going to tell you it's darolutamide, then apalutamide and then third being enzalutamide.

So we actually have a chance to have a differentiated 2 aspects of the combo regimen here versus what Pfizer has got because obviously, Pfizer has chosen to go with enzalutamide, which is their own AR inhibitor.

Okay. I remember covering Medivation back in the day. Okay. So as far as assuming you'll tell us what you're going to -- plans, I guess, in the next 6 weeks, when would you be ready to start the study? When would you actually kick off this Phase III? What else has to happen before you can actually go?

Yes. So we've said that we want to start this first Phase III study first half of this year. That means that, obviously, there was a lot of work that went into that Phase III study planning and execution as early as last year, actually Yigal, so quite a bit has been done. And between now or between the data update and then when we actually kick off the study, it's really just about closing that last little bit of trial execution.

But a lot of the heavy lifting has already been completed at this point. We'll obviously -- once we've got data in hand from dose optimization, we want to finalize our end of Phase I conversations with FDA to get sign off on the dose that's going to be taken into that first Phase III and other aspects of the protocol. But those are really the major aspects of what's remaining at this point.

And then obviously, since the partner AR drug is coming from a pharma entity, just can you comment at all in terms of funding of the study? And would it be -- would you do this yourself? Would you partner it? Would you just purchase the drug? Like can you talk to any of that aspect in terms of the funding of the study or the study conduct at this point?

Yes. We raised a lot of money last year on the back of the good data that we presented. We were able to raise close to $250 million last year. And so really, that has put us in a good funding position. So we are fully funded and then quite a bit for this first Phase III study in prostate. We're also fully funded for our first lung study that would be coming as well. And so the cash runway is into the second half of 2028, Yigal, and that's including these 2 different Phase III studies.

The reason to do that, of course, was because, look, we recognize the strategic value of this program, both to ORIC as well as just the broader prostate landscape. And so we did not want any aspect of this first Phase III study being beholden to having to do a partnership or having to go find further funding, and that's why we were so aggressive on the capital raising side last year. We have cash runway into the second half of 2028. The study is fast. So if we start first half of this year, we will have our answer by second half 2027. So call it by the end of next year, have the answer from that first Phase III study in hand, and we've got cash runway in the second half of '28, so well beyond the first readout here for our first Phase III study.

We obviously have ambitions that will go beyond that first Phase III study to unlock all those full set of ambitions for multiple Phase IIIs across prostate and even getting into areas outside of prostate, we're going to eventually want to bring a pharma partner on board for a more meaningful BD collaboration. But at this point, look, we're going to get free drug from our -- one of those companies of choice just to extend the existing free drug arrangements so that they'll also cover that first Phase III study. But no other cash needs at this point in terms of us going about that first Phase III trial execution.

Okay. So then is there a situation or a scenario where you could start the second Phase III like in a staggered fashion? Or as you point out, since the time lines to get to top line PFS are pretty soon, relatively speaking, you would just kind of wait, level set, see what that looks like and then decide whether you even need to do anything else.

No. We're going to be full on the accelerator, Yigal. So we'll start this first Phase III first half of this year, but we're simultaneously evaluating doing a lot of internal diligence, both in terms of internal data generation, but also kind of talking to external stakeholders to figure out where the next Phase III study would be within prostate so that we can get that up and running in a staggered fashion, as you referenced, as quickly as possible here because the name of the game is going to be to cover the prostate landscape quite quickly in terms of all the different lines or areas that we might want to elucidate this mechanism.

And then like I said, even studying the drug outside of prostate. So there's -- we have a lot of ambitions to develop this drug more fully even beyond this first Phase III study. I think the thing that people need to appreciate here is people might be stuck in some of the old paradigms of some of the much older prostate studies, even dating back to like you said, Medivation days, if you look at these recent studies, if you look at the Pfizer study, the primary endpoint is radiographic PFS, it's not OS, which means that for a relatively small-sized study and a relatively quick to enroll study and most importantly, a relatively cost economical study, you can get a Phase III readout.

And so as you think about -- look at Pfizer's first Phase III study, it's MEVPRO-1 is 600 patients in total that are enrolled in 15 months with a radiographic PFS primary -- sole primary endpoint. And what that means is that you can get the answer for not that expensive pool of dollars in terms of a Phase III population that is pretty substantial in terms of commercial opportunity. And so the ability to go do that in a second population is absolutely in our -- within our purview here at a small biotech to be able to do that. And so that's where I think that the longer that -- the more aggressively we can evaluate this program in different indications, both in prostate and outside, the better.

Okay. I've gotten a lot of questions about this program update, which I know you've been left to sort of go a little bit loose as far as what you might discuss in the second half of the year. But any clues that you could provide? Obviously, there are a lot of hypotheses about what you might show there.

And then related to that, since the Pfizer data are coming later in the year, I mean, obviously, you pointed out the benefits in terms of the tolerability on the heme and the diarrhea. So if you -- essentially, if you can meet -- at least meet what Pfizer showed on a PFS basis, I guess that's going to be a good place for you.

Yes, I'll ask Dominic to cover both of those.

Yes. I think on the first question on what the program update will entail, I think I'm going to tell you the same thing I told you on the e-mail exchange we had when we first put out the guidance. So we haven't said specifically what that is, Yigal. That could just be a general program update on where we are with the first study, how we're thinking about the second study to your earlier question or it could be some additional data that we think is relevant depending on the mature of that data set. So a little bit of TBD on that from your perspective.

With regards to the commercial opportunity here, this is prostate cancer. I know we spent a lot of time at Medivation talking about this. But if you look at the AR inhibitors today, it's really the backbone of treatment for prostate cancer patients. I think back in 2024, the 3 big AR inhibitors did $11 billion in sales. And that really only represents half of the ARPI market because there's still abiraterone, which is about 40% to 50% of the market, and it's still widely used.

So when we look at this opportunity, we think this is obviously a huge commercial opportunity. The 2 patient populations that we're currently studying are post-abi and post-AR inhibitors. Each one of those, if you just run the numbers, there's 17,000 to 20,000 patients in the U.S. alone. We just did some back of the envelope math that gets you to each of those about a $3.5 billion TAM, Treatable Addressable Market for each of those in the U.S. alone. And if you look at any standard analog for prostate cancer, the ex-U.S. market is almost as big as the U.S. market. So we think it's a huge market.

The beauty of this is we're combining with the standard of care, right? Both urologists, oncologists, they're very, very comfortable prescribing drugs like enzalutamide, apalutamide and darolutamide, and we're just kind of piggybacking off their coattails and not -- and providing a great, great benefit with not much more adverse events. So we think this is a huge commercial opportunity from our standpoint.

Now do you have to be differentiated, right? And the short answer is, no. And the perfect analog for this is actually the AR inhibitors. Enzalutamide, [indiscernible] innovation, we launched that in 2012. In 2024, that did $6 billion in sales. Apalutamide came 6 years later and is not really differentiated, and that did $3 billion in sales. So 6 years later, and it's basically doing half the number of sales. We're about 18 to 24 months behind Pfizer. So even with an undifferentiated profile, we think this is a blockbuster opportunity.

Now there are reasons why we think we have a differentiated profile, and that then obviously would increase that potential market opportunity for us as well.

I mean is there a scenario where because you get the better tolerability that, that will drive your PFS better because you're not going to get the earlier dropout. Maybe the potency side is the same, but you just have a better tolerability, so that will boost PFS. Is that a scenario that's...

Yes, it's an excellent question, Yigal. And I hesitate to kind of hypothesize too much about it right now, at least in the CRPC setting, mainly because if you look at the Pfizer profile that they showed you for their combination regimen at ASCO GU last year, I think most folks would agree that the tolerability profile was okay, but left room for improvement. But they clearly still got a pretty profound PFS at 14.3 months PFS. So they -- my point is they managed to keep those patients on in the CRPC setting despite the tolerability they were seeing.

I think certainly, if you go earlier in earlier lines, so let's take castration-sensitive prostate cancer, CSPC I absolutely think that what you mentioned is going to become a factor there where a safer profile could also lead to a more efficacious profile because you're, by definition, going to be able to keep patients on for longer. And the bar for safety is just going to be that much higher in those earlier lines. In other words, people aren't going to put up with a tox signal that they don't have to. And so that actually might lead to a longer PFS, certainly in the earlier line settings. We'll see if that plays out in CRPC as well.

Okay. I mean -- so I mean, you mentioned getting into a lot of other studies, and you just mentioned the castration-sensitive. That's sort of a part of the long-range thinking at some point, too, for this asset?

It is. Yes.

All right. Let's switch over because we spent 30 minutes on prostate. We want to make sure we give due time to the other half of your company. So enozertinib. So let's just talk about that one for a bit. You had the ESMO Asia data recently, which you showed the exon 20 and the PACC data. Can you just -- let's just summarize that, please, and just kind of highlight where you think it's differentiated. As we all know, this is not an uncrowded space for these particular variants.

Correct. Correct. We've heard for many years how crowded these spaces are, and we continue to see dropouts along the way in terms of the drugs not meeting the TPP profiles that you're looking for here. And so the way I would characterize it, Yigal, is we have 3 different populations that we presented on at ESMO Asia last year. So there was EGFR exon 20, EGFR PACC mutations and then finally, HER2 exon 20 mutations. We are nothing if not a data-driven company. We -- in the data we presented in HER2 exon 20, it was not competitive relative to the benchmarks that have been put out there. And so we've stopped further development in HER2 exon 20. We're totally focused on those first 2 populations in the frontline setting. And the reason is, if you looked at the data that we presented, while early and small end, it's developing nicely.

And so if you look at the frontline EGFR exon 20 and the frontline EGFR PACC data that we presented at the end of last year, the response rates in terms of ORR response rates was as good as the best of our competition out there in both of those areas. The tolerability profile was as good as the best in terms of both of those areas, in both of those target populations. And what stood out relative to all the competition by head and shoulders was the CNS activity of the drug.

So we have always talked about the differentiation of enozertinib is the fact that not only is it exquisitely clean for these targets of interest without the off-target toxicities that all these other drugs suffer from, but it also has profound or should have profound CNS activity based on all the preclinical characteristics of the program. You've now seen that evidence in spades. And so in 100% of the patients with measurable lesions across those 2 populations I just mentioned, we had CNS responses, 100% intracranial response rate in the patients with measurable lesions. Even in patients with what are known as non-measurable lesions, meaning multiple lesions that are below 1 centimeter in size, we have multiple examples of patients with complete responses where every single one of the brain lesions went away.

And as you and others know who follow the targeted therapy space for a while, Yigal, the issue in this space, whether it's EGFR exon 20, EGFR PACC or some of the other mutations that people have been following for years with multiple approved drugs is you have this dearth of drugs that are CNS active. And the reason that matters, and you referenced the crowded landscape, the landscape is not crowded when you start to focus on drugs that are CNS active. The reason it matters is because 1/3 of patients in the frontline at initial presentation have CNS metastases at baseline. Many more patients will actually progress in the brain.

And then you also have this third category of patients who have the brain metastases present in what are known as micro metastases where the metastases are there, they just don't show up on imaging yet. And where this plays out is in the long-term PFS of these drugs. And so you can look at amivantamab in the EGFR exon 20 space. You can look at mobocertinib. You will see the same dynamic that you've seen play out in multiple other of these target therapy spaces, which is drugs that are not brain-penetrant end up with very different PFS profiles for their patients with versus those without brain mets at initial presentation.

Drugs that are CNS penetrant don't have dramatically different PFS profiles in those 2 different patient populations. And so that's where we think the ultimate differentiation for enozertinib is going to shake out is in the PFS because with a well-tolerated profile, with profound CNS activity, you should end up with better durability than for these drugs that don't have CNS activity.

And just tell us a little bit more about the design of the molecule that allows for this CNS activity, the properties that allow for blood-brain barrier penetration, what is happening there that's achieving this?

Yes. Well, I mean, we've got 8 minutes left in the conversation. I could talk -- I can use all 8 minutes to tell you about the specifics of how the drug was designed that way. But I'll maybe simplify it, Yigal, by saying the drug was designed by the company from whom we licensed the drug, Voronoi, which is a South Korean company. They looked at the space and they said, look, all these other drugs are not getting into the brain, and it's a big issue. And so you have to have a molecule that's from a chemical property point of view and from a molecular weight point of view is small enough and can get into the brain, can stay in the brain without getting pumped out and be highly potent for these targets of interest.

And so all of that translates into the CNS activity that you're seeing today with the drug, which is all the preclinical profiling showed that, like I said, it gets in the brain, it stays in the brain. It gets into the CNS. And actually, we even mentioned during the Q&A of at ESMO Asia that we have multiple examples of patients. It's very rare actually in clinical trials to be able to draw CSF from these patients. But in the very few patients that we were able to do that in, every one of them had the drug in sufficient quantities of enozertinib in their CSF. So that's the proof in the pudding that the drug is in the CSF, and that's what's giving you the brain activity.

Okay. So then sort of cutting to the chase in terms of where you're going with this. You mentioned HER2 is out of the picture. I think Dom has mentioned many times, the second line is not something you're going to focus on. So you're basically going to focus on 1L EGFR exon 20 and 1L EGFR PACC. So what do you need to show there relative to the benchmarks to be competitive? And where are you leaning in terms of how you would do a registrational study? We've seen some examples of registrational studies already, as you know, from some of the competitors, and that's probably giving you some insight into what you may want to do.

Yes. Dominic, do you want to take that?

Yes. Maybe we'll start off with the data update in the second half of the year, Yigal, because it is a pretty comprehensive data update. So just to kind of rehash that. So we'll have 3 kind of cohorts of patient data that we'll have. And for each of those, it will be 20 to 25 patients. So in total, 60 to 75 patients. It will be first-line EGFR exon 20 as a monotherapy, that's one. EGFR exon 20 in combination with Ami, that's the second. And then we'll have first-line EGFR PACC as a monotherapy as well. So what we're going to show here again, we want to obviously see systemic responses. We want to show CNS activity. And here, we want to get a good look at durability as well. As Jacob said, durability is kind of where you expect to see the benefit from a CNS active agent.

With regards to benchmark, I think, generally speaking, from a response rate, you want to be 60% or better in each of those general cohorts. Now obviously, we'll have some data from competitors in the first half of this year. We'll obviously look at those and see how those translate as well. But again, the key thing for us is the differentiation on the CNS activity. I think that's where we -- initially, based on preclinical data, that was the hypothesis that kind of continue to show that in the clinic, both in the dose escalation and then on the dose optimization we shared with [indiscernible] as well.

With regards to are we leaning towards one or the other, again, Jacob said, we're a data-driven company. We're going to look at our data, compare it to the competitive landscape and see if it makes sense for us to pursue first-line lung in exon 20 or PACC or both or neither. Obviously, the data will drive that decision. But again, if we continue to show the differentiated profile that we've shown to date, we think we could be potential best-in-class here.

Okay. And just sort of at a higher level, speaking about cash and runway and prioritization, when you think about the R&D budget for the company and kind of roughly, like how much is going to enozertinib versus the prostate work roughly?

Yes. Yes, it's a good question. I think the obvious thing is prostate is a much larger patient Phase III study that you'd have to run just as a hypothetical analog would be for prostate, it could be a 600-patient study. I think for lung, for 1 of those 2 indications, it could be significantly less, call it, 50% of that. So that study obviously would be less as well. But again, I think they're both great opportunities, and we'll have to make that assessment on lung later the part of this year when we have the data in hand.

I'll put it this way, Yigal. The entirety of a Phase III experience in the front line for 2 lung populations is going to be less than or the same as one prostate study. And so from a -- we -- look, we recognize that where investor mentality these days is on targeted therapies, which is investors tend to run hot and cold on targeted therapies. So we know our cost of capital for lung is a lot higher in the minds of investors than it is for prostate and the company is mindful of that as we allocate our resources to these various opportunities.

Okay. And just in the last few minutes here, you talked in a bit of detail about the prostate market. But if you could just very, very quickly just kind of enumerate what the market sizes are for some of these indications like the EGFR exon 20 and the EGFR PACC. I know it's still an evolving calculation, especially for the PACC as some of these are -- there's a long tail of mutations there, which are still being identified.

Yes. I think if you look at the EGFR exon 20, let's call it about -- it's about 2% and look at PACC mutation, it's higher than maybe closer to 2.5%, 3%. So I think if you do the simple math on this, right, 4,000 patients in the U.S. for EGFR exon 20 and call it 5,000 for PACC mutations. It's a sizable patient population or opportunity across the board in the U.S. I'd say that the exon 20 is close to $1 billion plus TAM, whereas the PACC mutation being a little bit higher there, that could be closer to $2 billion as well.

So we do think people are under calling it the commercial opportunity here. And again, being the best-in-class here with the CNS activity could position us nicely if we continue to show that.

All right. Well, awesome. Well, we appreciate the discussion. Super interesting. And of course, looking forward to your sort of biggest reveal in a few weeks when we learn more about which way you're going to pivot on the Phase III for prostate. So we'll be -- we're watching our e-mail for that. So great to talk to you.

Sounds good, Yigal. Thank you for having us.

Thank you.

All right. Let's go ahead and get started. Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by my Squad, [ Rati Pinhe ], Priyanka Grover and Joyce Zhou. So, our next presenting company is ORIC and presenting on behalf of the company, we have CEO, Jacob Chacko.

Thank you, Anupam. It's my pleasure to speak to you today about ORIC Pharmaceuticals and the important work that we are doing within the oncology space. As always, I'll be making some forward-looking statements. I encourage you to look at our SEC disclosures.

So starting on Slide 3, ORIC stands for overcoming resistance in cancer, which in a nutshell is the mission of the company. We've assembled a talented group of drug hunters and drug developers that have worked together for many years at prior leading oncology companies and have developed many successful and commercialized products to come together to work on a pipeline of exciting therapies for patients.

So we have two late-stage pipeline assets, one focused on prostate cancer. That drug is called rinzimetostat and a second program called enozertinib, which is for lung cancer. Both of those drugs have presented -- we've presented a substantial amount of data on both of those drugs in the prior years, especially 2025. We look forward to presenting a lot more data this year, as you can see in the upcoming anticipated milestones.

The company is incredibly well funded such that we've got cash runway into the second half of 2028. The importance of that runway is not really the second half of '28 part, but the fact that you're going to get your first Phase III data readout for rinzimetostat, our prostate program in the second half of 2027. And so we are well funded for that first Phase III program, and we are also funded for our lung program, which is also going into Phase III studies.

So I mentioned the management team. We've been together for years. We've been together at ORIC. I've had the privilege of working with most of this team for 7 years at this point. I recruited this entire team into ORIC. We've had the privilege of working together previously and knowing each other for many, many years, even prior to ORIC, and that makes all the difference in small biotech in terms of the ability to weather the storms of biotech as we're all aware of.

Slide 5 highlights the pipeline that we're working on. So I mentioned there are two late-stage development programs, rinzimetostat, which is a PRC2 inhibitor. Both of these are small molecule oral inhibitors. Rinzimetostat, formerly known as ORIC-944 is a PRC2 inhibitor, which is being developed in prostate cancer in combination with two of the biggest drugs in prostate cancer today, apalutamide from J&J and darolutamide from Bayer. And enozertinib, which was formerly known as ORIC-114 is a selective and importantly, brain-penetrant TKI that is going after two different targeted therapy populations within non-small cell lung cancer, EGFR exon 20 and a group of mutations known as the atypical mutations, but more specifically PACC mutations.

Now in -- within lung cancer, we're obviously testing enozertinib in combinations with chemotherapy and also with subcutaneous amivantamab, which is an approved therapy from Johnson & Johnson for this indication, and we're also obviously testing monotherapy. The important piece here you can see and you can even see it from the clinical collaborations is the strategic importance of these populations of these targets, namely that these are high unmet need patient populations where there exists a dramatic area for improvement in both of these populations.

And you can see that the commercial relevance of these populations is pretty much self-evident. As you look at prostate cancer, even our initial indications within prostate cancer, which are focused within the castration-resistant setting and eventually the castration-sensitive setting you could see our blockbuster opportunities many times over. And within lung cancer, these targeted therapy populations while relatively small and smaller than the prostate cancer populations are again individually blockbuster opportunities.

Now on Slide 7, you can see what summarizes a very busy and transformative 2025. So starting with rinzimetostat. Rinzimetostat again is our PRC2 inhibitor being developed in prostate cancer. We reported a substantial amount of data last year that confirmed the potential best-in-class data and profile within metastatic CRPC.

Now as many of you know, we have one main competitor. It's a small company called Pfizer, which is working on the same mechanism, and they have demonstrated quite a bit of derisking data of this mechanism of action, in other words, a PRC2 inhibitor in combination with an AR inhibitor. Adviser is studying their drug in -- their PRC2 inhibitor in combination with their AR inhibitor, enzalutamide. We are studying our PRC2 inhibitor rinzimetostat in combination with the other two big AR inhibitors, apalutamide and darolutamide.

Now in all of these cases, we've been able to show in combination with apa and in combination with daro confirmed PSA response rates that compare quite favorably to Pfizer's response rates. We've shown really profound ctDNA clearance and I'll give you some snippets of those data later in the presentation. And most importantly, we've shown a clearly differentiated safety profile. The name of the game here in this space and with this target is going to be the safety profile.

And we are very encouraged by the fact that even with the early dose exploration data that we presented last year, we already see definitive evidence that, that safety profile is emerging. In other words, the benefit of our drug and its long half-life and its strong drug properties is emerging in the form of a strong, differentiated safety profile. That's important because it's going to be compatible with long-term dosing.

And as I said, the name of the game here in prostate cancer is certainly in CRPC, but especially as you go earlier line into CSPC, castration-sensitive prostate cancer, is going to be to have that clean tolerated -- well-tolerated profile. Importantly, last year, we selected the provisional recommended Phase II doses of our drug rinzimetostat in combination with both apalutamide and darolutamide. We initiated -- we presented a substantial amount of data related to that, which I will give you some highlights of that later today.

And importantly, we initiated dose optimization in combination with both of those drugs, and we look forward to presenting some of those dose optimization data later this year. We were also busy -- equally busy on the other program, enozertinib. So within lung cancer, we presented a substantial amount of data actually just 2 months ago at ESMO Asia and two different oral presentations of our drug and enozertinib as a monotherapy in EGFR exon 20 and separately in EGFR PACC mutations, both within non-small cell lung cancer.

I mentioned to you earlier that brain penetrance is the key differentiator for this program so importantly, while we're thrilled that we showed systemic ORRs that are as good or better than the competition in the space, the most important thing for us to show in that data update was the intracranial activity of the drug, and that's because of the high prevalence of CNS metastases within this population. And in that data set that we presented, we saw a 100% rate intracranial ORRs in patients with measurable disease.

That is an incredibly high number and it is one that is not often seen in this space, even across other targets within targeted therapy non-small cell lung cancer. So we're quite proud of that, and it continues to help differentiate the program relative to what is otherwise a fairly competitive landscape. We also had a well-tolerated safety profile. And importantly, we picked our -- we selected our Phase III dose at that time.

So on the corporate side, we were equally busy. We raised a lot of cash, as you can see from the slide. And importantly -- the importance of that cash was extending the cash runway into the second half of 2028, which, like I said, is well beyond the Phase III data readout for rinzimetostat, which we expect to occur in second half of 2027. So with that, let's dive into the programs. So rinzimetostat, as I mentioned, formerly known as ORIC-944 is a PRC2 inhibitor. For folks that have followed the prostate space, you know that PRC2 inhibitors have been studied by multiple companies with multiple drugs previously.

The issue has been, what you see here, this is what I like to call the problem statement. So the key limitations at the top of Slide 9 show you what has really plagued the field and the clinical experiments with PRC2 inhibitors previously, which is namely the -- running the gamut of things that you don't want to see in optimal drug profiles. So, in other words, poor in vitro potency -- poor in vivo potency as if that wasn't bad enough, inadequate clinical drug exposures related to things like CYP autoinduction and importantly, short half-lives. And then all of those drugs have also been plagued with suboptimal tolerability, which really comes back to the poor PK properties and the poor drug properties.

Now I mentioned the competitor compound from Pfizer, mevrometostat seems to have solved some of these issues, though not all of the issues. And importantly, by solving some of the issues, they have been able to show derisking clinical data that really has helped validate the promise of the synergy of a PRC2 inhibitor in combination with an AR inhibitor in prostate cancer. With rinzimetostat, we think that we have similarly solved actually all of these challenges.

And in that, I mean that we are selectively targeting the PRC2 complex. We go at it through the EED subunit of PRC2. We have an excellent in vitro and in vivo activity. We have synergistic activity with AR inhibitors that at this point, we've showed both preclinically as well as in the clinic. And most importantly, we have demonstrated many times over now the strong drug properties and the well-tolerated aspects of the drug both as a single agent, but also in combination with both of the AR inhibitors that we are studying it in combo with.

So I mentioned that we're conducting dose optimization right now. We're doing that in collaboration with J&J, with apalutamide and separately with Bayer, with darolutamide, and we expect to report more of those dose optimization data later this year. The big, big thing that's happening in the background, the team has been running very hard at actually for the bulk of 2025 and obviously, even now into early 2026 is standing up our first Phase III study. So for rinzimetostat, we expect that we will not initiate our first Phase III study in the first half of this year. As I mentioned, these are quick studies. There's a profound signal effect that is expected to be seen. And so we expect the primary data readout to come in second half 2027, not too far from now.

Now Slide 10 is one slide that summarizes a lot of complicated biology. So I'm going to -- I won't do it justice, but I will try to summarize for you essentially very complicated biology around the PRC2 complex. So PRC2 is an epigenetic modifier. As you think about the big AR inhibitors, the androgen receptor inhibitors in prostate cancer, they have done profoundly well in terms of treating patients.

But eventually, those AR inhibitors or the broader class of what are known as ARPIs, including abiraterone, eventually, those patients as well as they respond to the ARPIs eventually become resistant. So what happens is that the tumors mutate, they essentially become AR-independent and at that point, it doesn't matter if you were shutting down the AR signaling access. And so the promise of the PRC2 inhibitor that -- is that a PRC2 inhibitor is an epigenetic modifier and through the modifications with a PRC2 inhibitor, you should be able to -- the theory has been, you should be able to push the tumor to stay in an AR dependent state and in other words, allow the AR inhibitors to do what they're supposed to do, which is shut down that AR signaling and really should lead to more durable benefit of those AR inhibitors.

And as I mentioned, we have now seen that clinical evidence both in a single arm setting as well as a randomized setting from our competitor compound that Pfizer is developing. Now taking a big step back on Slide 11, why does this matter? Why are we talking about combining a PRC2 inhibitor with AR inhibitors. For folks that have followed the prostate space, you know that the AR inhibitors, the three big ones being Nubeqa, darolutamide from Bayer, Erleada, which is apalutamide from J&J and then Xtandi, which is enzalutamide from Pfizer, those three inhibitors in comp as well as abiraterone, which is now generic, the broader class called ARPIs have transformed the standard of care in prostate cancer.

You will be hard-pressed to find a physician or patient in prostate cancer that is not heard of or is treated by these drugs. And the commercial numbers obviously validate the statement I just made, which is that the three big AR inhibitors collectively sell $11 billion of revenue globally. The issue has been, if you talk to the prostate cancer physicians or the patients what you will hear is that these drugs eventually stopped working.

And when they stop working, there's not a good option for patients or what you'll hear is that the options that are there for patients are ones that the patients don't want to take. So in other words, things like chemotherapy or other modalities that are actually much more complicated to deliver, come with much more toxicity are administered by a different position altogether. And so the holy grail has been, can you come up with a drug that would make these AR inhibitors better?

And so the pitch is quite simple here, which is that if you have a small molecule oral inhibitor that is well tolerated, that you can add on to an AR inhibitor to extend the durability of that AR inhibitor, either after the patient has already progressed on another ARPI or even before they've ever progressed on the ARPI, that pitch is self-evident as to why that appeals so much to the physicians and patients.

Now I mentioned to you that this PRC2 target has been studied in prostate cancer before, in fact, studied by multiple companies with multiple drugs and the clinical data haven't generally panned out. Now why is that? So if you look at the first-gen compounds, and you see a couple of them profiled here as representatives, but really all the first 10 compounds seem to have the same general properties is what's displayed here on Slide 12, which is that you see that they really suffer from liabilities on a number of different fronts.

So they've had poor potency, they've had poor in vivo activity. Importantly, several of them have had what's known as CYP autoinduction. What that means is that those drugs will rev up the CYP enzymes and those drugs are also metabolized by the CYP enzymes. So that in this case of some of those drugs, the more drug that was given to the patients, the lower exposure of the drug, the patient actually saw biologically.

Clearly, that's not going to lead to a well -- a clinical experiment that's going to do justice to the mechanism of action. Now mevrometostat, which is Pfizer's drug, seems to have solved a lot of these properties. They have a drug that is very potent as good in vivo activity has held some of the drug property issues. It does not look like it has CYP autoinduction has a somewhat better half-life. So in contrast to the 1- or 2-hour half-life of the first 10 compounds, the Pfizer compound appears to have about a 5-hour half-life or so.

Obviously, that is still a profile with some room for improvement. But with that profile alone, they've been able to show some pretty profound activity in combination with their AR inhibitor where they have more than doubled the progression-free survival that you would expect from an AR inhibitor alone. With rinzimetostat, you see the representation on the right-hand side of Slide 12, which shows that we've got excellent cellular potency and in vivo activity clinical half-life of 20 hours, which is compatible with once a day dosing obviously leads to a well-behaved PK profile.

The toxicity that you expect to see here would be Cmax-driven toxicity, so that's why it's so important to have a long half-life with a well-behaved PK profile, and it does seem to be validating in the clinic. Now Slide 13 is a schematic of the study as it exists today. The left-hand slide is what has been completed, which is dose exploration. As I mentioned to you, we did dose -- we did both single-agent dosing with rinzimetostat, but, of course, dose exploration in combination with the two big AR inhibitors that I talked about, apalutamide, which is J&J's drug and darolutamide, which is Bayer's drug.

Having done a significant amount of that dose exploration last year, we identified that the drug works -- rinzimetostat works equally well with both of those AR inhibitors. It works at least as well as Pfizer's combination has been able to show, and it's been able to do that with a safety profile that at this point looks better than what Pfizer has been able to show. And we've shown that at multiple different doses.

So we selected doses for dose optimization, obviously, for Project Optimus purposes. And the right-hand side of Slide 13 is really what's going on right now, which is dose optimization in combination with both of those AR inhibitors. We're setting two different populations right now. So within the metastatic CRPC setting, we're looking at one population that is post abiraterone. So in other words, they've already progressed on abiraterone and they are now receiving an AR inhibitor, either apalutamide or darolutamide in combination with our drug rinzimetostat.

We are also separately studying a second population of interest within metastatic CRPC that is actually equally large, which is a population that has previously had an AR inhibitor, so either enza, apa or daro and is now being dosed with rinzimetostat in combination with either apa or daro. So all of that dosing work is ongoing right now. And as I mentioned, we expect to report some data from that dose optimization in the first quarter of this year.

Now to quickly review on Slide 14 and a few of the subsequent slides, just some of the key highlights from the dose exploration data that we presented last year. Slide 14 shows you a PSA waterfall plot. So why did PSA matter -- PSA responses mattered? These are generally thought of as early proxies of long-term durability within prostate cancer, obviously, the gold standard for an approvable endpoint remains radiographic PFS. We're not there yet. We're in the earlier stages. And so we look at PSA50s and PSA90s as one metric of the activity of the drug and another way to benchmark against, obviously, the competition.

Now first question you ought to ask when you look at a PSA waterfall plot like this of a combination regimen is what would you expect from an AR inhibitor alone in this setting. So in other words, if patients -- all these patients are in the metastatic CRPC setting, they've all progressed previously -- 100% of them have progressed previously on abiraterone up to one prior line of chemotherapy was allowed in this population. And in that setting, it is a very well documented population that with an AR inhibitor alone, you would expect to see roughly a 15% rate of PSA50s and roughly a 5% rate of PSA90s.

You obviously see a far higher rate here, a confirmed PSA50 rate of 40% as opposed to the 15% I mentioned. And you see a confirmed PSA90 rate of 20% as opposed to the 5% that I mentioned. So that is in line, actually higher than the numbers that you see from Pfizer and the randomized data that they presented. And importantly, you're seeing that regardless of the combo agent. So in other words, we see that same activity, whether it's apalutamide or darolutamide that we're combining with. We see that same activity at all the different doses that we tested. And so obviously, we're taking a few of those doses forward for dose optimization.

Now Slide 15, if you'll allow me to nerd out for a little bit is ctDNA data. And the question you should ask here is why does ctDNA doesn't matter in light of what I just showed you on the PSA activity. And the reason is there's now a literature that says that even more than the linkage between PSA responses, PSA activities to long-term durability measures like PFS, ctDNA actually tracks even better for a long-term durability -- for a proxy of long-term durability within prostate cancer. And this is why all the recent prostate Phase III studies have used ctDNA as an exploratory endpoint as well.

What you can see on the left-hand side of Slide 15 is that we have a 59% rate of taking ctDNA patients from detected to not detected. The right side of Slide 15 helps you contextualize whether that 59% is good or not. And so what I'll show you the first two bars on the right-hand side of Slide 15 are active standards of care that otherwise get used in this population.

You can see that enzalutamide -- and these are Phase III studies that looked at these agents. You can see enzalutamide achieved about a 12% rate of ctDNA going from detected to not detected, whereas chemotherapy, which would be another active standard of care in this setting has about a 32% rate of ctDNA going from detected to not detected in the case of rinzimetostat, we saw a 59% rate of going from detected to not detected, which also bodes well for the activity of this combination and the synergy of the combination.

So Slide 16 tries to summarize a lot of data from both ourselves and obviously, the competitor. The first two columns on Slide 16 are showing you a highly summarized version of the randomized data that Pfizer showed last year with mevrometostat, which, like I said, those data were profound full stop. You saw greater than a 2x extension of the PFS that you would expect with enzalutamide alone and that was in a controlled setting. The controlled -- the controlled arm performed exactly as you'd expect, which is a 6-month -- 6.2-month PFS and their treatment arm got a 14.3-month PFS.

And you can see the corresponding statistics that go with that. So as you look at PSA50s and PSA90s, Pfizer more than doubled, the PSA50 and the PSA90s that you would otherwise expect. But you can see it comes with a fair bit of toxicity. So as you look at the middle column, you can see a decent amount of toxicity. You would obviously expect to see two big classes of toxicity with the PRC2 inhibitor, which would be namely -- so hematological toxicity as well as GI toxicity, and you see both of those things.

You also see alopecia. You see obviously a high frequency of these things and also a high intensity. Now in the case of rinzimetostat plus the two AR inhibitors we looked at, you can see in the far right column. I won't go through everyone of these AEs, but you can visually see it's quite evident that you see less toxicity, both a less frequency and less intensity of that toxicity. And that's going to be at the end of the day, what wins the game here.

I won't spend too much on Slide 17 because I think you all know that the prostate market is large. And as good as the therapies have been thus far, there is need for better therapies, there's a need to kind of improve the standards of care that exist today. And you can see with any one of these potential Phase III studies for us, it's a multibillion-dollar opportunity just in the U.S. alone.

I don't have nearly enough time in this presentation to talk to you about the biological evidence for PRC2 inhibitors outside of prostate cancer, but really the right-hand side of Slide 17, attempts to show you to summarize for you several areas that we would intend to eventually develop our PRC2 inhibitor as well, which is there's ample evidence at least preclinically that PRC2 have the same epigenic synergistic effect in combination with KRAS inhibitors in lung and in colorectal cancer, and importantly, in combination with estrogen receptor inhibitors in breast cancer.

So these areas that we also look forward to developing a proof-of-concept in the clinic in the time to come. So with the time remaining, I do want to make sure we talk about our lung program as well. So enozertinib, formerly known as ORIC-114, is a brain penetrant inhibitor of EGFR. Slide 19 shows you the problem statement here, which is that as you look at this space for those that follow, the lung cancer space, you will instantly recognize that within targeted therapies for lung cancer, we have had a lot of good development of drugs for various targets within non-small cell lung cancer, but EGFR exon 20 and EGFR PACC mutations remain two classes or two slices of that non-small cell lung cancer pie that are still incredibly underserved today.

So there is one approved agent for EGFR exon 20, that is amivantamab from J&J. That drug is obviously not brain-penetrant. There's a lot of agents in development for EGFR exon 20 and others that are in development for EGFR PACC, none have shown profound CNS activity. With the exception, I would argue, of enozertinib. The CNS activity matters because of 50% of these patients will eventually develop brain metastases where you see the impact the durability of these drugs that are not brain-penetrant is because the patients eventually progress in the brain. That is the flaw in the armor of all of these drugs that are not brain-penetrant.

Previously, I and many of our team members worked at a company called Ignyta. We developed a targeted therapy for non-small cell lung cancer there and we saw the benefit of having a brain penetrating compound and what that leads to in terms of increased durability. And that's exactly what is missing from both of these spaces, EGFR exon 20 and EGFR PACC mutations. The other thing that has plagued the field historically with some of the first 10 compounds here were tolerability issues related to either GI tox or skin tox. A lot of that has been solved by us and by others in the field. And I think at this point, the remaining piece of the puzzle to solve is really the lack of CNS activity.

Now we presented a lot of data here just a couple of months ago. And the summary of that data, I'll show you some of the highlights and the slides to come. But the really high-level takeaway is that the data had response rates that were at least as good as competitors, if not better, in terms of systemic responses, but importantly, as I highlighted in my opening commentary, we had 100% intracranial ORR in patients with measurable disease. That is an incredibly high level of activity in terms of CNS activity.

And that was in the context of enrolling patients. So in contrast to the competition in the space, we enroll patients with active untreated disease into the study. In other words, they're allowed into the study. Almost all the other programs, certainly in the early stage, all of the programs excluded those patients and in later stages, most of the programs still exclude those patients. And what I mean by that is they require that if a patient has CNS metastases, those metastases need to have been treated with surgery or radiation prior to coming on the study.

That's obviously not a good way to detect whether your drug is CNS penetrant and able to treat CNS metastases, we allow patients with active untreated mets onto the study and in fact, enroll a substantial number of those patients and see that profound CNS activity in those patients as well. Now we've selected 80 milligrams once daily as the go-forward Phase III dose. And as mentioned, we're prioritizing first-line development in EGFR exon 20 and in EGFR PACC mutations in some cases, as a monotherapy and in other cases as combinations, and we expect a substantial amount of new data to be presented in the second half of 2026.

Slide 20 is a stylistic depiction of why that CNS activity matters. So the top half of Slide 20 just shows you some of the facts that I mentioned before, which is that at initial presentation, approximately 1/3 of patients have brain metastases at initial presentation. The important part, if you talk to a radiologist or you talk to a medical oncologist, what you're going to hear is that that's the 1/3 of patients that you know have brain metastasis because you can see it on imaging.

There is another group that obviously we don't know the size of that group that have what are known as micro metastases, meaning that the mets are there. You just can't pick them up on standard imaging these days. And so the number is certainly higher than 30% or 33% at initial presentation that have these CNS metastases. And then what happens is that eventually, as you go to later lines of treatment, up to half of these patients will present with CNS metastases.

But the biggest issue is really what you see at the bottom half of Slide 20, which is that for drugs that are not brain penetrant no matter how good they might be systemically. Eventually, patients will progress and for non-brain penetrant drugs, they will often progress in the brain. And so these CNS metastases will occur, that will be the site of progression. And at that point, the patient is really out of options. They have to go to something that's a lot more invasive in terms of treatment.

Where this comes out in the data. So as you can -- we're students of the targeted therapy lung space -- because, as I mentioned, some of us worked together previously at Ignyta. And what you can see time and time again, whether it's ALK, ROS, EGFR, any of the big targets in non-small cell lung cancer, is that for drugs that are not brain penetrant versus drugs that are brain penetrant, you will achieve generally the same systemic response rates, where you tend to have a big difference is progression-free survival. For the drugs that are brain penetrant, you end up getting longer progression-free survival.

The bottom half of Slide 20 essentially explains why that is. As you look at these drugs, both of which were developed in EGFR exon 20, both of which are not brain-penetrant, you can see there's a profound difference in the PFS, the durability of these drugs in patients with versus without brain metastases. And so for a drug that is brain penetrant, if you can close that gap and in other words, have both populations perform more like the good bars, in other words, the patients without brain metastases, you'll essentially end up getting a longer progression-free survival.

So Slide 21 shows you what we've done and what we are doing right now. So like I mentioned, we're focused on EGFR exon 20, both monotherapy of enozertinib as well as combos with J&J's drug, which is subcutaneous amivantamab as well as a combination with chemotherapy. And then separately, we're studying the drug in EGFR PACC mutations as a monotherapy. Now we presented a lot of data in two different oral presentations 2 months ago at ESMO Asia.

Slide 22 is essentially a one-slide summary of the key snapshot of those data. And what you can see in the top half of Slide 22 is that relative to competitor benchmarks in the pretreated population, the reason we're -- even though we're not focused on pretreated for later line development, the reason to spend a second here is because these are the most well-studied data sets, both from ourselves and from the competition.

You can see that enozertinib just delivers a response rate that's at least as good as the competitor benchmarks, if not better. And then importantly, on the bottom half of Slide 22, as you can see, obviously, as you move to the front line, you see even better response rates and then the 100% integral ORR that I mentioned earlier.

Slide 23 is just a little bit of a double-click on that activity that I mentioned to you. The waterfall plot speaks for itself in terms of the activity of the drug. So you see very good activity in frontline EGFR exon 20 in this waterfall plot. And like I mentioned, the asterisks at the top of the waterfall plot are showing you the patients that have CNS metastases at initial presentation. You can see even a greater percentage of those patients had CNS metastases at initial presentation than the 33% that I quoted to you earlier.

There is some sense of physicians and patients voting with their feet here. In other words, we do tend to enroll a higher percentage of our patients that end up having CNS metastases at baseline because the physicians know that the drug is brain penetrant. And you can see that regardless of whether the patient has mets at baseline or not, you see that good systemic activity.

And importantly, Slide 24 is, I'll call it, the triple click of those patients with CNS mets at initial presentation. And you can see with all the complicated annotations on the slide, the point of that is that we enroll patients -- several patients with measurable disease. We enrolled several patients who had active untreated disease before they came under the study it doesn't matter which of those categories they fall in, you see profound activity of the drug, including two complete responses.

And those complete responses, it's worth noting are in patients with what are known as non-target lesions. The reason why that's important is in patients with what are called non-target lesions in the brain. The only way to get an official response, so to speak, is to completely clear all the lesions. So in other words, if the patient has 5 lesions and you clear 4, that does not count as a response. The way the criteria work in patients with non-measurable lesions, you can see we completely clear the lesions in all those patients.

And here's one example on Slide 25. All the data, all the waterfalls, none of it -- all of it pales in comparison, I would say, to the actual patient stories. And this is where I spend a lot of my time is understanding the activity of these drugs and why it matters. So this is a 60-year-old female who presented with frontline EGFR exon 20 who had 5 lesions in her brain at initial presentation had no prior surgery or radiation for those lesions. And you can see after one cycle, she had a partial response, 47% reduction systemically and importantly after 1 cycle disappearance of all 5 CNS lesions.

So that is profound CNS activity. You can see that the drug safety profile that she experienced, which was well tolerated and a duration of therapy that at the time was 6 cycles and ongoing. Similarly, in the PACC population, you can see we have very good systemic activity here as demonstrated by the waterfall on Slide 26. And then similarly, as I showed you for EGFR exon 20, Slide 27 is the double click on the CNS -- the patients with CNS lesions who have these PACC mutations.

Again, you see profound activity, including complete responses in this population and that includes most of these patients actually having active untreated disease before study enrollment. Again, here, the patient stories are with -- speak volumes more than any other slide of data that I can show you. Slide 28 shows you a patient, a 67-year-old male, who came in with the PACC mutation -- frontline PACC mutation and had a systemic response of 43% after the first cycle. After the first cycle in the brain, he had a 66% reduction of his measurable lesions. But after cycle 4, that had moved on to a deeper response, in fact, a complete response and was at cycle 5 and ongoing.

So we get a lot of questions from investors around the market opportunity for lung, as some of you probably know, I think the investor enthusiasm waxes and wanes around targeted therapies over the course of time. It seems to be tied to what was the latest acquisition in the targeted therapy lung space. But you can see that these populations are sizable populations or populations that matter. These populations, any one of them, whether it's EGFR exon 20 or EGFR PACC is larger than ROS, larger than RET, there's a substantial commercial opportunity here. More importantly, there is a substantial patient need here in these populations for drugs that are truly active, well-tolerated and brain penetrant.

And so with that, in summary, you can see here on Slide 31, again, the active pipeline that we've got going in both prostate cancer and lung cancer, as I hope you've heard in my commentary today, we think that these drugs are substantially differentiated from the competition. There's a lot of milestones to come, a lot of activity going on at the company. And important thing we're about to embark on, one if not to two Phase III studies for these programs within the year to come.

So with that, I'll turn it over to Anupam for any questions.

Thank you, Jacob. We're coming up on time here. So I just first wanted to see if there's any questions in the audience. Yes. Go ahead.

If you -- bilateral glioma -- pediatric glioma is characterized by 85% of -- bilateral pediatric glioma are characterized by exon 20 EGFR mutant's main driver event, do you have any plans to make your inhibitor available for compassionate use or investigator-initiated trials in that setting?

Yes. We're aware of the data in that -- the clinical rationale in that space. We have not -- thus far not studied the drug in glioma. That's not to say that we're closing the door on that. So we'd certainly be open to a conversation around that.

On the dose optimized data that's expected in 1Q, can you give us any sense of more granular time lines? Is this going to be, I think, ASCO GU is coming up. There's also your press release webcast scenario that we could consider? Like how should we think about that?

So the data will be coming sometime between today and March 31 and this is probably how I'd characterize that.

Yes, solid guidance. Yes, all right. Okay. So in the next ...

Within this quarter.

Within this quarter?

Yes.

Next 75 days or so, yes? All right. So maybe then you could talk to us a little bit about the size and scope of the data that we're going to be getting and what you would really focus on given what you already know and what Pfizer has shown?

Yes, I'd be pleased to expand on that question. So we expect to see about 20 to 25 patients' worth of data. And what we've said is that, obviously, we're studying the drug in two different populations within metastatic CRPC. We're going to focus that Q1 disclosure on one of those populations of interest. Presumably, it will be the population that we intend to start that Phase III study in, in the first half of this year.

And then we intend to focus that disclosure on one of our AR inhibitor combo partners of interest. Again, presumably, that's the one that we intend to take into the first Phase III study. The 20 to 25 patients' worth of data, what we're going to present is like you've seen from us before, obviously, PSA50s, PSA90s, ctDNA data in terms of efficacy. We will have whatever is available in terms of durability because obviously, that's a key question here.

So we'll be looking for signs of durability that we are tracking towards what mevrometostat was able to show and certainly that we're hopefully tracking definitively better than an AR inhibitor alone in that space, so some type of landmark analysis on the durability side, and then most importantly, safety. As I mentioned, we're going to want to see that the safety profile is clearly differentiated from that of the competitor combination because that is what's ultimately going to lead to the long-term radiographic PFS and win the day.

I noted that in your comments, you noted at least 3 times that your first pivotals trial would read out in the second half of 2027, which would put you how far behind Pfizer in terms of timelines?

Yes. I mean it's exciting as I think our pipeline is, I think we get probably more questions about Pfizer and their time lines. So what they have said is that, in fact, Albert reiterated yesterday in his presentation that they're going to have their first Phase III readout for April 1 this year -- 2026. And so I guess it depends if that readout happens tomorrow or in December 31, but the point is, I think we're roughly, call it, 18 to 24 months behind them. We intend to run as hard as we possibly can to keep that gap or close that gap, but the race is on.

Thank you, Jacob.

Thank you.

Good day, and thank you for standing by. Welcome to the ORIC Enozertinib Program Update Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker, Dominic Piscitelli, Chief Financial Officer. Please go ahead.

Good morning from Singapore, and welcome to the ORIC Pharmaceuticals Enozertinib Program Update Conference Call. Earlier this week, we issued multiple press releases highlighting updated data from our ongoing Phase Ib study of Enozertinib in non-small cell lung cancer patients. You may find the press release is posted on the investor page of oricpharma.com. We have prerecorded our prepared remarks, after which we will host a live Q&A session. .

Before we begin, during this call, we will be making forward-looking statements, including forward-looking statements based on our current expectations and projections about future events. Our actual results may differ materially from those indicated by such forward-looking statements. For a description of risk factors, please refer to our recent filings with the SEC. ORIC specifically disclaims any obligation to update any forward-looking statements.

This presentation contains interim results based on data from Enozertinib trials as of the cutoff date set forth on applicable slide. During this presentation, we will not be speaking to any additional data subsequent to such date.

Now turning to Slide 3. During today's call, we'll discuss Enozertinib's preclinical differentiation Phase Ib clinical highlights from ESMO Asia, new preliminary first-line data in EGFR pack mutations and next steps followed by Q&A.

Joining me on the call today, we have Jacob Chacko, CEO; Lori Friedman, CSO; Pratik Multani, CMO; Matt Panuwat, CBO; and [ Keith Louis ], Senior Vice President of Commercial and Medical Affairs. Now let me turn the call over to Jacob.

Thank you, Dominic. Turning to Slide 5. We've obviously been busy at ESMO Asia with two oral presentations and one poster presentation that collectively summarize an enormous amount of Enozertinib data generated over the past 1.5 years in three different targeted therapy lung cancer population. This slide is a summary of the key takeaways from our Enozertinib experience, which we believe has established its potential best-in-class profile for patients with EGFR-mutated non-small cell lung cancer.

First, we've observed highly competitive response rates in both pretreated and frontline EGFR Exon 20 and EGFR PACC mutations, the two populations that we have prioritized for ongoing development.

Second, we've continued to demonstrate two key aspects that highlight Enozertinib's differentiation versus a crowded field of competitors, namely its profound CNS activity, which is critical because of the high prevalence of brain metastases in these populations, and its lack of significant off-target toxicities like cardiac, hepatic and hematological liabilities that are found with competitor inhibitors.

Finally, our substantial experience with Enozertinib points us to 80 milligrams once daily as the preferred dose for future development. We will continue enrollment and long-term durability follow-up in the first-line EGFR Exon 20 and first-line EGFR PACC population with the next planned update in mid-2026, ahead of the potential start of one or more Phase III registrational trials.

Slide 6 highlights why we are so passionate about developing Enozertinib as rapidly as possible for patients. EGFR Exon 20 and EGFR PACC mutation collectively occur annually in approximately 9,000 patients in the U.S. alone. There is one FDA-approved therapy for first-line EGFR Exon 20 and none for EGFR PACC mutation. And there is a complete lack of brain-penetrant compounds approved or in late-stage development to serve these patients. Either of these populations on its own represents a blockbuster opportunity in the U.S. alone, and both are among the largest, if not the largest, underserved targeted therapy populations that exist in lung cancer today.

Slide 7 summarizes the key aspects of an ideal target product profile that has yet to emerge to serve these populations, although we believe Enozertinib is well on its way to doing so. While the next-generation inhibitors, and Enozertinib included, have done a nice job of managing on-target toxicity, off-target toxicities continue to challenge the field.

Additionally, the prevalence of brain metastases and the brain often being the site of first progression mean that robust CNS activity is an absolute must for a best-in-class inhibitor. Ultimately, strong efficacy, both systemically and intracranially, combined with the manageable safety profile should result in the differentiated long-term durability.

Now I've already mentioned the importance of brain penetrants in effectively treating this cancer, and Slide 8 helps explain the rationale. 30% of patients have known brain metastases at initial presentation, and that number does not include the portion of patients who have brain metastases that are not yet detectable on conventional imaging. Over time, half of patients will develop brain metastases and the brain is often the first site of progression, especially for drugs that are not brain-penetrant.

The bottom half of Page 8 explains why this is such a problem. You can see that non-brain penetrant drugs have dramatically different outcomes for patients with or without brain metastases. There are countless examples in the targeted therapy space of best-in-class drugs that are brain penetrant and thus address this discrepancy.

Turning to Slide 9. You can clearly see that not only is Enozertinib demonstrating a response profile that is as good or better than competitor compounds, but you also see the preliminary evidence that for Enozertinib, the presence or absence of brain metastases does not make a difference. The drug delivers profound results for patients regardless of brain metastases.

In fact, we felt so strongly about this aspect of our drug that unlike every other competing drug in the space, from day 1, we never excluded patients from the study if their brain metastases were untreated before study entry. As Pratik will cover shortly, we've enrolled numerous patients with active untreated brain metastases and have achieved strong systemic and intracranial response rates.

With that, let me hand it over to Lori to remind you of the strong preclinical profile for Enozertinib before Pratik covers the Phase Ib clinical trial results and next steps for the program.

Thank you, Jacob. Slide 11 highlights our key aims in identifying a clinical candidate that would support a best-in-class profile for EGFR Exon 20 and atypical mutations.

Enozertinib was designed to have multiple areas of differentiation. First, Enozertinib has strong cell potency against a wide variety of EGFR Exon 20 and atypical mutations and demonstrate tumor regression in vivo. Second, Enozertinib is notable for its selectivity towards EGFR and while sparing all other kinases. Third, a crucial feature of Enozertinib is brain penetrant. This high brain exposure drives regressions in xenograft tumors grown in the brains of mice.

As shown on the right, these three areas of preclinical differentiation have all played out in the clinic with potency translating into clinical responses across the breadth of EGFR mutations, selectivity translating into minimizing off-target tox liabilities, and brain penetrants resulting in robust intracranial responses in patients.

Taking each area of preclinical differentiation in turn, starting first with potency on Slide 12. The A key differentiating feature of Enozertinib is strong cell potency across a variety of EGFR Exon 20 and atypical mutations. In this figure, potency is depicted on a color scale with dark teal blue being the most potent and gold being the least potent. When Enozertinib is compared to competitors in head-to-head in vitro studies, you can see that Enozertinib stands out with excellent potency across the spectrum of mutations.

Moving to Slide 13. A second differentiating feature of Enozertinib is selectivity. Off-target selectivity is one of the most important aspects for designing best-in-class compounds. In these data profiling multiple compounds across the kinome, Enozertinib is exquisitely selective, a key differentiation versus competitors. The table at the bottom of the slide summarizes the off-target data. Enozertinib has 0 off-target kinases inhibited, while other EDFR compounds inhibited multiple off targets, which can lead to adverse events not related to EGFR such as hematologic, cardiac or liver toxicities.

Finally, turning to Brain Penetrants on Slide 14. Brain penetrant stands out as one of the most distinguishing features of Enozertinib especially given the inability of approved and late-stage EGFR Exon 20 and PACC agents to tackle brain metastases.

On the left, in head-to-head studies in rodents, Enozertinib has a high free brain-to-plasma ratio comparable to Osimertinib and far higher than competitors that have minimal exposure in the brain. Shown on the right are results of an in vivo study measuring antitumor activity in the brain. This EGFR mutant lung cancer model was inoculated into the brain of mice and tumor shrinkage was measured by imaging. The Log scale on the Y axis shows Enozertinib achieving orders of magnitude deeper regressions in tumors grown in the brain compared to the competitor compound.

Next, I'll hand it over to Pratik who will discuss the clinical dose optimization results that show that these preclinical best-in-class properties are translating to patients.

Thank you, Lori. Before I get into the data, I'd like to provide an overview of the Enozertinib development program. All the data presented here at the ESMO Asia conference come from our global Phase Ib trial that is being conducted at 39 major academic centers in 10 countries in North America, Europe and Asia Pacific. Over 300 patients have been enrolled across the dose finding, dose optimization and dose expansion cohorts. .

Also, one key aspect of our program, which Jacob already raised is that unlike every one of our competitors, we allowed enrollment of patients with active brain metastases from the very beginning of our trial starting in dose escalation because we feel so strongly that CNS activity is necessary for a best-in-class molecule in lung cancer.

Now turning to Slide 16. We'll begin with our experience in non-small cell lung cancer with EGFR Exon 20 insertion mutations. We enrolled two populations of patients harboring these mutations. The first cohort to start enrolling with second-line post platinum-based chemotherapy in which patients were randomized 1:1 to receive either of the two provisional recommended Phase II doses we selected for dose optimization, namely 80 milligrams or 120 milligrams of Enozertinib once daily.

The second cohort, which started later, consists of first-line treatment-naive patients, and here, we enrolled the two dose levels sequentially one after the other. The first 15 patients received 120 milligrams of Enozertinib after which the remaining 18 patients up to the data cutoff received 80 milligrams. This shift was based upon safety observations we made at the 120-milligram dose in the second-line cohorts, which I'll discuss shortly.

Turning to Slide 17. Here, we have the demographics and baseline characteristics for the second-line cohort, totaling 45 patients randomized to the two doses of 80 and 120. Notably, across both dose levels, 38% had brain metastases at baseline, including patients with active CNS disease.

Turning to Slide 18. We have the safety profile for the second line post chemotherapy population by dose level. In general, treatment-related adverse events were predominantly Grade 1 or 2 and Grade 3 events occurred in roughly 1/3 of patients. Importantly, there were no significant off-target toxicities observed. For example, cardiac, hematologic and hepatic toxicity, all of which have been seen with other investigational agents. And finally, there was a low rate of discontinuations due to treatment-related events.

Dose reductions were significantly more frequent at the 120-milligram dose level with 57% of patients undergoing dose reduction down to 80 milligrams versus only 1/3 of the patients who started at 80. Looking at the table on the right, the most common treatment-related adverse events occurring in at least 20% of patients were diarrhea, followed by paronychia and stomatitis. These can all be attributed to on-target EGFR wild-type inhibition. Overall, the 120-milligram dose level had a higher rate of grade 3 toxicity, particularly diarrhea, which explains the high rate of dose reduction.

But that's not the full story. Besides more dose reductions at the 120-milligram dose level, there was also a higher frequency and duration of dose interruptions, which affected dose intensity. Thus, most patients assigned to receive 120 milligrams never truly saw that dose intensity and many fell well below even 80 milligrams. In contrast, the 80-milligram cohort was able to maintain this dose pointing towards 80 milligrams as our go-forward recommended Phase II dose.

Slide 19 depicts the reduction of ctDNA from baseline after the first 28-day cycle of therapy. You can see that there was a high and very similar rate of clearance at both dose levels with 69% clearance at 80 milligrams and 67% at 120. Thus, there seems to be little to no advantage to the higher 120-milligram dose.

On Slide 20, we'll turn to efficacy. Given what I just noted above that the 120-milligram dose level compromised dose intensity, I'll focus my discussion on the 80-milligram dose level. Here, we are looking at the efficacy evaluable population, which consists of patients who have received at least one dose of Enozertinib have at least one measurable lesion at baseline and have had the opportunity for at least three post baseline scans. The best objective response rate was 45%, all confirmed partial responses. And from the waterfall on the right, you can see that many of the PRs are deep with more than 50%, 60% regressions, and the disease control rate was 100%.

For the 40% of patients with CNS disease at baseline, looking at the table and the bars labeled with asterisks on the waterfall, you can see that there is no appreciable difference in response in these patients, which is the hallmark of a CNS active drug. Thus, Enozertinib, 80 milligrams once daily, appears to achieve a balance between an acceptable safety profile while providing strong clinical activity.

The next slide depicts the swimmer plot for the 80-milligram dose level in the second-line patient population. You can see that responses on Enozertinib generally occurred by 4 weeks which is the first on-study scan time point, but there are multiple examples of later responses occurring up to 4 or more months on treatment, demonstrating continued tumor regression with time. While progression-free survival and duration of response data are still immature, we can say that with a median follow-up of about 30 weeks, 2/3 of the responders remain on treatment.

On Slide 22, a we'll now turn to the treatment naive or first-line EGFR Exon 20 cohort, which is one of our main opportunities for future development. As I stated earlier, we initially dosed these patients at 120 milligrams but then shifted to 80 milligrams.

Turning to Slide 23. Our first-line experience to date consists of 15 patients who received 120 milligrams of Enozertinib followed by 18 patients who received 80 milligrams. In aggregate, 39% of patients had brain metastases at baseline similar to our second line population and higher than the literature average of 30%.

On Slide 24, we have the safety profile for the first-line cohort broken out by dose level. As we saw with the second-line data, here, there was also a higher rate of Grade 3 or greater adverse events at the 120-milligram dose level with 80% of patients undergoing a dose reduction, whereas there was only a 22% rate of Grade 3 or greater events at 80 milligrams with a 17% of patients undergoing dose reduction. Again, there were no significant off-target toxicities and a low rate of discontinuation. And as with the second-line cohort, the most common treatment-related adverse events were diarrhea, paronychia and stomatitis.

Note that of the dose reductions at 120 milligrams, approximately 60% of them occurred within the first couple of cycles. So these patients were more quickly dose reduced than in the second-line cohort and therefore, almost all we're receiving an average 80-milligram dose for their time on treatment. It was this observation that prompted us to shift from a 120-milligram dose and start a new cohort of first-line patients at the 80-milligram dose level.

On Slide 25, we have the available ctDNA results, which again show a high rate of clearance after one cycle occurring in 10 of 14 patients.

On Slide 26, we have the systemic objective response rate in the waterfall plot. We're looking at the efficacy evaluable population, those patients with the opportunity of at least three post baseline scans. Since in this cohort, we initially enrolled patients at 120 milligrams followed by a second cohort 80. As of the data cutoff, only the first group of patients are on long enough to read out for efficacy, follow-up is still in progress for the 80-milligram dose group.

Now based on my earlier comments on dose intensity, these patients, although they were assigned 120 milligrams because of the early and rapid dose reductions, they effectively received an 80-milligram dose. And so these data actually read more on the 80-milligram dose level. The best objective response rate here was 67% with a confirmed ORR of 60% and a disease control rate of 93%. On the right, you can see in the waterfall plot, multiple responses occurring in patients with brain metastases at baseline.

The next slide has the swimmer plot for the same 15 patients. And again, although many of the responses to Enozertinib occurred as early as 4 weeks, as in the second-line setting, we also see tumor regression over time with multiple late responses. At a median follow-up of 33 weeks, 80% of responders are still on treatment.

On Slide 28, we have the CNS-specific intracranial objective response rate using an independent radiological review employing the RANO criteria. On the right, you can see the responses in the waterfall. Seven patients had brain metastases at study entry. Three of these patients had measurable lesions, meaning that masses were 1 centimeter or larger, and all three had confirmed partial responses for an intracranial ORR of 100% for patients with measurable disease.

Four patients had what is termed nonmeasurable disease, meaning that the metastases in their brains were smaller than 1 centimeter, with nonmeasurable disease in the brain, anything short of 100% regression is termed non-CR, non-PD. So it's notable that two patients had total clearance of all their lesions thus achieving intracranial complete responses.

And finally, three of these five responders, including the two complete responses had active CNS disease, which means they received no prior treatment for their brain metastases. With the CNS ORR based on an independent third-party assessment using current CNS response criteria, we can confirm the CNS potency of Enozertinib it is able to achieve responses in the brain at the same rate as it does systemically, including in patients with untreated disease, which is a hallmark of a CNS active drug.

Turning to Slide 29. We have a vignette of one of the patients who had a complete CNS response. This is a 60-year-old woman with EGFR Exon 20 mutated non-small cell lung cancer and no prior therapy were presented with five nontarget lesions in the brain. These lesions had not been previously treated and therefore, would be considered active disease. She received 120 milligrams of Enozertinib and by cycle 1, she achieved a systemic partial response and an intracranial complete response which were later both confirmed. You can see the adverse events that she experienced with a Grade 3 event leading to a dose reduction. As of the data cutoff, she remains on treatment in response at cycle 6.

We highlight this case as another demonstration of Enozertinib's brain penetrant properties because these smaller nontarget lesions represent a setting where the blood-brain barrier would be largely intact. On the other hand, larger brain metastases can lead to a breakdown of the blood brain barrier, in which case even non-CNS penetrant agents can achieve some tumor regression. This distinction is important because one of the key properties of a brain-penetrant compound is not only causing regression of visible disease but also preventing the progression of currently clinically undetectable CNS disease. It's this property of decreasing the rate of relapse in the CNS that translates to the potential for a longer progression-free survival.

We saw evidence of this potent CNS activity during dose escalation and now have multiple examples here with our expanded EGFR Exon 20 experience. And as I'll discuss later, we saw intracranial CRs in our EGFR atypical population as well.

Turning to Slide 31, we'll shift to a discussion of the EGFR atypical patient data. Here, we enroll patients with non-small cell lung cancer including those with active brain metastases that harbor and EGFR atypical mutation, which includes PACC or PACC mutations, classical-like mutations and deletion 19 non-PACC mutations all as either Singleton or complex. In general, we were very permissive in terms of the range of EGFR A typical mutations we allowed into this dose optimization cohort. Although for future development, based upon the efficacy signals we've seen, we would focus on the first-line PACC population.

These patients were also allowed to have any prior therapy, including chemotherapy and EGFR tyrosine kinase inhibitors, such as Osimertinib and Afatinib. As a result, the median number of prior therapies for this patient population is two, meaning that on average, these patients are receiving their third line of therapy. A total of 47 patients were enrolled and randomized to receive either 80 milligrams or 120 milligrams of Enozertinib once daily. And because this is a later line population, there was a higher rate of CNS involvement at baseline. With 55% of patients having brain metastases at study entry.

On the next slide, we have a safety for these patients. As with the Exon 20 experience, the most common related adverse events were diarrhea, paronychia and stomatitis. Treatment-related adverse events were predominantly Grade 1 or 2 with no Grade 4 or 5 events and no significant off-target toxicities. There were no discontinuations due to treatment-related adverse events. However, as with the EGFR Exon 20 experience, there was a high rate of dose reductions at 120 milligrams with 68% of patients dose reducing. And 80% of those reductions occurred early in the first 8 weeks on treatment. This cohort was the last of the dose optimization cohorts to start enrolling. So by this time, investigators are quick to dose-reduce patients from the 120-milligram dose down to 80 milligrams, leading to a dose intensity in these patients of approximately 80 milligrams once daily. For this reason, they were analyzed by combining them with the 80-milligram assigned dose group.

Turning to Slide 33. We have the response data for the efficacy evaluable patient population, those patients with at least three post-baseline scans. In addition, this analysis is focused on those patients with PACC mutations, which is where we saw the strongest signal. As I stated earlier, we're combining all patients who were either assigned the 80-milligram dose or if they were assigned to 120, they actually received dose intensity of 80 milligrams. So of the 22 patients represented here, 12 patients started at 80, while 10 patients started at 120, but had an early dose reduction.

Focusing on these 22 patients, you'll see that the best ORR is 36%, all confirmed partial responses. With a disease control rate of 91%. And in the 59% of patients with CNS disease at baseline, looking at the table and waterfall plot, again, there's no meaningful difference in response. Overall, these results are all the more impressive given that this is a median third-line patient population, and they compare very favorably against efficacy benchmarks with other agents being developed in the same patient population.

Slide 34 shows the swimmer plot for these patients. And as before, we see many responses to Enozertinib occurring at the 4-week mark with additional examples of late responders, with a median follow-up of approximately 33 weeks, 35 responders remain on treatment.

Now before starting the next section, given that our initial treatment experience in the PACC population was so heavily skewed to later line patients, effectively median third-line patients. We felt it was important to provide a brief update here of our early experience in treatment-naive first-line PACC patients.

Turning to Slide 36. These are preliminary data from our ongoing first-line EGFR pack cohort who are all receiving the 80-milligram dose. These data were not available at the time of the abstract deadline for ESMO Asia but we are providing an early look here because it confirms our conclusion that 80 milligrams of Enozertinib once daily is a well-tolerated dose able to achieve significant clinical activity, including in the CNS.

Here, we have an early look at the first 10 patients with EGFR PACC mutations who have had at least one post-baseline scan on study. The safety profile we've seen in this cohort is in line with what we've seen to date at the 80-milligram dose level in other cohorts.

Turning to efficacy. Of these 10 patients, eight has a partial response giving an ORR of 80%. So far, three responses are confirmed and five are yet unconfirmed with still ongoing on treatment and pending confirmation. You can see the tumor regressions in the waterfall to the right.

Many of these patients also had CNS disease at baseline, indicated by the asterisks over the bars. We, of course, were interested to see if there was also evidence of intracranial response, and I'm happy to say there clearly was.

Turning to Slide 37. We have the CNS specific intracranial response rate here based upon investigator assessment using RECIST criteria. In this early look at our first-line EGFR PACC population, we had six patients with baseline CNS metastases at study entry, of which five had a post baseline scan. All these patients had active disease at baseline, meaning no prior treatment of their CNS mets.

On the right, you can see the responses in the waterfall. Of these five evaluable patients who have brain metastases of study entry four has measurable lesions and all responded with three partial responses and one complete response, resulting in an intracranial ORR of 100% for patients with measurable disease. The other patient has nonmeasurable disease, which right now is non-CR, non-PD.

While still early, we are very encouraged by these data and the potential of Enozertinib to be a best-in-class molecule in both the EGFR Exon 20 and EGFR PACC mutated patient population.

Finally, let me close with one more case vignette. This time of a 67-year-old man with non-small cell lung cancer and a PACC mutation. The patient had systemic disease as well as a target lesion in the frontal lobe of the brain, who received Enozertinib at 80 milligrams once daily and achieved a partial response in his systemic disease as well as a partial response in the brain, both confirmed.

He's only experienced Grade 1 skin toxicity and remains on study in response in cycle 5 as of the data cutoff. And hot off the press, we learned from the patient's position that the week before this conference that after the fourth cycle of treatment, the patient now has a complete response in the brain. How about that?

So this concludes the data I wanted to review today. I'll now pass it back to Jacob to put our results into perspective, but I think you'll agree that through this major update to the Enozertinib program, we have laid a strong foundation to support its best-in-class potential. Jacob?

Thanks, Pratik. Well, Pratik obviously covered an enormous amount of data. The most relevant which is summarized on Slide 40. You can clearly see that not only is Enozertinib demonstrating a response profile that is as good or better than competitor compounds, but you are already seeing the preliminary evidence that for Enozertinib, the presence or absence of brain metastases does not make a difference. The drug delivers profound results for patients regardless of their status of brain metastases. .

And while the data are too immature to comment definitively on durability, we obviously like what we've seen thus far and are looking forward to providing longer-term follow-up in future updates.

Turning to Slide 41. We have previously mentioned that our potential registrational development priorities for Enozertinib are focused on frontline populations in both EGFR Exon 20 and EGFR PACC mutations. We believe today's substantial update establishes Enozertinib's potential best-in-class profile for patients with EGFR-mutated non-small cell lung cancer. We've observed highly competitive response rates in both pretreated and frontline EGFR Exon 20 and EGFR PACC mutations, out two populations of interest. We have continued to demonstrate Enozertinib's two key differentiators profound CNS activity and a lack of significant off-target toxicities, two factors that we believe will be key to eventually establishing long-term differentiated durability.

Finally, we've selected a preferred dose of 80 milligrams once daily for future development, and we will continue enrollment and long-term durability follow-up in these two frontline populations with the next planned update in mid-2026, and ahead of the potential start of one or more Phase III registrational trials.

We'll wrap up our prepared remarks on Slide 42. We're very proud of the team and pipeline that we have assembled here at ORIC, and we're looking forward to providing additional updates for both Enozertinib and ORIC-944 over the coming quarters.

Before we open it up to Q&A, I'd like to thank our investigators as well as the entire ORIC team who worked diligently to tackle our mission on behalf of patients. And most importantly, I'd like to thank our patients and their families who we hope to help overcome resistance in cancer. With that, let's open it up for Q&A.

[Operator Instructions] and our first question comes from the line of Anupam Rama from JPMorgan.

Congrats on the data and go [ Buckeyes ]. So within the second-line EGFR Exon 20 data set, you guys talked about how your response rate was lower than at the 120 mg than the 80 mg. You alluded to this being driven by some safety. Can you dig into what exactly you're seeing in terms of the AEs impacting dose intensity.

And then a second question, just what gives you confidence in the 80 mg moving as your Phase III dose? And when do you think you might have FDA sign-off to move forward with the dose?

Anupam, thanks for the question. Go [ Trojan ], and I'll ask Pratik to address your questions.

I think I'd have to take the [ Buckeyes ] side of things. So thanks for the questions. I'll take them in order. So yes, you're right. We did see a lower response rate in the second-line EGFR Exon 20 cohort at the 120 versus the 80 there was a higher rate of Grade 3 diarrhea at the 120-milligram dose level, which largely explains the higher rate of dose reductions as well as some of the skin tox we saw again at the 120.

But beyond the higher rate of dose interruption, there were also more dose holes. And the issue with those holes is you have periods where you're not going to have enough drug on board. And so the patient may progress in this window or actually never have a chance to respond. So we saw this when we looked at the average daily dose of the patients in the 120-milligram dose group, with the dose reductions and interruptions, although they were assigned 120 milligrams, they actually had an average daily dose of 65 and some patients went below 50 as their average daily dose. So they just weren't getting continuous target coverage necessary to either achieve or maintain response.

That's in contrast to what we saw at the 80-milligram dose where patients had lower rated dose reductions and dose holds, and so most of those patients actually saw the effective dose of 80, which allows for continuous target coverage and the full efficacy of the drug. So that's kind of how the safety played off into efficacy in that second line cohort.

Now in terms of confidence that 80 milligrams are dose moving forward to Phase III and our sort of feeling about FDA's what there are will be as well. So I think at this point, we've generated a robust data set with Enozertinib at both the 120 and the 80-milligram dose levels across all the cohorts, we have over 170 patients treated. And so I think within any given cohort and across all the cohorts, they collectively support 80 milligrams being the go-forward dose. But let me go into a little more detail.

First, the second-line cohort data, which EGFR cohort data, which I just mentioned, the 80-milligram dose level, we saw a 45% confirmed ORR which compared to other benchmarks where it's good or better in that same patient population. Second, in our first line EGFR Exon 20 cohort Here, we did report on the patients who were signed 120-milligram dose level, but with the high number of early dose reductions and the key here they were early, these patients actually received an average daily dose just about 80 milligrams. So we feel those data also reinforce the clinical activity of Enozertinib at the 80-milligram dose level. But of course, we have an ongoing 80-milligram cohort in the first-line Exon 20. So we'll report on that next year.

And then finally, the sort of late-breaking data we disclosed on the call in the first-line EGFR PACC population these patients are all receiving 80 milligrams, and we saw an 80% ORR in the first 10 patients evaluable. And on top of that, four of these patients had active measurable brain mets at baseline at all four had an intracranial CNS response, 100%, including one CR.

So I think collectively, these data really support our choice of 80 milligrams at the RP2D. And importantly, this is a highly active dose, and we're not leaving any efficacy on the table.

So now in terms of FDA and Project Optimus, as they've said, the objective of this initiative is to determine whether or not a lower dose of a given drug may be equally efficacious, but better tolerated and trying to move away from the MTD paradigm. I think our data support that conclusion for Enozertinib that 80 milligrams has a better safety profile, while it's retaining clinical activity. And frankly, I think the clinical activity could be better than we saw at 120 because of the dose hold and interruption issues that I discussed. So we'll see how the cohorts play out. But I think we feel pretty confident about FDA's concurrence with our decision.

Our next question comes from the line of Prakhar Agarwal of Cantor Fitzgerald.

I have two, so maybe first one, can you help us put into context a CNS activity of Enozertinib relative to your competitors? And secondly, if you can just put more final details on how the overall profile of efficacy and safety you shared today compared to your competitors, especially for the first line setting in both EGFR 20 and PACC mutations.

Yes. Prakhar, thank you for the question. Overall, I'll ask Pratik to address your first question. Overall, we believe that Enozertinib data that we presented today specifically at the 80-milligram selected dose, which is what Pratik just highlighted in the last set of questions, are best-in-class for EGFR Exon 20 and PACC mutations full stop.

I'll ask Pratik to kind of elaborate that on the CNS side, and then I can address the other part of your question.

So we presented quite a bit of CNS data, but in particular, across the first-line patient populations, the first-line EGFR Exon 20 and the first-line EGFR PACC. Across those, we had 12 patients with CNS disease. Seven of those patients had measurable CNS disease and all responded. So the intracranial ORR was 100% and one of these was a CR. And then in the patients with nonmeasurable disease, we have five of them, and we had two more CRs in that group and nonmeasurable just for information's sake are tumor lesions that are less than 1 centimeter in size. And then on top of this, this is all these 12 patients, nine had active untreated brain mets. So these are patients who didn't have any other treatment to those brain mets apart from Enozertinib most of our competitors really don't claim to be CNS active and a few that do haven't really shown convincing intracranial data as convincing as what we've shown today.

And then one thing we didn't mention in the prepared remarks was we had the opportunity, which is very rare to collect CSF from several of our patients to see whether the drug can be definitively identified in the CSF and having crossed the blood brain barrier. And so I can report that with three samples of patients on Enozertinib, we're achieving therapeutic levels in the brain in every one of those patients. So yes, I think the CNS penetrant has been demonstrated in humans and the activity is clear.

And then Prakhar, on the overall profile, I mean, the systemic response rates that we've observed with as we profile today are generally on par with or they exceed the best competitor data sets from other multinational studies across these two EGFR populations that we reviewed. You have to keep in mind that our ability to equal or exceed those benchmarks is in the backdrop of the fact that our study enrolled more difficult patients to treat based on the higher percentages having baseline brain mets. And then keep in mind, even in that group, most of those patients had active untreated CNS disease. Those are patients that were literally not enrolled in the early data sets from any of our competitors.

On the tolerability front, clearly, at 120 mg, we're kind of beyond the tolerability threshold of what we view to be competitive but 80 mg, the treatment discontinuation rates are for are generally similar to, if not better than those from the competitor trials. And importantly, it has not been associated with significant off-target toxicities that you do see with the competitor compounds, and that comes in a variety of different combinations that include cardiovascular hepatic and hematological events, and we do not see those with Enozertinib. So that's on the tolerability side.

And then as Pratik did say on the CNS and is covered quite nicely, we've obviously demonstrated definitive and profound CNS activity with 100% intracranial response rates in first-line EGFR Exon 20 and first-line PACC mutations, which are our target populations moving forward. There's actually no benchmark to date on the EGFR Exon 20 side from any competitor. And our -- on the PACC side, our CNS is significantly higher than the top data sets in first-line pack.

So it's obviously the last piece of the puzzle here is durability. It's obviously too early to compare on durability at this point just given where our data sets are. But as you can see from the swimmer plots. And as you look at those early signs, even of durability, and we look forward to updating on that next year, we believe that the strengths of Enozertinib compelling systemic activity, the improved tolerability, the strong CNS activity all collectively should lead to better long-term clinical durability in the future.

Our next question comes from the line of Maurice Raycroft of Jefferies.

Congrats on the data update. Following up on the brain mets line of questioning. Your data set contains a higher proportion of brain mets at baseline versus comp data sets. And you said in the prepared remarks, you didn't exclude any patients with active brain mets at baseline. Can you talk more about how this factors into enrollment. Was there a concerted effort to do this? Or was there any enrichment for these patients?

Yes. Let me have Pratik take that. Thanks for the question Maurice.

Yes. So you're right. From the beginning, we've been confident about certain brain penetrant properties based upon how it was originally designed and all the subsequent preclinical profiling that we've done, which is why -- as you said, we have allowed enrollment of these patients with stable untreated brain mets from the very beginning of dose escalation, which is different from the more narrow enrollment criteria used by a lot of other agents that are in the same space.

And just as a reminder, I mean, our original Phase I dose escalation data that we presented at ESMO 2 years ago, 86% of patients had brain met at study entry a very high rate which set that study apart from all the other agents.

But to answer your question, the short answer is no. We haven't made any special effort to disproportionately enroll patients with brain met into our study. But I guess I'd just say investigators are voting with their feet or enrolling with their feet, so to speak, by enrolling these patients onto our trial. I think it goes to show the overall need for CNS penetrant drug. We've been enrolling these patients in the face of other competing trials that are enrolling the same patients. And so now that we have many examples of clear CNS activity including 100% intracranial response rate in our first-line patients with measurable disease, I'm sure we'll continue to get these patients.

Got it. That's helpful. And for patients with brain mets, you're breaking out if brain mets were active and untreated and whether the lesions are measurable for your naive patients. Are these specific parameters representative? And can you talk about why these distinctions matter relative to competitor programs?

Sure. Yes, I'll have Pratik continue on that one more.

Yes. No, that's a good question. I think we have been kind of explicit about breaking up active, as you said, and measurable. And that's because many members of our team have lived the importance of CNS activity. and how the FDA wants to see it demonstrated, both myself as well as many of -- as I said, members of our team worked on Entrectinib, where CNS activity was a key differentiating feature.

So with that program in our discussions with FDA, and they've since made sort of more formal guidances that captured those discussions that we had. There's a number of important considerations that they outlined in terms of how they like to see CNS activity demonstrated.

First of all, for them, CNS mets to be truly considered evaluable. They must be active. So either they haven't been treated or if they're treated and the mets have progressed since that last treatment or there's been a sufficient interval since there were latest treated, so something on the order of 12 weeks. So the met need to be active. And then they look at measurable disease looking RANO criteria, and that's the metric by which they judge CNS activity. So that's why we're focusing on active measurable brain mets, because it's the regulatory basis for ultimately getting a CNS efficacy claim.

And our next question comes from the line of Brad Canino from Guggenheim.

Great to see all these data really all at once here. I'm probably going to put the cart before the horse a bit here on this question because I know it's too early for any sort of median PFS or DOR, but what can you say about the durability you're seeing thus far? And you're really calling out two elements. It seems like dialing in the right dose for a safety profile around the 80 mg and the CNS responses. So when do you think you'll have a good sense for whether those properties are resulting in an improved PFS versus the benchmarks?

Sure. So yes, I mean, we don't right now have estimal medians that we can provide. We did provide the swimmer plots, and as you can see from the multiple swimmer plots, most of our responders are still on treatment. So at the second-line EGFR Exon 20 cohort at the 80-milligram dose, six of nine are still on treatment after immediate follow-up of 30 weeks, which is about 7 months in the first-line EGFR Exon 20, 8 of 10 are still on treatment, same follow-up about 7.5 months. And in the third line EGFR PACC, similar follow-up, 6 of 8 responders are still on treatment. So that's kind of what we have right now. But you're right, the CNS activity will play a key goal, given that we had anywhere from 40% to 55% of patients with brain mets at study entry. A non-brain penetrant drug would have a very different PFS in patients with brain mets versus those without. And we saw that with mobocertinib and with the any chemo combo. But with CNS active drug, which we believe certainly is the PFS shouldn't dramatically be different between those two patient populations. So we expect to do an update on next year, and we should have the mature data to confirm that.

Our next question comes from the line of Colleen Kusy from Baird.

Congrats on the data presentation. So you touched on this a little bit Jacob, but just on the treatment-related AE discontinuation rates, you said I think relative to competitors was low. But I was just curious, the discontinuation for the 80 mg dose appeared a little bit higher than the 120 mg dose, even though we saw higher tox at the 120 mg dose. So just any color on why you might be seeing that higher discontinuation rate?

Yes. Colleen, I want to clarify my comments should what it should have reflected is essentially the safety profile at 80 mg obviously, overall is better tolerated than at 120 mg. Some of the individual stats are actually turned around on 120, but I'll ask Pratik to kind of walk you through the reasons for why that is.

Sure. So that second-line EGFR exon 20 cohort was the first cohort we started enrollment with, and so there was sort of some investigator learning along the way. But if you look at the discontinuation rate at 80 milligrams across the entire patient experience that we presented at 6%. So that number is the sort of collective rate, and that's as good, if not better than the other agents in this class.

The reason for the low discontinuation rate in the 120, and it's kind of -- yes, it perplexed me as well when we first through, but it's really sort of safety and efficacy being two sides of the same coin. And so at the 120, we had the dose reductions. And as I said earlier, those dose reductions come with dose holds and those dose holds lead to impaired efficacy. And so instead of these patients coming off for safety events, they come off because they either don't respond and progress or they progress. And so what might have been a safety discontinuation ends up being a progression discontinuation at the 120-milligram dose. So that's sort of the explanation.

That as the investigators got more experience with the drug, especially at the 120 milligram, as I said in my remarks, they started to dose escalate very quickly and maintained dose intensity, but now it is at the 80-milligram dose level just because that's the dose reduction from 120 milligram.

Got you. That's super helpful. And then not sure how many members of the team are in Singapore for ESMO Asia this weekend, but just curious any color from the general feedback that you're hearing from investigators on the data update.

Yes, Colleen. There's four of us here in Singapore, but I'll ask Pratik, Pratik have obviously spoken to a lot of investigators here in Singapore.

Yes. So this conference, I encourage people to attend. And I came to this conference when it first started 10 years ago, and it's grown considerably. And so it's a good chance to see a lot of our Asian investigators from Korea, Taiwan, Hong Kong, Australia. So we were able to link up with both our investigators as well as just other KOLs here who are giving talks and such.

And I think the biggest flash was clearly the CNS data. I think people were impressed with the response rates with the fact that it was in patients with active disease. And now we're moving beyond anecdotal case vignettes but really sort of response rates with the safety profile is the 80-milligram dose level that people feel comfortable moving forward with. So that's the feedback we've gotten so far.

Our next question comes from Derek Archila from Wells Fargo.

So again, I wanted to get your thoughts on a potential Phase III design in the first-line EGFR Exon 20 patient population, particularly given that Ami Chemo is already approved there and just how you're thinking about maybe relative to some of the other Phase III trials?

And then just one follow-up, since you're already evaluating Eno and combo with Ami, I guess any color on the potential treatment are you might pursue in that trial?

Derek, thanks for the good questions. Yes, I mean, I'll ask Pratik to kind of cover off on the detail of your questions. But at a high level, we're obviously going to see -- we presented a huge amount of data here at the conference. We'll see a lot more of our own data in the two first-line settings, first-line EGFR pack and first-line EGFR Exon 20 over the next coming quarters. We'll also see a lot of competitor data over the coming quarters. And so all of that will have a bearing on the questions you asked. But we've been actively thinking about that Phase III trial design for both of those populations. So let me ask Pratik to hit that.

Yes. So you're right. So Ami Chemo has been approved in the frontline setting. But the approval of a new agent or in this case, a regimen doesn't automatically make it the standard of care that needs to be the sort of control arm of any future Phase III. Despite the fact that any chemo is approved for first line, we haven't had any trouble getting patients who are second line post chemotherapy only post -- without any Amivantamab, and that's in the U.S. So chemotherapy is still widely used in the first-line setting. It's still in the guidelines, not just in the U.S., but European and other guidelines.

I think just indirectly, you can get some read as well the Ami Chemo label was approved in March of' '24, just 6 months after the [ Thermo ] Phase III started. And FDA had the Ami Chemo NDA in their hands well before then. And I don't think [ Ervance ] has said that they ever had to consider changing the control arm or are concerned that their control arm of chemotherapy is going to be invalid. So as it stands right now, chemotherapy remains an acceptable standard of therapy for first-line EGFR Exon 20 and a big consideration is that any Phase III would be a global trial. So you have to consider global clinical practice where chemo remains an option on all the guidelines, as I said.

And then I think you asked about, yes, what regimen we might take into Phase III, given that we are also besides all of the single agent data generating any combo data Enozertinib plus Amivantamab is ongoing in a separate trial. We also have ongoing -- now a little dose -- exploration of Enozertinib plus platinum-based chemotherapy. So there's actually three options that we're looking at for a potential Phase III for the Enozertinib regimen, single agent, combo with chemo and combo with Ami. So we're going to let those data play out, especially the combo with Chemo and Ami to see what makes sense moving forward.

Our next question comes from the line of Yigal Nochomovitz of Citigroup.

Congrats on the data. I had two related commercial ones and then one on the data itself. In the past, you've talked about a commercial opportunity in the U.S. in the neighborhood of around $3 billion, $3.5 billion for [ Enzo ], I'm wondering if you could just walk us through a little bit how you get to that number. And then obviously, as you've already highlighted on the call, it is a competitive landscape, both for frontline Exon 20 and frontline PACC. So could you just kind of discuss in a little more detail your views as to what supports success commercially in both of those settings.

Yes, sure. [ Keith Louis ], who's heading up our commercial and our medical affairs efforts at ORIC, is here with us in Singapore. So I'll ask him to take both of those.

This is Keith. Thanks for the question. Regarding the EGFR Exon 20 population, that accounts for about 2% of non-small cell lung cancer and the EGFR pack atypicals are slightly higher, about 2.5% of NSCLC. And that's just based on the literature out there.

And then regarding our duration assumptions in Exon 20, we assume treatment duration of close to 1 year. And then in PACC, we assumed duration of about 16 months, and both of these numbers are premised on the current best data from the competition. And then obviously, there's upside to those duration numbers. If our CNS profile that we discussed on today's call, translates into a durability benefit.

And then regarding pricing, we take into account the current market pricing of various TKIs in non-small cell lung cancer.

And I think the second question you asked about was around why we think Enozertinib could be potentially successful commercially in these base populations, frontline Exon 20 and frontline PACC. And as we discussed, as Jacob and Pratik mentioned in their presentation, we think Enozertinib has the potential to be a best-in-class drug in this space, specifically addressing unmet medical needs of frontline patients with EGFR Exon 20 and PACC mutations. Given the 30% rate of brain mets at presentation for non-small cell lung cancer patients and the fact that about half of these patients will develop CNS mets over the course of their disease, we think a confirmed brain penetrant properties are going to be a key differentiator and really a game changer for treating oncologists and for non-small cell lung cancer patients.

I would also say adding to this ideal product profile is the convenience of an oral once-daily regimen. And then when you couple that with a manageable safety profile as a selected 80-milligram dose that we are going to take into potential Phase III with no significant off-target toxicity and low rate of discontinuation, I think this really sets us up to be an ideal product profile and particularly on the manageable safety profile, it's especially important because patients may achieve responses in later cycles, as we saw as late as the fourth or fifth cycle and they continue to respond on therapy for years.

And then Yigal, you mentioned you had a question on the data as well.

Yes. Thanks. Yes, it was just sort of a quick one. I was just curious, in the frontline PACC patients where you have the 10% response rate in those with the measurable CNS disease. I was just curious of those, how many also had the systemic responses.

So yes, I mean, by RECIST, they were also responders. All of them.

Our next question comes from the line of Matthew Biegler from [ OpCo ].

This is Tracy on for Matt. We just had a couple of questions. Are the responses seen in EGFR Exon 20 near loop or far loop mutations? And are the responses seen in the two most common PACC mutations or complex PACC mutations?

Yes. Thanks, Tracy. I'll ask Lori, our CSO, to take those.

Thanks for that question. So we use the Guardant ctDNA assay to really exhaustively characterize the EGFR mutations. And as expected, we enrolled patients with a broad spectrum of EGFR mutant. Specifically, in the EGFR Exon 20 cohorts, we do see responses in both the near loop and the far loop mutations which is consistent with our preclinical data.

And then in the EGFR PACC cohorts, we also had robust responses in Singletons, including the two most common mutations, the G719X and S768I as well as responses in a variety of complex mutations. So our response rates, for instance, in the first-line treatment right naive PAT cohort are comparable for the Singleton mutations at 75% for best ORR and the complex mutations at 83% best ORR. So we feel that the preclinical data has translated very nicely to the clinical responses.

Our next question comes from the line of Corinne Johnson of GS.

Maybe you could talk a little bit more about your registrational trial plans. And in particular, I'm curious how you plan to further build the case for differentiation against these CNS metastases. And how does that kind of feature as you think about patient selection and stratification in the registrational programs?

Yes, sir, I can answer that. I mean, I think -- as I said, there's a number of factors that we -- that still have to play out in terms of how we design our Phase III plan. First of all, which one are we going to prioritize first-line EGFR Exon 20 or first-line EGFR PACC. I think we have great activity, both systemically and in the CNS in both of those indications at the 80-milligram dose as a single agent. Then within the EGFR Exon 20, there is the -- as I mentioned earlier, the options of single-agent combo with chemo and combo with Amivantamab. So those are considerations. .

I think as we have already done, we're always going to lean heavy into the CNS activity. We feel that the 80-milligram dose is able to achieve that in so far in 100% of patients in the first-line setting with measurable disease. So I think there's a number of factors that you still need to sort of have to play out to make those decisions. And then obviously, the durability assessments in the various indications as well. So I think it's too early for us to kind of give you the actual sort of decision, but these are the variables that we are considering.

And Corinne, it's a good question. I'll just add on to a couple of things that -- add on a couple of things to what Pratik mentioned, which is one of the reasons we obviously went out of our way in the presentation to highlight and specify exactly which patients had measurable disease in the brain. And then which of those were active in untreated diseases because as Pratik mentioned in the prepared remarks, those are the two variables that matter to FDA. And so we have experience of this directly from developing Entrectinib, which is a brain-penetrant compound that several of us were involved in at Ignyta where if you want to get data into the label, the FDA wants to see patients with measurable disease in the brain, and they want to make sure that those patients have active in an untreated disease. And so that's why we made such a point to highlight those 2 aspects of the data.

And our last question comes from [ Johnny Fan ] from EVR.

It's [ John Afric ] from Evercore. I wanted to ask you guys had any more details you could share about the kinetics of the response and how they differ for patients on the 80 mg dose and versus those at the 120 mg dose that got dosed down?

Sure, John. Thanks for the question. I think it was cutting out a little bit, but I think you were asking about response kinetics in the patients. I'll ask Pratik take that.

Yes, it's the same. So in the 80-milligram dose level, we see the responses majority happen at the 4-week mark, which is the first time we check. We saw that in the second-line EGFR Exon 20. We're seeing that in the first-line PACC, EGFR PACC. So even with the lower dose. That's why, like I said earlier, we don't feel like we're leaving any efficacy on the table because the kinetics of the 80-milligram dose response are as quick as what we saw at the 120.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.