All right. All right, so we're already live, so let's go. All right, so good morning, everyone. My name's Cory Kasimov, one of the senior biotech analysts here at Evercore, and it's my pleasure to host our next discussion with ORIC Pharmaceuticals, the company's CFO, Dominic Piscitelli, and CBO, Matt Panuwat. So thank you guys both for being here. Really appreciate it. I guess, you know, we'll start this discussion where we've been starting them all. It's kind of a reflection back on the year now that we're shockingly enough in December. I'd love just to kind of level set the conversation by asking you to kind of look back and talk about what you see as the company's main accomplishments over the course of 2025. Yeah, thanks for having us, Cory, so at a high level, ORIC is a clinical- stage oncology company. ORIC actually stands for Overcoming Resistance in Cancer, which is our underlying mission. Given the team that we've assembled, we focus on small molecules, and the three areas are prostate cancer, lung cancer, and breast cancer. We currently have two programs in the clinic. ORIC-944 is our allosteric PRC2 inhibitor that we're studying in prostate cancer. We're currently studying that in combination with apalutamide and separately in combination with darolutamide, and we do have clinical trial agreements with both J&J and Bayer for those collaborations. The second program is ORIC-114. This is a selective brain penetrant EGFR exon 20 program that we're studying in three mutated forms of lung cancer: EGFR exon 20, HER2 exon 20, and EGFR atypicals. We'll talk about that a little bit later in the presentation as well. We had a pretty productive year. We had two data updates on 944. We have a big update coming up this weekend on 114 at ESMO Asia, and we did some financing as well. So we're well capitalized. We got cash runway into the second half of 2028, which gives us, you know, sufficient revenue or runway, I should say, excuse me, gives us basically about runway about almost a year past our top line phase III data readout expectations for 944. Perfect. So we'll not surprisingly start this discussion with ORIC-944, and last month, you provided additional data from the phase I dose escalation combination study, and I guess to begin, what are the key learnings from that data set, and maybe how does it compare to what Pfizer has shown to date with their agent? Yeah, you know, I think stepping back for a second, Pfizer has been putting out data on this program for the last couple of years. They put out some really interesting data back out in 2023, you know, smaller Ns, but it was single arm data. I think the more compelling data they put out was at ASCO GU this past February. This was an 80-patient study, 40 patients in each arm. These are patients that had failed abiraterone and could have seen chemo. And what they showed here was some pretty impressive results, basically. They showed in the treatment arm a radiographic PFS of 14.3 months versus a control, which was Xtandi, of six months, so more than doubling of the radiographic PFS benefit there. They also gave us early PSA responses. So PSA 50, they had a rate of 34%. It's confirmed PSA 50 and a PSA 90 of about 12%. So that was kind of the benchmark we had to measure ourselves. So this year we put out two data sets. Collectively, we put out 20 patients' worth of data. And what we were able to show here is a PSA 50 of 40% and a PSA 90 of 20%. So again, numerically slightly higher than what Pfizer was able to put out. I think what's more interesting on the safety and tolerability side, if you compare the toxicity and safety and toxicity on their program versus ours, you see we had much less, much both less frequency and severity of both on-target toxicity. So they had, if you look at diarrhea, they had about an 80% rate diarrhea, 60% dyschezia, and they actually had a 40% rate of alopecia, which we didn't see any as well, so. Okay. So look, it's a huge market, right? It goes without saying. So there's ample room for both products to be successful. But when you think about potentially, you know, differentiating from mevrometostat, is it standout across the board? There's an opportunity on efficacy and on safety. Is there one area that you think is kind of more amenable where you can show that differentiation more clearly? Yeah, Matt, you want to take that? Yeah, I'd probably start out by saying I think you started your question correctly. It is a substantial market, and so I think at the end of the day, I think commercially to be relevant clinically, we don't feel that we need to be differentiated. And I think the reason why we say that is there's just so many patients with metastatic prostate cancer, and two, we kind of see it in the marketplace already. There are, you know, the standard of care across prostate cancer really is the ARPIs. There are four of them, all generally indistinguishable from an efficacy standpoint. All four of them are doing extremely well. You know, enzalutamide was launched in 2012. It's doing over $6 billion a year. Apalutamide, relatively undifferentiated from enzalutamide, launched six years later. It's doing $3 billion a year. And we see darolutamide's growing extremely fast as the fourth ARPI, again, undifferentiated on efficacy. So I think we've seen that play out in prostate cancer. So we feel, again, if we are number two behind Pfizer, it gives us plenty of a market space to play in. That being said, I think Dominic kind of covered it. Our data is still early. We're still in dose escalation. But so far, our PSA responses are trending higher than what Pfizer has shown. So we are, you know, excited by that. And then two, I think more compelling is the safety so far. And I think safety does matter, especially in prostate cancer. It's not kind of front and center usually for oncology therapeutics, but I think prostate cancer is different. As you think about an oral therapy, if you believe in the Pfizer data where they had a 14.3-month rPFS, patients will be on drug for a long time. They are studying mevrometostat in earlier stage prostate cancer. Again, there's a lot of urologists, so I think safety, you can really differentiate there and make a meaningful difference, so I think we have potential to do that as well. Yeah, I think all very good points. And I think the proxy you use with the ARPIs is perfect, I mean, in that exact indication. So I think it speaks for itself. Curious, your view, what's the importance of ctDNA in prostate cancer? Yeah, I think a couple of things. I think it's increasingly becoming a really interesting biomarker in prostate cancer. I think for a few reasons. I think one, there have been, you know, increasingly publications showing that ctDNA clearance actually translates extremely well to long-term PFS benefit and overall survival across a number of phase III studies with standard of care. So I think that's a good metric. It basically complements PSA. I think the, you know, the one thing that you don't always have in prostate cancer is RECIST responses because so many patients don't have measurable disease. You can measure it like in other solid tumor studies. And so I think it's another indication of clinical activity where you're actually looking for more of a direct, you know, tumor impact. So I think for those reasons, it's becoming, you know, increasingly reported in a lot of development stage areas for prostate cancer. You know, we demonstrated a very significant ctDNA clearance rate. You know, one is one of the highest, I think, that we've seen lately that correlates better than some of the standard of care therapies out there that have translated into a long-term rPFS and an overall survival benefit. So we think it's a, you know, an interesting data set that we provided that just helps supplement kind of the data we're generating right now. Okay. So looking ahead, the question we're constantly getting now is, what can we expect to see in the Q1 2026 dose optimization update? Yeah, yeah, I think that's a question we get quite often these days. So again, what we kind of gave in the second half update on 944 was basically the conclusion of the dose exploration and kind of told you the doses that we're moving forward with. So with darolutamide, we're moving forward with a 400 mg and a 600 mg in combination with 944. And then for the apalutamide, we're actually doing three doses. We're doing 600 mg, 800 mg, and 1,200 mg doses of 944 with apalutamide. This is the approved doses for both drug apalutamide and darolutamide. So what the expectations are for Q1 here, we're saying 20- 25 patients' worth of data. This will be from one of the two combinations. Again, we're studying both combination with apalutamide and combination with darolutamide. We'll give you one of those combinations. It will be across the provisional RP2Ds that we're bringing forward. And what you should expect here is, you know, the standard stuff we've shown you already. So PSA 50, PSA 90, safety, tolerability. We talked about ctDNA. That's something we'll probably show as well. The key part here will show you early durability. Now, again, this will not be a mature PFS. It'll be way too early for that, given we just started the dose optimization in the second half of the year. But it'll be an early look on durability. So think of a landmark analysis at a point in time, whether it's three months or four months. Okay. All right. So then in terms of selecting that potential combination partner, what are the key characteristics you're looking for to make that decision between darolutamide or apalutamide? Yeah, so if you, honestly, if you stack all three of the AR inhibitors side by side with enzalutamide, darolutamide, and apalutamide, they're really indistinguishable from an efficacy standpoint. I mean, some people argue that darolutamide is a safer drug overall. Coming from, being that Matt and I worked at Medivation, maybe we have a slight bias for enzalutamide. But the reality is they're all great drugs. The data we've had to date were really indistinguishable both from a safety and an efficacy standpoint. So either one or both, you know, we're studying apalutamide and darolutamide. Either one of those two could be viable options for us. So obviously we look at the data. One thing we'll look to do is obviously think about longer term what we want to do from a strategic standpoint, but it's really indistinguishable. Ultimately, look at the data and then make a decision on that. Okay. And then this is, I realize, putting the cart before the horse a little bit here, but what can you say today in terms of kind of what your phase III plans could look like and the timing around that? And maybe the follow-up there is, do you anticipate making adjustments or keeping this flexible until you see Pfizer's pivotal readout? Yeah, so that's probably one of the top questions we get is whether we would wait for the Pfizer phase III study, which is referred to as mevrometostat 1, to read out before we started our phase III study. And the answer is no. Our current plans are to start that first phase III study in the first half of next year. So what basically has to happen between now and then is one, we have to determine which combination agent to go with, whether it's apalutamide or darolutamide. Two, we have to select the dose of 944 to combine with. And then, you know, we're in a position to start that first phase III study in the first half of next year. Now, we are studying two patient populations. We're studying the post-ABI patient populations, which is the data that Pfizer showed at ASCO GU. It's the data that we've shown you earlier this year, but we're also studying post-ARPI patients as well, and that's something we're very interested in as well. Pfizer is not pursuing that. Pfizer did put out some really interesting data back in May of 2023 on their earnings call, where they showed, as it was the end of 35 patients, and with the combination of mevrometostat, which is their PRC2 inhibitor plus enzalutamide, they showed a radiographic PFS of almost 12 months in these patients, and these patients had failed enzalutamide already, so what you typically would expect in that patient population is about two to three months, so they had basically tripled what you'd expect in radiographic PFS, so that is a patient population we're studying as well, so those are the two that we're currently considering to start in the first half of next year. Okay. And then before we move on to 114, this is a little bit of a layup question, but can you talk about how you're thinking of the commercial opportunity for PRC2 inhibitors in prostate cancer? And maybe the follow-on to that is strategically, would you like to keep this yourself as long as possible? Yeah, you want to take the commercial? Yeah, I think the first one, I think the commercial opportunity, I think we kind of started, it's very significant. I think there's a lot of references suggesting, you know, an incidence of 30,000, 40,000, 50,000 metastatic castration-resistant patients every year. And so it's, you know, the real question is just what, at what point are they getting an ARPI in that paradigm? And so I think there's a number of patients, almost all of them really should be getting an ARPI according to the treatment guidelines and based on the clinical data that's available. And so I think, again, in the data we've presented so far, it's currently in patients that have previously had abiraterone, which in the U.S., that represents approximately about 50% of the market. And so again, that's substantial, I think, as Dominic said. We are also exploring ORIC-944 in patients previously treated with enzalutamide, apalutamide, and darolutamide for the other kind of 50% of the market. So I think that will evolve. I think either way, it's a very substantial market. And then I guess too, you know, again, back to the Pfizer randomized data in patients that have previously been treated with abiraterone, they had a 14.3 months rPFS. And so again, if you kind of multiply those number of patients by, you know, a treatment duration north of 12 months, the market opportunity is substantial. Multi-billion dollars easily in the U.S. just in that one indication, let alone we've seen Pfizer do studies. They're now launched three phase III studies, even in earlier line settings where the treatment duration is even longer potentially. So the commercial opportunity seems pretty substantial. Yeah, and maybe just to add on to what Matt's saying, you know, one question we get is, do you have to be better than Pfizer in order to win here, right? And you can look at, there's many, many analogs out there. And probably the most obvious one is the AR inhibitors. You know, we talked about the three AR inhibitors, enzalutamide, apalutamide, darolutamide, collectively doing $11 billion. Enzalutamide was launched in 2012. It did $6 billion last year. It's growing mid-teens. Apalutamide was launched six years later and is doing $3 billion in sales. And then lastly, darolutamide was launched about a year after that and it's doing about $2 billion and growing pretty significant. I think the point is this is prostate cancer. This is large. Even if we were second to market, call it 18-24 months behind Pfizer, even if we had a non-differentiated profile, we think this is a significant opportunity for us. Now, as we talked about previously, there is reason to believe where we could be differentiated and whether maybe safety, which we think that is a huge differentiation when you think about moving into the castrate-sensitive, you know, hormone-sensitive patient population as well. So your second part of your question, Cory, was on the strategic front. I think the short answer is we are prepared to start that phase III study in the first half of next year on our own. As I said, we raised about $240 million mid-year, which gives us cash flow into the second half of 2028, which is well beyond the top line data readout of our expected first phase III study for 944. So we are well capitalized. We have the team in place to operationalize that. Does it make sense to partner at some point? Obviously, it may make sense. Obviously, that's something you don't plan for. You kind of just move forward. The reality is we do think this should play in the castrate-sensitive prostate cancer market, and it may make sense to think about a partnership. Now, when we think about partnerships, these things come in various forms and structures. The key thing here is we want to retain significant operational control and strategic control of the asset, of course. Great. Okay. All right. So in our last five minutes, I want to make sure we get on to ORIC-114 enozertinib. You know, there's data coming up at ESMO Asia this week, actually. I guess, can you kind of give a little preview of what we can expect to see there? I know you're having an event as well, and will this begin to speak to some of the potential differentiation you could get for this asset and what's the crowded market? Yeah. So the key areas of differentiation for 114 and the pushback on the program is always like it's crowded. There's a lot of people in late-stage development. Now, the two key areas that we think are really unaddressed right now is on the safety and tolerability side. So if you look at safety and tolerability, it really comes in two forms. On target tox, you think GI and rash, and you want to minimize that as much as possible. You're going to have some rash. You're going to have some diarrhea. But talk about off-target tox is equally important. There's a number of these assets out there that you see: QTc prolongation and elevated liver enzymes and things like that, which you want to minimize that as much as possible. If you look at our Kinome screens, they're exquisitely clean. But the key area of differentiation for us is CNS activity. So the reason for that is if you look at this patient population, about a third of these patients present with baseline brain mets, and about 50% of them actually have brain mets over the treatment paradigm. And the brain is the point of first progression in a number of these patients. So having a CNS active agent there could really differentiate as well. So preclinically, we've shown a lot of data on this, and we'll show some more data this coming weekend at ESMO Asia that hopefully continues to support that differentiation angle. Okay, and then I believe it's middle of next year we would get the frontline combination data. Yeah. And sorry, I didn't answer the second part of your question. Oh, you're good. What to expect at ESMO Asia? So we're going to show, we have three presentations: EGFR exon 20, HER2 exon 20, and the atypical. Two out of those three are breakers, so maybe we'll focus on those. So in the EGFR exon 20, in the second line patient population, we'll have about 25 patients' worth of data. One thing to note here is we allow patients with active brain mets in our studies where others have kind of excluded that. So what we kind of consider the benchmark here is about 35% ORR or better in that second line EGFR exon 20 population. In the first line EGFR exon 20, we'll have about 10 to 15 patients' worth of data. And the benchmark there is around 55% or better for that patient population. And then when we think about PACC mutations, these are the ones we've enrolled are heavily pretreated. They're basically third line patients. There are two prior median lines of treatment, and they're the benchmark if you go and look. It's low 20s, so we're saying 25% or better obviously would be good for us as well, and again, we do want to continue to show the CNS activity. Okay, makes sense and then what I was going to ask about is the data you should have middle of next year, frontline combo with SubQ, amivantamab. You know, are there concerns around additive tox issues with this combo? Yeah, that's a great question. So the data that we've committed to for next year is first line atypicals and the first line EGFR exon 20 in combination with amivantamab. So that will be, you know, that's on track for mid-2026. I think you're right. The one thing you have to overcome there with the combination with is you're basically on target tox with doubling up on EGFR exon 20 on target toxicity. The interesting part there is no one else is doing that. Everyone else is either taking a monotherapy approach for first line exon 20 or combining with chemo. So it could be a pretty interesting scenario for us. Okay. And then, you know, it's early, still a lot of data to generate and stuff like that, but how are you thinking about the market opportunities here for 114? Yeah, I think a couple of things. I think it still remains to be a very significant unmet need. I think all we have approved today is chemotherapy or amivantamab in combination with chemotherapy that gives relatively limited benefit for targeted therapies. So I think the market is still, you know, pretty wide open. When we break down the three subsets, they're all approximately about 2% of lung cancer. So 2.1% for EGFR exon 20, about 2% for HER2 exon 20, and potentially 50% even higher for atypical mutation. So it kind of ranks 5%-6% of non-small cell lung cancer, which is basically on par with ALK. And we know that's a multi-billion-dollar market. So, you know, about 10,000-12,000 patients in the U.S. annually. So very significant. Here, it is crowded. It is a smaller patient population than prostate cancer. And so we are really looking for differentiation. We're looking for best in class. And I think generally that leads to long treatment duration, which is kind of key for this market. But if you check all those boxes, it could be pretty substantial for a targeted therapy. Got it. Very helpful. All right. Well, I typically end these things with a sneak peek question into 2026 and key catalysts coming up. I I think it's pretty obvious what your key catalysts are. Yeah, I think we hit it. So we're out of time. We can end it there. Appreciate you guys being here with us today. Thanks for having us. Yeah, thanks. Of course.