Thanks everyone for continuing to join us here at the Guggenheim Biotech Conference. My name is Brad Canino. Happy to be sharing the stage for the next fireside with ORIC Pharmaceuticals. We've got Matt Panuwat, Chief Business Officer, Dominic Piscitelli, CFO. Thank you so much for joining us. Maybe just to kick off, provide an overview of the company and where you see the development priorities for ORIC today. Yeah. Thanks for having us, Brad. ORIC Pharmaceuticals is a clinical-stage oncology company. Our name is our underlying mission, which is to overcome resistance in cancer. Given the team that we've assembled, our key areas of focus are small molecules, and we focus in prostate cancer, lung cancer, and breast cancer. Our two key lead programs, the first one is rinzimetostat, formerly known as ORIC-944. This is our allosteric PRC2 inhibitor that we're studying in prostate cancer in combination with both apalutamide from J&J and with darolutamide from Bayer. Last year, we showed you our dose escalation data. This year, we're expected to show you guys our dose optimization data, and we're expected to start the first phase III study for that drug in the first half of this year. The second lead program is enozertinib, formerly known as ORIC-114. This is our selective brain-penetrant EGFR inhibitor, which has shown great potency against exon 20 and PACC mutations. Again, we've shown you some dose optimization data last year at ESMO Asia, and we'll have additional update in the second half of this year and potentially start that phase III study in one or both of those indications shortly thereafter. Okay. Well, we are all anxiously waiting for the phase III readout of Pfizer's mevrometostat in prostate cancer. I guess remind us what you saw from Pfizer's phase II randomized data, and then your own dose escalation that gives you conviction to be ready to launch into a phase III with your own program in the first half of this year. Yeah. We often get that question, is: "When is the phase III data from Pfizer coming out?" Obviously, we don't know. I guess at JP Morgan, they did indicate it was coming in 2026, and it looks like there's various analyst reports that kinda say either first half, mid, or second half, so your guess is as good as ours. So if we rewind back to ASCO GU of 2025, Pfizer showed us a randomized dataset in post-Abi patients. It was a total of 80 patients, and what they showed here was really a profound benefit. The treatment arm of mevrometostat plus Enza showed a PFS of 14.3 months versus a control arm of Enza alone of 6.2 months, so more than doubling of the PFS benefit. They also showed us a nice benefit on the PSA responses. They had a PSA response of 34%, at PSA 50 of 34%, a PSA 90 of 12% as well. So that obviously de-risked the mechanism, and obviously, was a direct read-through to our program as well. What we showed you guys during our dose escalation data in 2025 was early proof of concept data. So we showed you PSA 50 of 40%, that's a confirmed PSA 50, versus Pfizer's 34%, and a PSA 90 of 20% versus Pfizer's 12%. So again, numerically higher with all the caveats of cross-study comparison in small N. And then, on the safety side, we did show a more favorable safety profile. We did see significantly less adverse events, both in severity and in frequency, which we think is a key differentiation of our program as well. So those two things in combination give us, obviously, high conviction on the program, and we wanna move that into the phase III study in the first half of this year, and we'll have a Q1 update this year from the dose optimization, which we'll talk about a little bit later. Okay. Why do you believe mevrometostat is able to demonstrate that differentiated efficacy and safety profile? How important have those differences been in terms of your investigator conversations as you've talked about the clinical trials? Yeah, I think that's a good, good question, Brad. I think a couple things. I think mevrometostat does seem to be differentiated in a few things from a molecule standpoint. I think, one, we are targeting the PRC2 complex a little bit different, so we are an EED inhibitor hitting that subunit versus Pfizer's EZH2. There are some advantages there. And then, I think a lot of the data we've published and shown preclinically is just our molecule has extremely solid drug properties, kind of across the board, so better solubility, better bioavailability, just really predictable PK, and so we've studied that extensive preclinically. Now, we actually have some clinical data that supports that as well, and so I think there's ways to differentiate. Again, it's still a little early on the efficacy side, but I think as we've shown, you know, PSA responses, which is kind of an early biomarker read in prostate cancer, seems to be generally consistent with the Pfizer data, so we're obviously very happy by that. And then again, the data we've presented so far seems to be there could be a trend that the safety profile could be better as well. And so, again, in the Pfizer dataset that we've seen, you know, a lot of Grade 3, 4, and higher GI tolerability issues, hematological tox, and stuff like that. So those are things we haven't quite seen yet, and again, we're optimistic that we can differentiate both on the efficacy and safety, but again, time will tell. But so far, so good. The corollary question is, of course: Do you think you need to continue to be differentiated versus Pfizer for the asset to have value? Yeah, I think a good question, and I'll come back to this in your, your follow-up to the, the last question as well. But I think, one, we don't believe we need to be differentiated in prostate cancer because it's such a huge market and such an unmet need, and I think we say that with a reasonable level of conviction, mostly because the way the market is today. It's generally treated across lines of therapy with ARPIs or second gen and novel hormonal therapies. There's four of those. All four are relatively undifferentiated on efficacy. All four of them have been extremely significant commercial success. That's enzalutamide, abiraterone, apalutamide, and darolutamide. So, there is some differentiation on safety, with darolutamide, but that was the fourth ARPI inhibitor to launch, essentially 70-80 years after the first launch, in the space. It's doing very well commercially. So we don't believe we need to be differentiated. That being said, you know, the earlier signs point to there could be some differentiation. Back to what we're hearing, you know, the safety actually matters a lot in this population, and so, prostate cancer is a little bit unique area of oncology. It is often diagnosed and treated in the urology setting. There's a lot of patients that get treated in the community, so safety is a very significant differentiator in this space as you think about an oral therapy, the potential for extremely long durability, at least in the Pfizer data, with an rPFS of 14.3 months, you really wanna have a safe and tolerable therapy that patients can stay on it for a long time. And so the feedback that we're getting from clinicians or early market research is that safety is a very significant differentiator in this space. ... Yeah, and just to put a final point on the AR inhibitors that Matt outlined, like enzalutamide in 2024, which is the first—we launched, Matt and I were at Medivation, we launched that in 2012. That did $6 billion. Apalutamide came six years later and is doing $3 billion. So we're, you know, based on the current timing, we're about 18-20 months behind Pfizer, so that puts us in a great position. Again, we don't need to be differentiated, but based on the, based on the early profile, we do think there's a good chance we could be pre-differentiated, specifically on the safety side. Okay. Well, you have some additional, for the first time, dose optimization data expected in 1Q of this year. Can you walk through what we should expect to see in this update? And then, you know, durability is obviously a key component of this, but knowing that our PFS won't be mature, what type of durability should be expected to be able to be shown? Yeah. No, I'm glad you said that, because you're right. Durability is obviously an important component of this, but what we're showing is not going to be a mature PFS. So we caution to obviously compare it to Pfizer's mature PFS of 14.3 months. So we will have an update in Q1 of this year. What we've said, it'll be 20-25 patients worth of data. It will be from one of the two patient populations that we're studying. As you guys know, we're studying in a post-Abiraterone patient population, as well as a post-AR inhibitor patient population. And we're also studying it in combination with two different AR inhibitors, apalutamide and darolutamide. So the Q1 update will be 20-25 patients from one of the two patient populations, from one of the two, combination agents that we're, we're studying. And this is intentional. This is basically a, you know, a kind of an early look at the potential phase III study that we want to start in the first half of the year. So that's kind of the objective of this Q1 update. And obviously, for competitive reasons, we don't want to just put everything out there unnecessarily. So, what we want to show here now is PSA 50, PSA 90. We want to be consistent to what we've shown you guys before, which has been, you know, numerically slightly better than what Pfizer have shown. On the safety and tolerability side, we want to be at least as good as what we've shown you before. Lastly, with your point on the durability, it will not be a mature PFS. We'll give you an early look on durability. Think of this as a landmark analysis at three months or four months. What we want to show here is that things are obviously looking good, patients are not coming off drug, and from a trend perspective, it's trending better than what you'd expect from an AR inhibitor alone. Mm-hmm. And you mentioned, so it'll be data on one of the ARPIs. What will determine, though, which ARPI you actually move forward with into phase III, and how do you anticipate that decision to be communicated to the investor community? Yeah. No, great question. So based on the data that we've shared with you guys, you know, so far, there's been no meaningful difference between the two AR inhibitors, both apalutamide and darolutamide, from a safety and efficacy standpoint. We think they're both great drugs. Each has their own benefit, if you think about it. Obviously, darolutamide is not a CYP inducer, so you don't have that CYP DDI that you see with both apalutamide and enzalutamide. Darolutamide is taken twice a day with food, whereas apalutamide is once a day with or without food. So again, each drug is a great drug. We think they're both potential great strategic partners, being J&J and Bayer. So, you know, I think at the end of the day, it will come down, obviously, we'll look at the data, but we don't expect any significant, meaningful difference. And it will probably come down to some strategic considerations as we think about which AR inhibitor we want to do the first phase III study. And I do want to emphasize that it's the first one. We don't want to commit to saying all future phase III studies have to be with the same AR inhibitor that we choose for the first phase III study. And I guess, you know, I guess depending on which dataset we show you in Q1, that'll be a good sign of which one we'll probably move forward into the phase III study. Are you ready to go it alone for at least the initial phase IIIs, or will you need some sort of strategic plan in place to kick that off? Yeah. You want to take that, Matt? Yeah, good, good question. I think, one, you know, we are planning to start at least our first phase III study this year. That's obviously where the focus is right now. If you think about prostate cancer, obviously, there's a number of different studies across lines of therapy. We don't necessarily... I think Dominic has said we will select one AR inhibitor for that first phase III study. That doesn't mean we couldn't use a different one for another phase III study. So there's some things to think about long term. You know, we're currently well capitalized. We have the first phase III study is fully funded, and so we do feel comfortable that we can obviously, one, operationalize that. We have a number of folks at ORIC that have run phase III studies in prostate cancer before, so we feel good from a capability standpoint. We feel very good from a financial standpoint, so we do not need a corporate partner to start that phase III study. Over the longer term, again, there are a number of other studies we could do, be doing. There's a number of other combinations we could do it, be doing. There's other therapeutic areas, within oncology we could be doing. So I think, again, over the long term, it would make sense to potentially bring a partner on board to help us kind of execute on the program. But we certainly don't need to do that, anytime soon. We'll do that, obviously, when it, when it makes sense to do so. Yeah, and just to emphasize the runway component of it, as Matt said, we raised, you know, $244 million mid-last year, and that was purposely to make sure we had sufficient runway, that we weren't subject, A, to the markets, to what Pfizer says or doesn't say, and we could just operationalize the first phase III study. So right now, we have cash runway into the second half of 2028, and based on our current timing, assuming we start the first phase III study in the first half of this year, we could have data in the second half of 2027. So we have cash runway passing beyond that data readout. Okay. Now, maybe out a bit on the market opportunity then, what can you tell us about the size of the metastatic CRPC market, really depending on the prior Abi exposure or post-Abi exposure, knowing that that could be a labeled indication of post-Abi for this first study that Pfizer is running? ... Yeah, a great question. I think, there's a lot of sources out there that would point you to probably about 30,000-40,000 mCRPC patients in the U.S., annually. A vast majority of those who would have seen an ARPI, in prior lines of therapy, and so I think that's a good place to start. I think a lot of our data, as we've looked into, what is the prior therapy? It's probably 40% or higher that were prior abiraterone, and then the other half being kind of the AR inhibitors, interchangeably. I think if you look at prescription data from last year, it's about 50% of prior abiraterone. That's what you can see in the U.S.. If you look at different clinical studies, it kinda gets you to that ballpark, but we kind of assume about 40%-50% would be prior abiraterone within that population, and the rest of it being the AR inhibitor. Okay. Yeah. If you do the numbers, right, if you look at the post-AR inhibitors and assume, you know, I think it's 15,000-17,000 patients, you assume a duration of what Pfizer showed of 14 months. You look at the current price of AR inhibitors, they're all pretty much in the same range. You get to a pretty sizable market, right? I think if you did that math, the opportunity is about $3.5 million for just the post-Abi setting alone, right? That setting alone, obviously, the post-AR inhibitor is probably similar to that as well. And if you look at the analogues, U.S. to ex-U.S. for prostate cancer, ex-U.S. is probably 80%-90% of the U.S. market as well. So it is a sizable market opportunity. I think people know that from a prostate standpoint. So we think it's a great opportunity for us, even if we're second to market and undifferentiated. But again, we do believe there's good reason to believe we are differentiated. Okay. And then, what is the vision you have now of how PRC2 inhibitors will fit into this landscape, which obviously has a couple of interesting options today, but is highly competitive, rapidly evolving? What do you see and what do you hear from KOLs? Yeah, I think, we're obviously following it very closely. I think one, we do like PRC2 inhibitors in general. They're oral therapies, Pfizer being twice daily, we're once daily, so I think there is a nice advantage of that as you think about how big the market is and how it's treated. So the feedback from KOLs obviously like the general profile. Today, the only other considerations in the mCRPC setting is really ARPI switch, which doesn't really work too well. That's obviously a common practice that people use, or it's chemotherapy, which a lot of patients actually just forgo chemotherapy altogether, so not a great regimen there either, and Pluvicto, which has some access issues, some tolerability challenges. But if you look at kind of the active therapies there, Pluvicto, they're on label in the mCRPC setting for 9.6-month PFS, and chemotherapy generally gives you about seven to eight months. And so with an oral therapy, as long as you're in that ballpark, we think that would be extremely well-received. And so the Pfizer MEVPRO-1 study, it does assume a control arm. They are randomizing against physician's choice of enzalutamide or chemotherapy, and so they're expecting that arm to do about seven months in the control arm. And so again, if that is a positive study, they should be kind of in the nine-month or north of that range. Again, they saw it dramatically better in their earlier studies. So if that is a positive study, that should be very clinically meaningful and very commercially meaningful as well. That's kind of our expectation. And again, so that plays well against all of the emerging therapies out there to date. We're still waiting to see longer-term durability with the T-cell engagers, ADCs. You know, there's a lot of stuff going on, but I think with an oral therapy, something that's very safe and well-tolerated, so far, it looks to be a very promising therapy for earlier lines prostate cancer. Okay, great. Maybe in the remaining time, move over to enozertinib, or ORIC-114, previously known, the EGFR inhibitor. Maybe give an overview of how you plan to continue to invest in this program following what was a pretty comprehensive early, phase I update in 4Q, and, and what additional data you expect to disclose over the course of the year. Yeah, so we did provide a pretty comprehensive update at ESMO Asia last year. When you look at the data in both the first line and previously treated patients for both EGFR exon 20 and PACC, I think from a systemic response rate, we were basically as competitive or if not slightly better than some of the competitors out there. I think it was really the differentiation for us is the CNS activity. If you look at patients in the first line setting for both PACC and EGFR exon 20 with measurable disease, we had a 100% CNS response rate, which is really super. It's a great result. The reason this is important, if you look at the prevalence of patients with CNS mets in these patient populations, about a third of the patients do present with known CNS mets at baseline, and if you look over the treatment regimen, about 50% of them will have CNS mets. We do think this is a significant unmet medical need. We think this is where we could be differentiated, and obviously, we'll have to prove that out to the market over time. I think for the second-half update, what we have is three data readouts. The first one is first-line EGFR exon 20 as a monotherapy. The second is EGFR exon 20 in combination with amivantamab, and the third is first-line EGFR, EGFR PACC mutations is, as a monotherapy as well. For each of those patient popula-- each of those cohorts, I should say, it'll be 20-25 patients, and what we wanna show you there is obviously systemic response, CNS response, safety, tolerability, and durability. So that's where I think the thing is. Now, we do have some competitors coming out with some additional data in the first half of this year. Obviously, that'll help us refine what the benchmark is and what we need to beat from a... to in order to be differentiated, best-in-class in that category. Yeah. I think the competitor companies probably get this question a lot as well, but as you think about these different segments of EGFR, how large of market opportunities do you actually think they can be? ... Yeah, it's actually, we view, you know, it's a very significant unmet need and commercial opportunity. It is a targeted therapy, and so what we've seen in lung cancer, you really wanna be best in class, where I think we've kind of talked in prostate cancer, you can be fourth to market and actually do okay. I think here you really need to be a best-in-class inhibitor. Looking at the EGFR exon 20 side, it's generally estimated about 2% of lung cancer, so that gets you, you know, about 4,000, 4,000 to 5,000 patients in the U.S., annually. And then, the PACC market seems to be a little bit bigger, about 2.5-- at least 2.5% of lung cancer gets you to kind of 5,000 or 6,000 patients in the U.S. So essentially, 9,000-10,000 patients a year in the U.S., about 4%-5% of lung cancer. So that generally starts looking from a prevalent standpoint, like the ALK market, which we know is a multi-billion dollar market. And then two, the data that we've seen so far on the exon 20 side, current standard of care would be amivantamab chemotherapy, gets you a PFS of about 12 months. That's not a very well-tolerated therapy. Potentially, you could do better with an oral, and so I think we'll see some data coming out from other competitors with TKIs to see if they can improve on that, or let alone if ours can improve on that. And then what we've seen on the PACC side, you can get durability of about 16 months. And so, again, there is potential there for relatively long duration of therapy. Again, we have a brain-penetrant molecule, so we think that generally bodes well. You see a lot of patients progress in clinical studies with brain mets, and so the fact that we're fixing that again has potential for really long duration of therapy, and so that can really add up to a sizable market. Yeah. And you guys do have an amivantamab combo approach going on as well, which is relatively unique. So how do you think about that relative to a monotherapy approach? And how much of that combo is really a focus for you? Yeah. So in the first line setting, EGFR exon 20 first line setting, if you look at what historically people have done, have taken one of two tried-and-true approaches. One is monotherapy, the other is in combination with chemo. You know, one different approach that we're doing is the combination with amivantamab. Matt was able to structure, secure a clinical supply agreement with J&J, and we're combining our drug with amivantamab. And the rationale here is pretty straightforward, right? It's like amivantamab plus us, we bring the CNS activity to the table. They obviously grab a bispecific, so they hit EGFR exon 20, so you get broader and deeper coverage on the various mutations on EGFR exon 20. And then lastly, you know, it's a bispecific, so it also, it's some MET, which is also some of the resistance mechanism, like C797S. So it's an interesting, it's a different approach. Obviously, when you're combining two EGFR inhibitors, you have to worry about combining on-target toxicities in form of EGFR wild type, so think of rash and diarrhea, rash and GI-related toxicities. So that is interesting. That is a possibility that we've kinda consider moving that forward as well. So I think when we think of the first line, we think there's three possibilities for us in exon 20. It's monotherapy, it's combination with amivantamab, or it's combination with chemo. So obviously, we'll, we'll kinda look at that data in the second half of this year, compare that to what the benchmarks are, and determine what we want to do with that program. If it makes sense, if we're undifferentiated, then it may not make sense for us to kinda move that forward. It may look for, you know, put it in Matt's camp and look for a partner. But if we are differentiated, obviously, we'll have to take a hard look at that and see what makes the most sense for the program. You know, one question we get sometimes is: Would you rather do that first-line EGFR exon 20 study or a second study in prostate cancer? Obviously, we're a data-driven company, so we'll look at that collectively and determine what the best use of capital is. Okay. Well, you touched on this a little bit, when you were talking about the phase III for prostate, but just overall, if you could discuss the current cash and cash runway and what that includes in terms of milestones for both of these programs? Yeah. The current cash runway is into the second half of 2028, and that's a fully burdened number that does assume we're doing a phase III study for rinzimetostat on our own, and that also assumes we're starting a phase III study for enozertinib on our own as well. That's fully burdened, includes all the clinical, the CMC, and everything else. The one thing it does not include is it does assume we're securing a clinical supply agreement from either J&J or Bayer, depending on which one of the two partners we decide to go with. The key thing there is, again, cash runway into second half of 2028, which is past the expected top-line data readout for rinzimetostat, the phase III study, which is, again, second half of 2027. and that gets us, obviously, the dose optimization data in Q1 for rinzimetostat. We have to start the first phase III study, and then we also have kind of a, another placeholder milestone, which is a program update in the second half of the year. We haven't provided much color on what that could be. That could just be a general update on where we are at the program or how we're thinking about the second phase III study for that, for the prostate, and then for enozertinib, it does assume one phase III study in there as well. Okay, perfect. Well, Dominic, Matt, thank you so much, and thank you, everyone, for listening in. Appreciate it. Thanks for having me.