Hi, everyone. Thanks for joining. I'm Matt Biegler. I cover these guys, Oric, joined by Dom and Matt. Good to see you guys, as always. Yeah, I mean, high level, right? It's a company based on making, I think you'd agree, best-in-class assets, right? You've got a best-in-class PRC2, which is kind of analogous to EZH1, works on the same access. MEVPRO-1 is a big readout from a competitive standpoint that's coming up and hopefully de-risk the class. You've also got what looks like a best-in-class exon 20. I guess from a high level, you know, if you're interested in investing in Oric, I mean, what do you Why should we buy the stock right now? What are we getting right now, versus where do you want to be a year or two from now? Yeah, that's a good summary, Matt. And thanks for having us at the conference. As you said, Oric is a clinical stage oncology company. We've got two programs in the clinic. Given the team that we've assembled, we really focus in three key areas, which is prostate cancer, lung cancer, and breast cancer. And the first program, as you mentioned, rinzimetostat, which is formerly known as ORIC-944. This is our allosteric PRC2 inhibitor. Here, we're studying this in prostate cancer in combination with AR inhibitors. We're currently doing it with both apalutamide from J&J and with darolutamide from Bayer. Last year, we kind of wrapped up the dose exploration portion of the study, and we started the dose optimization. The goal is to start the first phase III study in that program in the first half of this year. The second program, you know, enosertinib, this is our eGFR inhibitor, which has shown high potency on both exon 20 as well as PAK mutations. We've showed you a big, big chunk of data on the latter part of last year at ESMO Asia, which I know we'll talk about a little bit later. We'll have some more update in the second half of this year. Kind of think about the phase III strategy there as well. We're looking at both first-line eGFR exon 20 and first-line PAK mutations there as well. A lot going on. You know, I think when I think about what the street is missing from a valuation standpoint, I think this is with rinzimetostat, this is prostate cancer. This is a huge patient population. I think the data that Pfizer presented back at ASCO GU in 2025 significantly de-risked the mechanism, right? They showed basically a doubling of the PFS benefit with a doubling of the PSA response. One, they de-risked their mechanism, but they also showed us that when you see the PSA50 response rate doubling, it does translate into durability as well. Our program, we profiled it pre-clinically, and we feel like we've got everything we've done, we're as good, if not better than them. Based on early clinical data, which again, I'll caveat with small Ns and cross-study comparison, but numerically, our PSA responses were slightly higher than them, and the safety profile looked more favorable than what Pfizer had shown as well. enosertinib, again here, I think what people do underappreciate, I think, is the potential market opportunity here and the fact that CNS activity does matter, and I think no one has shown that CNS activity to the extent that we've shown, both in PAK mutation and eGFR exon 20 mutations as well. We're excited to the readouts we have this year, as you said, these kind of are de-risk targets, and we potentially have potential best-in-class programs around this. Yeah. Let's talk about rinzimetostat first. I think it's probably most relevant from a catalyst perspective with MEVPRO-1 coming up. I mean, as I said, I mean, I think it's important to de-risk the class. What are your kind of internal expectations for Pfizer's readout? I mean, does it have to hit a hazard ratio of 0.5, like we saw in the phase II, or is there a situation where, let's say, even if it misses the primary endpoint, but it trends in the right direction, I mean, does this still kind of give you confidence that PRC2/EZH1 is a real approach in prostate? Yeah. Yeah. I think the short answer is, we do not think it has to hit 0.5. Just to kind of rehash the data they presented at ASCO GU, they showed, as you said, a PFS benefit of, like, eight months. It was 14.3 in the treatment arm, for 6.2 in the control, so a hazard ratio of 0.5. If you look at how they powered the phase III study, which is known as MEVPRO-1, and it's basically the same patient population, these are patients that had failed abiraterone and could have seen up to one round of chemo. They basically powered it for a hazard ratio of 0.66, right? They're assuming that the treatment arm does about 10 months, I think it's 10.2 months, and the control arm does 6.7, 6.75 months. Again, that's physician's choice between enzalutamide or docetaxel as well. If they hit that, if it's 10 months or better on the PFS, and they hit, you know, stat sig, I think that's a huge win for us, obviously for them, for patients, and for us as well. It's further validation in that. Again, they are assuming, I guess, some degradation from the 14.3 to the 10, there is somewhat some cushion in there. We think that study, that MEVPRO-1 study, has a good chance of achieving, being successful, I guess. Now, the timing of that study, that's a question we get often from investors. We've heard different versions. Pfizer's just said it's in 2026. That could be first half or second half, we don't know. If they for somehow miss for some reason, where it's trending in the right way, but it doesn't hit stat sig, you know, it's difficult to speculate on what that scenario looks like. The real reason is why did the underlying miss? Like, for instance, if it is because of adverse events relating to discontinuation rates or dose interruptions, that is a place where we could differentiate based on our profile as well. Mm-hmm. Makes sense. Walk us through the kind of the pitch for Rinzi here. Is it more selective for the methyltransferase complex? ISO works a little bit different than inhibits PRC2 or EZH1. Does it have better solubility? Is it both of these characteristics? Like, why is this a better drug than mevrometostat? I think you covered it, Matt. I think we differentiate on a couple of things. I think, one, we're just hitting the complex a little differently, the PRC2 complex has a couple components to that. One is EZH2, which is kind of what is, I think, most commonly referred to of the PRC2 inhibitors. We're hitting the target from an allosteric site, it's technically an EED inhibitor, there is some efficiency with that in terms of hitting EZH2. We do know also inhibiting EZH1 can be important. In certain settings, you can get overexpression of EZH1 if you inhibit EZH2, an EED inhibitor naturally inhibits both. There are some advantages to that. One of the main rationale was really just having just better drug properties in totality, so it just seems to be a more, you know, just a more amenable drug binding pocket at the end of the day. All of the things that come with that. You mentioned solubility, that is definitely one of them. We have a molecule that's much more soluble than the all of the other kind of known EZH2 inhibitors. You know, essentially, that translates into much better bioavailability across species. We obviously have a much longer half-life. All of those things we saw pre-clinically that kind of put us in the camp of, like, we think we have, you know, a really best-in-class PRC2 inhibitor. Now that it's in the clinic, you know, we're starting to get more confidence of that. I think even the early data, we wanted to test our molecule very quickly in a single agent, experience. We did a quick dose escalation just to get a really good sense of: Are the drug properties, does that translate in the clinic? We did see that. We did see. You know, again, we're kind of seeing a 20-24-hour half-life, which is, you know, wildly differentiated from any other PRC2 we've ever seen. Most of the other ones have been plagued with a lot of issues, with, you know, most notably, it all kind of correlates into a really short half-life. 3-4 hours is kind of the class. That also seems to be what Pfizer has shown. They haven't shown a lot of PK data, but if you look at it seems to be relatively short half-life, which requires kind of high and frequent dosing, and that's something we haven't seen. There is kind of a number of differentiating features that, again, we hope will kind of play out as we dose our patients longer and see more clinical activity. Yeah. Could you expand on the phase I data set and how you are seeing that translation from preclinical into clinical, and how that differentiates from what mevrometostat showed? Yeah. I think a couple of things. I mean, the most important data I think we put out is probably the most recent. That was kind of our latest update in Q4 last year. A couple of things with that. I think, you know, the good thing about the Pfizer data, I think that Dominic has mentioned that I think most people are following is, you know, we did see the randomized data, so they ran a really nice study, saw some nice PSA responses, saw some ORR, and essentially that translated into a very long RPFS, which is, again, that is the primary endpoint of their study, so that is the key metric. They had essentially, you know, kind of de-risked the target for us in a lot of ways. What we've tried to do, really for ourselves and obviously for investors too, is to try to benchmark rinzimetostat to mevrometostat in any way we can. I think we've published a lot of preclinical data. I think we've always been confident our data looks equally as good, if not, you know, if not better, preclinically, and so, you know, we're trying to benchmark everything we can clinically. We don't quite have the RPFS yet. That's gonna take some time to generate, but at least in the earlier metrics, we're seeing some really nice activity, and so we're looking at PSA50s, PSA90 responses. Those seem to be essentially numerically, you know, very consistent with the Pfizer data, you know, maybe a little bit more. We are still kind of testing our molecule in a couple different doses. As of the last update, we are also testing our drug in different AR inhibitors. We're doing apalutamide and darolutamide versus enzalutamide. So far, the efficacy, again, it's early still, but we look to be essentially on top of Pfizer on some of those earlier metrics. Again, so far, at least to the earlier data, it looks like there's a very different signal on the safety profile. I think that's kind of what I think people have kind of noticed. We don't seem to have the same rate and severity of GI tolerabilities, which is kind of one of the potential limitations of mevrometostat, and also the hematological toxicities, which is kind of one of the known on-target toxicities of PRC2 inhibitors. Much lower rates of that. Again, we think that will bode well. You know, these are oral therapies that have the potential to be dosed for extremely long periods of time, we think that there's a really significant advantage to having something that's has more better safety and tolerability. Makes sense. I still get questions on how this class of drug works. Obviously, it's an ATP-competitive JAK inhibitor. I mean, is it working on the level of the chromatin to shut off androgen receptor expression, or does it work in a different way to, like, change lineage plasticity and bring you back to a more, let's say, AR-sensitive state? Yeah. It's actually both of those. The first one is definitely true. That's probably the bigger picture. What essentially it does is, you know, move the prostate cancer cells, you know, back to an earlier state. Kind of the markers you can see from that preclinically. We've published on this, so others have as well, the results are very consistent. You do see luminal markers increase when you dose with a PRC2 inhibitor. You see AR signaling increases. There's a lot of metrics you can see that actually kind of justifies that. I think your next level of, "Okay, why exactly is that happening?" We've started to put out data. It is related to chromatin remodeling. Mm-hmm. It does make, you know, AR, essentially, it can be, you know, more active, essentially when it's blocked, and it has to do with the chromatin and the sites, in the histone methylation. That's exactly how the mechanism works, in prostate cancer, which is somewhat different than some of the other tumors that people are exploring PRC2 inhibitors in. ... Yeah, I definitely do want to ask you about potential other opportunities for this drug later, but now I just, I want to talk more about the unmet need in prostate. I mean, to me, like with RP switching, what do you get? Maybe five months RPFS at most, right? It seems like there's a huge unmet need for something that can kind of be tacked on to the lutamide class and make it better. Yeah, I can take that, Dom. I mean, you know, ARPi inhibitors are the, you know, the standard of care across multiple lines of prostate cancer, that has been the trend that's still ongoing. It's essentially how early are you getting it in the treatment regimen? We do know from, you know, a commercial market opportunity, I think there was over $11 billion in sales last year of the ARPi inhibitors. Half of that is generic abiraterone, so it's literally a over $20 billion market growing significantly. The unmet need is very substantial. Some of these earlier lines of therapies, patients are on treatment for four or five even plus years, it's pretty dramatic what those can do. As we think about our positioning our drug, is essentially it's also an oral, you know, on top of standard of care. We're hoping either once you've progressed on ARPI inhibitors, you can essentially reverse that and keep patients on it longer, and that's essentially the data, the randomized data Pfizer has shown, some of our earlier data that we've put out as well. What Pfizer is doing is taking that data and moving even into earlier lines. They are doing a treatment-naive mCRPC setting, and then obviously a castration-sensitive setting. Again, the potential is of the drug, not only to reverse the resistance, but also just preventing it from the outset. You know, an interesting strategy, if that works, again, that could be very dramatic from an unmet need. Other than that, you're right. it's very common to do AR switching, even though, you know, I think most people would say it doesn't work well. That being said, it's fairly safe, even six months is obviously better than nothing, and 2, the alternatives are chemotherapy, which many patients actually don't even go on to chemotherapy. They actually refuse it, or it's radiopharmaceuticals and kind of Pluvicto today. There's a lot of other things coming as well. It's kind of an interesting space to follow. We think something that's very well tolerated in oral, it just has a place to go wherever the ARPi inhibitors are today, which is, you know, essentially everywhere across the spectrum. I think one of the knocks, if you compare it to, like, the lutetium, some of the radio drugs, some of the newer ADCs that are out there, is that, you know, this class and the combination doesn't get as high PSA50 responses. I just want to ask you, is PSA50 a great metric for kind of like the downstream? Ultimately, what's more important, which is radiographic PFS/OS. If it's not, like, you know, why aren't we seeing as high PSA50s as some of the other classes, despite the fact that Pfizer has shown really good PFS data from this drug, from the combination? Yeah. Yeah, great. Yeah, go ahead, Dom. Start that one. I'll start, Matt. Great question. I think the short answer is, I think we caution people to kind of look at PSA responses across mechanism. I think when you look at the PSA responses that Pfizer showed, again, they doubled the PSA50 from 30, you know, it was 34% versus, like, 15%. The regulatory endpoint at the end of the day is radiographic PFS, so that's what you should be looking for. Obviously, PSA can, you know, wax and wane over time. We just caution it's all about durability at the end of the day, and it's really about looking at the radiographic PFS at the end of the day. Pfizer kind of gave us that, right? They've shown us that you saw an increase in PSA50 responses, and that translated into the benefit. As Matt said earlier on, the 14.3 months that they showed in that patient population is really, really profound benefit if you look at some of these other therapies, even with less treated patient populations. We think that's the ultimate endpoint. Obviously, PSA response is good. I think a lot of people are trained to kind of look at that as a biomarker, but at the end of the day, it's the radiographic PFS that matters. Makes sense. We talked about maybe moving upstream here into RP naive, castration sensitive. What about other cancers where you think this access could provide a benefit if you hit it? Matt, as you know, we're kind of looking at two distinct patient populations right now in the mCRPC setting, right? That's the post-abiraterone setting. That's the patient population that Pfizer showed us at ASCO GU, and we've shown you that data from our data set in 2025 as well. The other patient population that we like is post-ARPI. Again, this is post-enzalutamide, apalutamide or darolutamide. Pfizer did show us some really interesting data back in 2023, where they showed a radiographic PFS in that patient population of about 12 months. Again, to your point, what you'd expect to see enzalutamide, post-enzalutamide, is about three months, and they showed us about 12 months. We thought that was pretty impressive. Again, the goal here for physicians sometimes is to keep patients off of chemo or defer chemo as long as possible. We think that is an interesting patient population that we're exploring as well. Pfizer did have interesting data there, but they chose not to do that. They chose to go into the ARPi naive patient population, which again, we think is an interesting patient population, but we do think that patient population is shrinking over time, 'cause most people are treated with an ARPi inhibitor in earlier lines. I mean, that's how we look at the metastatic CRPC setting. When we look at castration-sensitive, we absolutely think this drug should be moved into earlier lines. Obviously, those studies are much larger and longer in duration, but they are obviously larger commercial opportunities as well. We need to think about how we want to do that, whether it makes sense for us to do that alone or with a strategic partner overall. Outside of prostate, you know, we have done some preclinical work where we've shown some really interesting data preclinically in combination with KRAS inhibitors, both in lung and CRC. You know, we're thinking about how we want to do that. Obviously, prostate cancer is our first priority, given the data that we have, but we do want to think about potential, some proof of concept studies in other indications as well. Makes sense. It sounds like we're going to get a lot more data from Renzi this year, and it sounds like you will choose what the combination partner is going forward to. Maybe just talk a little bit about what data you plan to present later this year? We've got three what's called milestones for rinzimetostat this year. The first is a Q1 update, as you referred to. The second is to start the phase III study in the first half of the year, we have a vague program update in the second half of the year, which we haven't provided any color on at this point. The Q1 update will be 20-25 patients worth of data. As you know, we're studying two distinct patient populations. We're doing post-AR inhibitors and post-ABI. It'll be one of those patient populations, it'll be one of the two combinations, either be the combination with apalutamide or the combination with darolutamide. 20-25 patients from the dose optimizations. That will be across the doses. As you know, we're studying multiple doses in the dose optimization to satisfy Project Optimus. What we want to show there is PSA50, PSA90, safety, tolerability. We'll show you ctDNA data. Then we'll show you an early look on durability, right? This is not going to be a mature PFS that we can kind of cross-compare against Pfizer data. We're thinking of landmark analysis at, call it, three months or four months. The way we're framing this is basically for the PSA50 and PSA90, we want to be consistent to what we've shown you previously, which again, was as good, if not slightly better than what Pfizer showed. On the safety and tolerability, we again want to be at least as good as what we've shown you previously. Again, Matt referred to earlier, that data set we think really distinguishes us from the Pfizer data, they showed at ASCO GU in 2025. On the, you know, when you look at the landmark analysis, again, this is an early look, 20 - 25 patients across two doses. You just want to make sure things are trending in the right direction and there's no surprises in that data set. Yeah. Are we going to be able to, obviously, with all the nuances of cross-trial comparisons, like, will we be able to compare to the data that mevrometostat's put out? Because that's all been in a post-abiraterone setting, right? If you give us post-AR inhibitor, like how easily comparable will the two data sets be? It will be more difficult. again, I'm just cautious of the any cross-style comparison, even if it is a post-ABI, because of, as you said, right, there's different patient populations. We don't know the baseline characteristics of the patients, again, we're going to have 20-25 patients worth of data, right? Trying to do some cross-study comparison on PFS or something like that we just caution that given the small end there. Yeah. Okay, cool. Let's move to enozertinib. I mean, what's the main kind of point of differentiation here? Would you say it's the CNS penetrance and CNS activity? I think that sums it up nicely, Matt. I think on the safety side, we've shown we're consistent. We definitely had less off-target toxicities. From the CNS activity, I think what we've shown in the first-line eGFR exon 20 and first-line PAK was really best in class, right? We saw 100% overall response rate in patients with measurable disease, and it's important to note that this included patients with untreated and active brain mets. We're really excited about that data set. We think CNS activity does matter here. I know you know the targeted space, the targeted lung cancer space well, and it's a high prevalence, right? About a third of these patients present with known brain sign brain mets, and, you know, about 50% of them see brain mets at some point during the treatment paradigm. We think that's a significant unmet need. Obviously, there's some competitor data that we're expecting to see in the next, call it, you know, few months, which we'll look at and compare and kind of contrast to see if we're continuing to be differentiated from these competitors as well. That will obviously influence our strategy when we give the update in the latter part of this year, excuse me, on which patient population we pursue or how we design those studies, or if it makes sense not to pursue it if we're not differentiated. We understand that we're behind here, and we need to be differentiated. We feel that all the data that we've shown today continues to show our differentiation, but we need to continue to show that in order for us to move forward into a phase III study. Yeah, thanks for explaining it that way, because, I mean, it, you know, if I go back a year ago, I think the pitch was you want to combine with amivantamab in the front line because you add the CNS penetrance, where ami doesn't necessarily have that. Ami has to combine with chemo. You could be a chemo-free option. I think that made a lot of sense, but I also think given the quality of your data that you recently put out, like there might be a monotherapy option here, and it might not even be front line. How are you currently thinking about the development of this drug? Is the answer just like TBD, like we're going to see kind of how ArriVent's furmonertinib does, maybe that changes the landscape? Like, how are you kind of viewing all the, these- Yeah, that's a great question. The short answer is, and I think you know this by now, we're a very data-driven company. I think what we want to see is obviously the ArriVent data, as well as any other competitor data that we see this year, to kind of see what the benchmark is, and then obviously compare it to our second half update this year. As you said, in the exon 20, we really have three potential paths, right? We have the monotherapy data, which again, looks really, really interesting based on the ESMO Asia update. We are doing the combination with amivantamab, which really would be a distinct approach because no one else is doing that, and you kind of highlighted the rationale for that as well, being we bring the CNS activity, they kind of bring some additional coverage on eGFR exon 20 insertion mutation, and they also hit MET as well, which could overcome certain resistance mechanisms. Lastly, you know, we are going to look at chemo combination from a safety standpoint as well. We really have three options in the first line, eGFR exon 20 space. Again, the decision will be data-driven based on our data and competitor data. The PAK mutations, we are doing just monotherapy. We'll look at that data's update in the second half of this year, and again, compare it to the competitor space. There, the gap is, you know, we're not as far behind, I'd say, from the competitor standpoint. Ammi's, you know, out there, but, you know, we'll look at what that looks like. Obviously, we have the ArriVent data that they shared. I think it was at World Lung last year as well. Yeah. talk us through your recommended phase II dose. 80 megs kind of seems like the sweet spot, between, you know, safety and efficacy. Would you agree? Are you pretty confident in that as your recommended phase II dose, both on the monotherapy and in combination? Yeah, I think we feel highly confident 80, you know, 80 mg is the dose, at least for monotherapy. We still are exploring the combination. Again, that's kind of data that will come out later this year. I think that's a question that we have, obviously, for ourselves, but what the combination dose will be. I think we're highly confident of the 80 mg monotherapy. It was a relatively big data set, you know, across lines of therapy, across patient populations that we put out. You know, in totality, I think it's over 170 patients. You know, we've dosed so extremely thorough, you know, dose exploration, you know, exercise with that molecule, so we think we feel very good about the 80 mg. It seems to be, you know, generally, you know, safe and well-tolerated, extremely low discontinuation rate. We feel strong there. We also optimized for 120 mg. That was kind of the other one that we feel is kind of at the upper limit of dose. At that level, you know, we actually saw, you know, a lot of dose reductions and some more top tolerability issues. Even looking at the efficacy, you know, across different settings, we actually saw, you know, essentially higher efficacy, even at the 80 mg dose. It seems to be more effective. Patients are, you know, extremely well-tolerated, and the safety profile looks really great at 80. I think that we feel great about that from a monotherapy standpoint. That is kind of what we're focused on now. you know, really prioritizing the frontline opportunities, both in eGFR exon 20 and PAK. I want to just wrap up with the setup from a stock perspective here, because it seems like for a long time now, your stock has been kind of held ransom at gunpoint by MEVPRO-1 and whatever Pfizer is saying through the tea leaves, and ostensibly, we'll finally see data from that trial. You guys will report out, you know, combination data from your own optimization, you know, on the first half of this year as well. Do you think maybe some of the focus of the stock towards the back end of the year shifts over to Eno, or kind of how are you thinking of the overall setup for shares, you know, as we, as we round into 2027? Yeah, I think the short answer is I've given up on China as the market does. I think you're right. I think the two catalysts that we control, you know, the two catalysts for us, obviously, are our data, right? We have the ORIC-944 data in Q1. Assuming that's tracking in line, I think that gives people further confidence on the program, and there's no surprises in that data set. People get to see the patient population and AR inhibitor, that we're probably gonna move forward for that first phase III study. I do want to emphasize that the first phase III study, 'cause only 'cause we choose one of the two AR inhibitors for the first phase III study, does not mean that we're gonna have to do all our phase III studies with that AR inhibitor. I think the, you know, not with ORIC-114, with, you know, enozertinib, but it is a show me story, right? We need to see the data, investors want to see the data, and we need to kind of lay out why we think we're differentiated and why we're best in class and why that matters. A little bit of a different story because I think enozertinib is a show me story that you have to be differentiated in order to move forward. Mm-hmm. When you look at rinzimetostat, I think it's somewhat different, right? Even in the base case where we're as good as them, both on safety and tolerability and efficacy, I think it's a potential blockbuster program. Obviously, if we differentiate on safety, that's nothing but upside as well. Somewhat of a different setup. Again, we're data-driven people, we'll kind of see what that data looks like. Probably one of the bigger catalysts for us will be the MEVPRO-1 data, as you kind of alluded to. We don't know what that looks like. We kind of walked through the statistics of the study on that. We think, you know, we would expect that study to be positive, we obviously think that's a direct read-through to us as well. Nice. Dom and Matt, fun as always. Thanks so much. Looking forward to a fun year. Yeah, great. Thank you again, Matt. Thanks, everyone. Good to see you, Matt.