Hi, everyone, and thanks for continuing to join us here at the Stifel Virtual Oncology event. My name is Brad Pineno. I'm one of the senior analysts here covering biotech. Very happy to be joined on the Next Fireside Chat with ORIC. We've got Jacob Chacko, CEO, and Dominic Piscitelli, CFO. Jacob, Dom, thanks so much for joining us. Thanks for having us, Brad. Great. Can we just start off with a quick intro to ORIC and how you're positioning the portfolio now? Yeah, so ORIC stands for Overcoming Resistance in Cancer, which in a nutshell is the mission of the company. We essentially are focused on small molecule drug development, primarily in three solid tumor large indications, which would be prostate cancer, lung cancer, and breast cancer. The two lead programs are ORIC-114, which is a brain penetrant inhibitor of EGFR exon 20, atypical EGFR mutations, and HER2 exon 20 mutations. We're developing it in all three of those populations right now. That is a very selective and brain penetrant inhibitor. Those characteristics obviously lend it quite a bit of competitive differentiation given the other molecules that are out there today for those indications. Our second lead molecule is ORIC-944, which is an inhibitor of PRC2, which is, as many folks know, an epigenetic modifier that's been implicated in a number of different tumor biologies, but in particular in prostate cancer. We're developing that in combination with two different AR inhibitors, apalutamide and darolutamide. We're doing dose finding for both of those combo regimens today. If things sort of stay according to the base case plan here, we'll have both of those programs into pivotal studies next year in 2026. We're chugging along quite nicely. Right. Now, on PRC2 inhibition for prostate cancer, I think across three programs, we've seen quite a number of and volume of patient clinical data emerge over the past several quarters. How do you now think about the quality of evidence to support that as a mechanism for prostate cancer patients, you know, really leaning on Pfizer's randomized data, but also some of Epizyme's data and your own? Yeah, so PRC2, Brad, has been an area where I'd say for years, the clinical results have disappointed relative to what all the preclinical biology and preclinical biological understanding of the underpinning mechanisms would have suggested. What I mean by that is you referenced, you know, Epizyme's molecule tazemetostat, which obviously came from Epizyme. There was another company called Constellation that had developed a couple of different molecules that were also PRC2 inhibitors. All of those have been focused on the EZH2 subunit of the PRC2 complex, which is the catalytic subunit. It's not so much about the subunit itself, but really about the drug properties where those first-generation compounds really fell short. Tazemetostat, which you asked about, falls exactly in that camp. Those first-generation PRC2 inhibitors are really poster children for poor drug properties. What I mean by that is, you know, having half-lives on the order of an hour or two, having CYP autoinduction, which is a property whereby you're revving up the CYP enzymes that are then metabolizing your drug. Epizyme, which had developed tazemetostat, had shown, and they were kind of famous for showing just chart of dose-dependent decreases in exposure. Literally, past a certain point, the more drug you give, the less exposure you get. That's obviously not the kind of properties you'd want to see in a drug. When we've gotten questions as to why do we think tazemetostat in the CHELLO-1 study last year did not, was not able to, in a statistically significant fashion, beat the control arm of enzalutamide alone when they tested tazemetostat with enzalutamide. It beat enzalutamide, but not in a stat-sync fashion. Really, fundamentally, it comes down to just the poor drug properties of that compound. In contrast to that, Pfizer with mevremetastat, which is also a PRC2 inhibitor focused on the EZH2, the catalytic subunit, seems to have solved a lot of the issues of the prior generation of compounds. They have much better cellular potency. They have much better in vivo activity. They do not have CYP autoinduction. It looks like their half-life is improved, although certainly beatable. They have a half-life of about four to five hours and have then showed some pretty compelling results, both in single-arm phase one settings in two different populations within CRPC, but also most recently after ASCO-GU in a randomized setting where they knocked the pants off the control arm. The control arm of enzalutamide in a post-abiraterone-treated CRPC population where chemo had also, prior chemo had also been allowed, the control arm got six months of PFS approximately, which is exactly what you'd expect. That's what enzalutamide should do there. The treatment arm got over 14 months, so eight-month delta over the control arm. A phenomenal result, which explains why Pfizer has already started two phase three studies in that setting and is now starting their third phase three study in the CSPC setting this year, first half this year. With ORIC-944, our compound, we have a 20-hour clinical half-life. We don't have CYP autoinduction. We're every bit as potent in both the cellular assays as well as the in vivo activity as Pfizer's compound. As I mentioned, we're in dose finding, dose optimization right now with two different AR inhibitors, but feel that anything that Pfizer has been able to show with mevremetastat in combo with enzalutamide, we ought to be able to show at least that, if not better. We'll get a chance to see that later this year as we get our first data coming out of those combo studies. If that PFS benefit is real, you know, 14 months absolute, eight-month delta versus control, how do you envision PRC2 inhibitors will fit into the prostate cancer treatment paradigm? It's a great question, Brad. I think it'll completely revamp the prostate cancer paradigm is the way that, if those, and when you say if those results are real, I think that was a big caveat that people had after the Pfizer phase one setting where in two different CRPC populations, they were way outperforming with their combo, what you would expect with enzalutamide alone. The big, big question was, you know, that wasn't a randomized setting. Can you trust that those results are real? Obviously then in a phase two setting, which is what they resulted, presented ASCO-GU in a randomized control setting, they, you know, did the results that you talked about, were they beat enzalutamide quite handily? The reason why I say that that'll completely revamp the way that these patients are treated is, first of all, it means that a PRC2 inhibitor ought to be able to be used anywhere that you use an AR inhibitor today within the prostate landscape. Used in combo with an AR inhibitor. The AR inhibitors, of course, are the mainstay of drug of treatment in the prostate landscape today. The three big AR inhibitors, enzalutamide, apalutamide, and darolutamide, collectively do $11 billion of sales globally per year. They themselves have remade the way that prostate cancer patients are treated. If you can now take a small molecule drug that is well tolerated and throw that on top of an AR inhibitor and get even longer durability, that's why it is such a home run in terms of the way that the treatment paradigm works today for prostate cancer patients. Because for folks that have done the doc calls, you know that medical oncologists and urologists love their AR inhibitors. If you can put on a small molecule regimen on top of that that gives you even better results, that, first of all, is a game changer for them because then they do not have to default those patients to the next step of chemotherapy or harder to deliver regimens like radioligand therapies or even the T-cell engagers that are coming along today. The other big thing is not only extending where the AR inhibitors are used today, but there is a concept called AR switching today for the AR inhibitors where if somebody is on enzalutamide, darolutamide, or apalutamide, they generally do quite well. They have long durations, but eventually they progress. What all the docs will tell you is they really shouldn't do AR switching at that point, which is to cycle the patient to a different AR inhibitor. They really should use one of these other modalities like chemo or, you know, radioligand therapy like that I mentioned earlier. Despite knowing that that's what they probably should do, they still do AR switching. It's because they love their AR inhibitors and they're just looking for a way to eke out longer durability with an AR inhibitor before going to one of the other modalities. If with a PRC2 inhibitor, you can actually make that AR switching concept a reality for them with actual clinical data. The 14 months that Pfizer showed in the randomized setting, it would be an absolute game changer for the way that those patients get treated today. What you would absolutely see then is AR inhibitor is prescribed upfront with a PRC2 inhibitor. You get longer durations that way. If a patient eventually becomes, you know, progresses, for any of the patients who've gotten AR inhibitor alone and then eventually progressed, you would also want to give them another AR inhibitor, but with the PRC2 inhibitor. Makes sense. Now, the Pfizer data came in February. Talk through how you have adjusted your timelines for disclosure for your own phase one B data after we got those data. What rationale supports this new strategy of disclosure? Yeah, I'll start on that. Dominic can chime in. Apologies for the background noise here as well, Brad. The rationale was really that Pfizer, in addition to presenting the Kaplan-Meier curves and the mature PFS data that we've just rattled through from their randomized study at ASCO-GU, gave another little nugget, which was, you know, really quite helpful, which was the PSA waterfalls. They showed PSA waterfalls for that study that corresponded to those long durabilities that we saw. They showed the PSA waterfalls for both the treatment arm and the control arm. Just like they more than doubled the PFS of the treatment arm versus the control arm, they also more than doubled the PSA activity in the treatment arm versus the control arm. As a result, they showed both broad and deep PSA responses. They had a 34% rate of PSA50s in the treatment arm as opposed to the control arm, which had a 15% rate of PSA50s, which is exactly what you'd expect with enzalutamide alone in that setting. They had a 12% rate of PSA90s in the treatment arm as well. What it does, Brad, is it then gave us the ability at ORIC with ORIC-944 because obviously we're earlier stage than Pfizer is with their program, gives us the opportunity this year to start looking at the side-by-side comparisons of the clinical activity of the combo therapies. What I mean by that is this year we've now got two updates we're planning for, one in the first half, one in the second half, which would be entirely focused on PSA activity, PSA waterfalls, you know, looking, like I said, at the breadth and the depth of the rate of PSA 50s and the rate of PSA 90s of ORIC-944 in combo with both apalutamide and darolutamide and seeing how that looks and how it stacks up with, you know, Pfizer's PSA activity, which gives us and gives, you know, Wall Street and obviously strategics an opportunity to then see the de-risking of ORIC-944's combo regimens in relation to Pfizer's even before we've got more mature, you know, PFS-type durability data, you know, available, which obviously the soonest for data along those lines would be next year. Looking at the PSA activity this year will be quite helpful. How important is PSA as a surrogate for PRC2 inhibition, especially when it doesn't seem to explain the full durability effect size that you normally would see from that level of PSA with other AR inhibitors, other modalities in prostate cancer? Yeah, I guess to that, I'd say a couple of things, Brad, because I've gotten that question before. I always chuckle a little bit when people say, well, it doesn't correspond to what I expected to see on the PSA 50s or the PSA 90s. I say, what did you expect to see? The reason I ask it that way is, you know, folks that have followed the prostate space for a while and especially looking at PSA, so if you think about the hierarchy of evidence in prostate cancer for looking at the activity, the efficacy activity of a drug, you know, you look at the level of PSA 50s, PSA 90s as sort of the first order of evidence that ought to translate long-term to what is ultimately the regulatory endpoint, which is radiographic PFS, you know, and then ultimately OS. The real key point though, Brad, is that PSA 50s, PSA 90s are very mechanism-specific and they're very line of therapy specific. That's why I pose the question back to folks of what did you expect to see? Because you can't sort of take the experience of what was the PSA 50s or PSA 90s of, say, an enzalutamide or an apalutamide in a frontline setting or, you know, what's the PSA 50s or PSA 90s of a, you know, radioligand therapy and try to compare them, you know, it's apples and oranges to try to then compare that to what should a PRC2 inhibitor do in a metastatic CRPC population that is post-abiraterone and has had chemotherapy. In other words, what Pfizer has shown you is the two key parts of the equation, which is they showed you the PFS, the durability measure, the radiographic PFS, and then they showed you the corresponding PSA plots that lead to that PFS. Not only that, but they've also shown you that in, because they showed you the PSA activity for the treatment arm and the control arm. They show you the 34% rate of PSA 50s in the treatment arm, the 15% rate in the control arm, again, more than doubling that PSA activity. The whole story kind of hangs together. Now, the other piece, which might be the part of the equation that is missing, you know, for folks to kind of say, you know, the PFS activity was profound, but I was, you know, hoping for a higher number. I don't know what the number should be, but hoping for a higher number on PSA activity. I think the other piece is the mechanistic explanation, which is really that if for folks who are, you know, really deep on epigenetic modifiers, you know that PRC2 inhibitors, by inhibiting PRC2, you are also hitting KLK3. KLK3 is a gene that regulates PSA levels. Essentially what you're doing is by affecting PRC2 inhibition, you're pushing up the levels of PSA because of your impact on KLK3. I can guarantee you that when Pfizer is showing that PSA waterfall plot, the levels I've shown that we've talked about verbally, they're overcoming sort of an artificially elevated level of PSA because of the impact on that KLK3 gene. The same thing will be true for us because of the PRC2 inhibition. We are almost certainly going to be, you know, pushing up PSA levels because of hitting the KLK3 gene, and then the combo is going to have to overcome that. That is probably the dynamic that would explain any delta that people are looking to see. Since we'll use the first half 25 data and the second half 25 data, but first in the first half, it's really a basis for comparison to the Pfizer data. Do you think you need to show better PSA results compared to the Pfizer data? Dominic, do you want to take that? Yeah, I think the short answer here, Brad, is no. I think what they've showed, again, they showed a confirmed PSA50 of 34%, unconfirmed PSA about 50%. That's kind of the benchmark. I think we need to, when you look at prostate, this is not, you know, targeted therapy. This is a huge market, as you know. The perfect analogy is really, you know, staring us all in the face, right? I was at Medivation. Medivation Xtandi was approved in 2012. It's doing almost $6 billion in sales. Apalutamide from J&J was approved six years later and is doing almost $3 billion in sales. This is just a big market. If we're as good as them, this is obviously a huge opportunity, commercial opportunity for us. Obviously, there's potential for us to be better. I think at the base case, if we're as good as them, this is obviously a large market opportunity for us as well. The only thing I'd add on to that, Brad, is, you know, just to kind of flesh out some of the numbers around Dominic's statement there is that the very first phase three study that Pfizer is doing, which is MEVPRO-1 in a CRPC setting for patients who are post-abiraterone, so again, mirroring the randomized data setting in which they just showed us, that is a $3 billion-plus global opportunity for just that indication alone. Then their second study, you know, MEVPRO-2 is an even bigger indication than that. MEV-Pro3, which is in the CSPC setting, is an indication that's approximately $10 billion globally. This is the point that Dominic's making, which is that those are massive market opportunities. You know, we're not trying to be heroes here. We don't have to beat them at the end of the day. We just have to have a profile that's as good as them. You can see that perfect analogy in the AR inhibitors as Dominic talked you through. Now, there's a whole host of reasons why we think our combo might actually end up being better than theirs. You know, I did mention the 20-hour clinical half-life for ORIC-944, far less interpatient variability in what we've been able to see. While both compounds get to similar levels of PD, target engagement, H3K27 trimethylation, we do it with far less variability. Having a 20-hour clinical half-life means we can dose QD, we'll have lower Cmax. That ultimately should lead to a better safety profile, which we haven't touched on yet as well. There is a whole host of reasons why we actually might end up being better than them, but we do not think we need to be. Two-parter on the data as well. How comprehensive of a data set should we expect across the two disclosures? What is going to be that incremental learning between the first half data set and the second half? What's the focus that's new versus the first half data set? Yeah, Dom, you want to take that? Yeah, I'll start it and Jacob, feel free to chime in. As you know, Brad, earlier this year, we showed you six patients' worth of data for the combination with apalutamide. You know, based on that data, we had three out of six patients had a PSA 50 and two out of six patients had a PSA 90. I think what we're giving, and it's important to remember, we're still in dose escalation. The data readouts in the first half of this year and the second half of this year will be from the dose escalation portion of the cohort. The goal would be focused on PSA responses. What we're showing you is more patients. You know, we showed you six patients in January. We'll show you about 12-15 patients in the next update in the first half of this year. The later part of the year, probably somewhere around double that. Twenty to twenty-five patients' worth of data. It is just more data, again, focused that we are trending at least in line with the Pfizer data, kind of the benchmarks that they have laid out for us on the PSA aspect of it. Yeah, so ultimately, Brad, what you'll get is a bigger and bigger end through the course of the year. Then obviously in the second half data set, you know, we'll have a much clearer sense of exactly what the provisional RP2D doses are for the darolutamide combo and separately for the apalutamide combo. You’ll have a very clear sense of the activity level of the drug in those combos at exactly what the provisional RP2Ds are as opposed to the first half update, which obviously will be, you know, still dose escalation. Now, you anticipate starting hopefully a phase three in the first half of 2026. You mentioned the Pfizer studies are ongoing, the phase threes. Dominic, you've been in companies that have conducted prostate cancer trials before. When would you expect to see the first top-line phase three data from a Pfizer phase three? Yeah, I'm glad you asked, Brad. The, because this is, I think, maybe another source of some level of confusion amongst the Wall Street understanding of the PRC2 development program for both us and Pfizer today, which is people, I think, ultimately revert to what were the, you know, AFFIRM studies and PREVAIL studies and how long were they, how much did they cost, how many patients. That is not the case for these programs, either ours or Pfizer's, at least in the metastatic CRPC setting. Pfizer's publicly on record saying that they started MEV-Pro1 in October of last year. That's that study in that post-abiraterone setting where chemo's allowed. The primary completion date for that study for them is end of this year. That means that's roughly a, call it 15-month timeline. They say they're going to launch, not file, launch in 2026. Obviously very quick timelines. That total study is 600 patients for the whole study with a radiographic PFS being the primary endpoint. For us, we at ORIC with 944, we're still obviously figuring out where we would plan to develop this in a phase three setting. We like that post-abiraterone setting. If we did our own study in that post-abiraterone setting, we would start first half next year. The NDA filing would be by the end of 2027, and that would be for a 2028 launch. That would also be a 600-patient study. I can tell you for us, for them, that's way overpowered at 600 patients, but we do not mind overpowering it to make sure that the study hits. The point being that 600 patients over the course of 18 months, that's a very quick timeline. It's obviously not that costly a study when you think about for a small biotech, the cost per patient would be roughly about $150,000 per patient. You're talking about a study that is approximately a $100 million study that you can run in 18 months and leads to a $3 billion global opportunity. The ROI math pencils out quite nicely. Yeah. I'm trying to think about how Pfizer's prior abiraterone requirement may impact eligibility. I know that drug is still used a lot in hormone-sensitive and mCRPC, but now there are three other options. Is your base case that an FDA label would specify prior Abby, or do you think there's an ability to broaden that to any prior novel AR inhibitor? It's a great question. Ultimately, Brad, I think the answer is we don't know. It's a little too early, too premature at this point to know exactly how those regulatory discussions will play out. I think from a conservative point of view, what we're thinking of is that potentially a second phase three study we might run might be a post-ARPI study where you actually broaden the aperture to your point to say not only post-Abby, but we'll also take a patient who could have had a prior APA, darolutamide, or enzalutamide. You basically open up a study where, you know, any of the prior, any of the four ARPIs, a patient could have had any one of them, and then you take them onto the study to kind of enable the label that you're talking about, which would also obviously be a multi-billion dollar opportunity. It would give you a chance to hoover up any patient who's post-ARPI from a commercial perspective. Don't know if the. We may have finally lost him. Yeah, sorry, let's keep going, I guess. Go to the next question. Yeah, we'll see if you can get back on it. I think the other interesting regulatory question that I have is given that APA and DARO are your combination partners are not technically approved in the metastatic CRPC setting. How does this influence how you think about the control arm of your pivotal study in that setting? Because obviously Pfizer will use enzalutamide, which is approved currently for that pivotal study. That's a great, great question, Brad. I think big picture is, as you know, neither apalutamide or darolutamide have a label in a metastatic CRPC setting. We have actually had conversations with an advisory board, top KOLs in the prostate cancer space. The feedback we received is we probably would not need that third arm, that contributional component arm, whether it's apalutamide or darolutamide as part of the study. Obviously, it would be part of the discussions we'd have at the FDA level when we're ready to start that study. Our base case assumption is that we would not need that arm because there's just an abundance of data that kind of shows, you know, the AR inhibitors are generally speaking interchangeable from an efficacy standpoint. Okay, very helpful. Maybe last for me, you know, you're getting APA and DARO from supply agreements that are ongoing with J&J and Bayer. Do these agreements enable them to actively review the data? If so, at what frequency? Yeah, these are pretty standard agreements. There's no economic hooks. There's no control or anything like that. We obviously retain full rights to the program from a control perspective and from an economic standpoint. These are just general stuff. Generally, these agreements, there's, you know, there's an early look at data before you disclose it. That's pretty typical. I would just assume that is kind of the base case. There's no right of first refusal or anything like that going forward, no other hooks into the deal. Pretty standard supply agreements where they get an early look before data is published. Okay. I think we're at the end of time here. Dominic, thank you for joining us. Jacob, thank you as well. I'm sure he's trying to get back in, but I appreciate him dialing in from Hawaii and joining our conference here. Thank you so much. Thank you everyone for listening in. Thanks a lot, Brad. Appreciate it.