Okay, great. Thanks, everyone, for continuing to join us here at Guggenheim's second annual Healthcare Innovation Conference. My name is Brad Canino, Senior Analyst here. Excuse me. Happy to do the next fireside with Oric Pharmaceuticals. We've got Dominic Piscitelli, CFO, Matt Panuwat, Chief Business Officer. Correct? Yes. Thanks so much for joining us. Dominic, if you want to kick off, please, and provide an overview of your Oric and what the development priorities are today. Sure. Thanks for having us here at the conference, Brad. It's a pleasure. Oric Pharmaceuticals 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, our key three areas of focus are prostate cancer, lung cancer, and breast cancer. We've got two clinical programs. The first one is ORIC-944. This is an allosteric PRC2 inhibitor that we're studying in prostate cancer. We're doing this in combination with both apalutamide, which is J&J's drug, and daralutamide, which is Bayer's drug. We do have a clinical supply agreement for both of those that's ongoing. Our second program, ORIC-114, is a selective brain penetrant EGFR HER2 exon 20 program that we're studying in three distinct patient populations, non-small cell lung cancer populations, EGFR exon 20, HER2 exon 20, and EGFR atypicals. That is moving along. That will potentially be in two phase III study next year, assuming all goes well with the studies. We are well capitalized. We ended Q2 with $436 million in cash and investments on a pro forma basis. That gives us cash runway into the second half of 2028. That does assume full success for both programs, and that assumes we are starting phase III programs for 114 in the second half of next year and 944 in the first half of next year. Okay. Let's dive into 944 a little bit. Can you just describe the underlying post-ARPI tumor biology where you're first bringing this mechanism and the mechanisms of PRC2 inhibition that supports having a clinical benefit for that population that has relapsed on an ARPI? Yeah, I'll start, and Matt, feel free to chime in. At a high level, when you look at the AR inhibitors, you know, enzalutamide, apalutamide, daralutamide, they provide a tremendous benefit for patients across the board, across the treatment landscape. Over time, they do gain resistance. Basically what's happening is the tumors are transitioning from an AR-dependent state to an AR-independent state, whereby making these AR inhibitors less efficacious. With these epigenetic modifiers like ORIC-944, like mevrometostat from Pfizer, what's basically happening, you're kind of pushing them back from an independent state to a dependent state, allowing the AR inhibitor to kind of resensitize them or synergize them and making the AR inhibitors work again. Obviously, we've seen some of this data from some competitors like Pfizer out there as well. Now, for this class, how de-risked do you consider PRC2 inhibition at this stage for prostate cancer? Because we've seen a bunch of data generated to date across a number of different programs now. Yeah, that's a great question, Brad. They've been studying PRC2 inhibition in prostate cancer for 10-15 years. I think the underlying issue was that the first generation PRC2 inhibitors were really plagued with poor drug properties, you know, poor in vivo activity, poor in vitro activity, short half-life. Some of these had CYP autoinduction issues. There was never really any great data. I think what happened was in, I think it was May of 2023, Pfizer kind of put out some really compelling data, a single-arm study, but in two distinct patient populations where they really saw a tripling of the PFS benefit that you'd expect to see with enzalutamide alone. They had, you know, these are in the post-ABI patient population, it was N of 12. They showed a radiographic PFS of 17 months. You'd expect to see something like five months with enzalutamide alone in that patient population. In the post-ENZA patient population, they showed a radiographic PFS about 12 months, where you'd expect to see something like three months with ENZA alone. That was really somewhat de-risking. More recently, at ASCO GU early this year, Pfizer presented randomized data. This is an 80-patient study, 40 patients in each arm. What they showed was in the treatment arm, they had a radiographic PFS of 14.3 months, and the control was six, so more than doubling of the radiographic PFS benefit. They also saw a doubling of the PSA benefit as well. PSA 50 was 34% in the combo versus about 17% in the control arm. That's kind of significantly de-risking the asset overall, I think, and kind of validating the mechanism, as well as kind of showing that with this mechanism, you do see PSA response does translate into PFS benefit. How would you describe the physician feedback, particularly the clinical investigators that are involved with your phase I and II trials for PRC2 inhibition to the ASCO GU data, the randomized data that Pfizer presented? Yeah, Dominic. Yeah, I would say at least from our perspective, the feedback has been very positive. I think it was a very nice study that Pfizer did. It is a randomized control study. Phase II, you do not see that a lot in prostate cancer. A lot of times, for most cases, companies go straight from phase I, single-arm data, and just straight into phase III. I think it was good to see that. I think it was a very, you know, nice study design. The control arm did exactly what you would expect it to do. Enzalutamide was the control arm after abiraterone, six-month PFS. That is kind of in the range of just other studies. I think overall, all good. I guess the question would be, you know, how do you compare that data set to what is out there? I think in our view, that is, I think, the best data set in patients that have already failed an ARPI. The only other somewhat comparable study would be PSMA4 by Novartis with Pluvicto. In that study, they saw a radiographic PFS of 9.7 months was the primary endpoint there. Again, compared to Pfizer with an oral therapy on top of standard of care of 14.3 months, it is pretty promising for the class. At least from our view, you know, the feedback we've received is just that that is a very promising profile for a new class of agents in prostate cancer. Yeah, and then just to add to that, I think Matt's right. I think there's definitely a shift. I think when Pfizer initially put out the single-arm data, the pushback was always, well, single-arm data, it's small ends. With the randomized data set, I think there's a lot of opinions that have changed, a lot of KOLs that we've spoken to were really waiting to see that. I think post that ASCO GU update, I think there's a lot of believers in the data and the mechanism. Yep. For your program, what have you demonstrated in phase I for the 944 ARPI combos relative to the Pfizer data? Yeah, a couple of things. I'll start by, you know, we put out initial data last year as single agents. We really wanted to make sure our molecule had really nice safety, tolerability, PK/PD, because as Dominic said, the first generation just didn't have those. They weren't optimized for prostate cancer. We really wanted to demonstrate we have a good molecule. We did accomplish that and then moved into the combination studies, which is where really the promise lies both on preclinical data and the clinical data we've seen. Earlier this year in May, we had an update of our phase I study. We're doing a combination study with apalutamide and daralutamide, kind of the two other AR inhibitors aside from enzalutamide. With that update, you know, I think we thought it was very promising. It's still dose escalation. It was 17 patients across kind of different doses and different combinations. Even with that small data set, I think we're encouraged. The PSA 50 response rates confirmed are higher than what we've seen from Pfizer, kind of with their optimized regimen. The PSA 90 confirmed responses were much higher than what Pfizer's reported. Also, equally important to us is just the safety and tolerability seems to be very good. Pfizer seems to have, you know, relatively high rates of grade three, grade four AEs, and those were just things that we didn't experience with our profile. We will have another update coming up, you know, this year and next year as well. I think we're, you know, we're very encouraged by the data set we've put out so far. Why do you think it is that 944 is able to demonstrate a differentiated efficacy and safety profile versus Pfizer's? Yeah, I think a couple of things. I'd probably start with, you know, one, our molecule was designed for prostate cancer, was kind of one. And then two, it was prospectively designed to have just really good drug properties, so really good half-life of just all the things you want in a molecule. To pause, just to the Pfizer data, you know, the phase II randomized that we saw was mevrometostat 1250 BID, so two and a half grams per day in combination with enzalutamide. They're dosed high to get exposures that they need for activity, plus there's drug-drug interaction, plus they have to overcome a very short half-life. I think all of those things, you know, are not something we've seen with our molecule. You know, back to our single agent experience, we're seeing a half-life of about 20-24 hours. Easily kind of once daily therapy, I think, is the key. The other thing that Pfizer presented this year is they're actually switching their dosing regimen to go into phase III. They're using a lower dose and with food. In the data that they present, they're seeing a higher AUC, lower Cmax, which they say translates into a safer profile. I think in some ways that profile is essentially what we have with the once daily, you know, oral therapy, a really nice PK profile, lower Cmax, higher AUC. The benefit that we're seeing is just a safer molecule that we can dose well, you know, and have really nice exposures. Okay. The corollary question to this is you move to larger N, do you think you have to be differentiated in order to win in this space? We actually say we don't think we have to win. I think it really comes down to a couple of things. I think, one, just prostate cancer, there's such an unmet need. It is such a significant opportunity in the number of patients that are out there. Two, I think we have the perfect analogs in prostate cancer. It's where you have four relatively undifferentiated ARPIs. You have abiraterone that was approved in 2011. Dominic and I were at Medivation where enzalutamide was approved in 2012. Then apalutamide came several years later, completely undifferentiated from enzalutamide, and then daralutamide after that. All three of those collectively are doing $11 billion in sales last year. That includes abiraterone, which is generic. That's about half of the prescriptions. You can just see from the sheer size of the market opportunity and the fact that many of those drugs are very indistinguishable from an efficacy standpoint, very small safety nuances, but all of them are highly commercially successful. We feel like even if we have a molecule that's about similar to Pfizer, the market opportunity is so substantial. We do have once daily dosing. We have the opportunity to combine with a different AR agent, let alone we might have a safer profile and maybe the efficacy could be better too. We think there's a number of ways that, again, we hope the data will support going forward. Yeah, and if you look at Pfizer started mevrometostat late 2024. We're planning to start our first phase III study, it's called first half of next year. You're talking about 15-18 months behind them, being second to market, even with the undifferentiated profile. You know, if you look at all the comps out there, you're going to gather 30-35% of the market. As Matt said, if you even look at our early data, again, with all the caveats of small N, caveats of cross-study comparison, you know, we do seem to have slightly better PSA responses in the early data, and the safety profile seemed to be much better as well. That does matter on these prostate cancer patients that are on drug for an extended period of time. Yep. Okay. Now you outlined the preliminary data from the phase I. You plan to update that this quarter. Maybe sketch what you plan to present, and should we focus on anything new from this update of the interim data? Yeah, I'll take that one. A great question. The update that we had in the first half of the year was pretty substantial. The update that we have for this quarter will be more incremental in nature. It'll be more of an operational update, basically us kind of closing out the dose exploration portion of the study. At the time we gave the May update, we kind of said we had selected the doses for the dose optimization for the daralutamide combination, and we said we want to explore maybe one or two more doses for the apalutamide combination. This update will be around 20 patients' worth of data. This will include the 17 patients of data that we've showed you in May, and it will include, you know, the standard stuff that we showed you in May. It'll be PSA responses, safety, tolerability. The new thing that we'll probably throw in now is CT DNA data. There's been a lot of publications around the importance of CT DNA data and the correlation with CT DNA clearance and durability, whether it's PFS and OS benefit as well. It is really kind of an operational update, kind of setting up the update for Q1 of next year, which is probably a more meaningful update. Yeah, so let's roll into that then. What is going to be the focus of that first Q1 update for the dose optimization? Yeah, so the reason that is probably more relevant is that we'll be at the provisional RP2Ds from the dose optimization that we've selected. So what we've committed to, it'll be around 20-25 patients' worth of data from one of the combinations. So it'll either be the combo with apalutamide or the combination with daralutamide. Obviously, you'll have again the standard PSA 50, PSA 90, safety, tolerability. The thing we'll show there will be kind of the early look on durability. Now, this will not be mature PFS data that you can cross-compare to Pfizer. This will be early look. So think of a landmark analysis at, you know, three months or four months and kind of see how the patients are tracking. Kind of a more meaningful update because it's at a more relevant dose and obviously one of the AR inhibitors that we're most likely to move forward with. Got it. Okay. What will determine which of the ARPIs, apalutamide or daralutamide, you move forward with into phase III? How do you think that decision is going to be communicated to investors? Yeah, I think at a high level, you know, everything we've seen to date, both preclinically and clinically, you know, we've said that we've seen safety, tolerability, and the PSA response has been consistent across AR inhibitor. From that perspective, we're kind of agnostic on which AR inhibitor to go with. They each have their, you know, maybe their pros. You know, daralutamide, you don't have this CYP interaction that you do with either apalutamide or with enzalutamide. Daralutamide is twice a day with food. Apalutamide is once a day without food. You have the, you know, it's consistent with 944. Generally, they've each got their pros and cons, but generally speaking, we feel comfortable we can go with either one of those compounds into phase III. It'll come down to obviously just some strategic considerations as well as the overall data set to see if one of those have made an edge over the other, basically. The communication strategy, are you able to speak more about that? Yeah, we haven't said that yet. We typically kind of provide further guidance in January of every year for the next, call it 12 to 18 months. Stay tuned. Maybe we'll provide some more at some point first half of next year. Okay. What else might be gating to starting the phase III in the first half, like your kind of preliminary guiding to? Yeah, no, that's a great question and a question we get quite often. You know, the things that could potentially be gating is financing. Now, as you know, we did raise mid this year, raised $125 million in a pipe and did an ATM drawdown for about $118 million. With that, we are well capitalized to fund this study. Financing is not a consideration. People have asked us if waiting for the Pfizer phase III data readout is a gating factor, and the answer is no. As far as we're concerned, we're full speed ahead unless there's a surprise in the data set that, you know, we share in first quarter of next year. Okay. How do you plan to catch up to Pfizer, which I believe now has started four phase III trials or has announced plans for four? I think they've officially started three. So far as for their dosing in three, so we do know that. I think there's some people have mentioned there could be a fourth coming soon. Yeah. So then the question around how do you catch up to a pharma that's already blanketing a landscape like that? Yeah, I think at a high level, you know, the first study they started was October 2024, where again, we're going to start, we're planning to start our first phase III study in the first half of next year. Call it 18 months or so behind them. Again, even being second to market with a same profile puts us in a great position and assume we have better safety or efficacy, that's obviously in a great position as well. We feel like we're well suited. That study, you know, is about 600 patients. You know, we could have potential data called the second half, mid to the second half of 2027 as well. We're not too far behind them, and I think we're in a great position. Now they are moving forward into earlier lines of therapy. We're also exploring other patient populations. We are enrolling patients that are post AR inhibitor. We'll potentially at some point determine whether that makes sense for us to pursue that patient population or other patient populations as well. Their third study, MERPRO-III, is actually in the CSPC setting. We like that study a lot, and the reason for that is a huge patient population and it's a long durability as well. That study is pretty big, and that study does take a long time. It is hard for us to do as a small biotech based on the current cost of capital. It may make sense at some point to consider some strategic partnership around that. Now, given if we're trading at a different, you know, stock price where cost of capital is less, is there a possibility we could do that ourselves potentially? It also may make sense to kind of blow this program out into earlier lines with a strategic partner. Yep. Yeah, I think the key point that Dom mentioned is just we're not that far behind. If we're in a position to start our phase III next year, we could get to a launch about 18 months behind Pfizer, which is actually not bad in the grand scheme of things. One of the ways that we did catch up is we're not planning to do a phase II randomized study, you know, so that in some ways we're able to shave years off the development plan just by simply, you know, having the program already de-risked by the data they've presented so far. Yep. Okay. I apologize for this question because it's somewhat of an FDA crystal ball question. What population for that first study in the post-ABI population, what do you think the indicated population for that would be on a label? Would it be agnostic to prior ARPI or specific for ABI? I think that's a good question. We are guessing somewhat, and we haven't seen that label. We haven't seen that trial design yet. It is somewhat of a black box. I guess from my personal view, I would expect that the label would be reflective of the actual phase III design. I think the label would be in post abiraterone patients. Again, it is a similar class, a similar somewhat modality of abiraterone versus the AR inhibitors, but it is different. The target is SIP17 as opposed to an AR inhibitor. There are differences there. We have seen clinical data is a little bit different. I would think that the label that the FDA would grant them would be, you know, specifically in patients that have failed abiraterone, which at least based on script data we can see today is about half of the second-gen ARPI use. Yeah, and that has been pretty consistent over the last several years. Yep. Okay. And then just a broader question on prostate, given there's a lot of development with other mechanisms there, how do you expect the PRC2 inhibitors to slot into the evolving treatment paradigm for prostate? Sure, I'll take that one as well. I think the landscape is extremely wide open. You know, Dominic and I have been in the space for, you know, 10 to 15 years now back when we were at Medivation. Once you fail a second generation AR inhibitor, essentially you go into chemotherapy. That has been the case for the last 10 years. You do have Pluvicto now. That's kind of the latest entrant that is, I think, still trying to figure out where exactly that slots in. Other than that, I think it's a pretty dramatic space of there's a lot of pockets to kind of go after. I think if the phase III mevrometostat data is reflective of the phase II data with an oral therapy that is kind of managing some moderate level GI effects, I think that stands out pretty good compared to chemotherapy, which would be one and having it all oral. You do not have all of the limitations that Pluvicto has with the nuclear medicine and PSMA positive and things like that. We think, you know, having something, a new mechanism that's oral, that's on top of standard of care, we would think that that fits in, you know, relatively early in the treatment landscape. I think that's kind of reflective of Pfizer's phase III trial design where they're kind of repeating their phase II data in the post abiraterone setting and then essentially moving forward, you know, earlier lines from there. Okay. Maybe we'll spend a few minutes on the EGFR program 114 as well. You've got a lot of data, kind of phase I, II stage from this program coming from Q4 updates to mid 2026 updates. Can you outline what to expect from those? I think more importantly too, how do you think about the hurdle rates for what those data need to show to also advance the second program into later stage development? Yeah, so we do have an update later part of this year. We'll have be at ESMO Asia. The data we'll be presenting at ESMO Asia will be more in the second line or later setting. We have made a strategic decision to focus kind of in the first line setting. Maybe I'll just cover what we expect to show at ESMO Asia. At that update, we'll have three patient populations, EGFR exon 20, HER2 exon 20, and EGFR atypical. In that second line plus setting, we'll have around 20-25 patients in each of those three cohorts. It will be across the two provisional RP2Ds of 80 and 120. You know, decent update there as well. The benchmarks there, I'd say in EGFR exon 20 and atypicals in the second line plus is probably, you know, call it, I don't know, 35% or so. In the HER2 exon 20, it is probably higher than that, it's probably 50%. We'll also share some early first line EGFR exon 20 data as well. In the first line setting, we're saying that benchmark is at 55% or better in that first line EGFR exon 20. Jumping to mid 2026, we'll have EGFR atypical first line data. There we're saying the benchmark's probably 55% as well. The combo with Amivantamab in EGFR exon 20, we're saying that that benchmark is 65% as well. We'll see a lot of data from ourselves, obviously and competitors in the next six to nine months so we can do the apples to apples comparison. I do encourage people to make sure you're not comparing second line or third line data with first line data when you're looking at this data. Again, we'll have a lot of update and then again, a lot of competitor update in the next six to nine months. Of that suite of opportunities, how focused are you on the Amivantamab combo and what is the rationale for that combination development? Yeah, I might want to take it. Yeah, I would say we're obviously excited by that combination as well. It gives us another kind of area to explore. That is a combination that others are not doing in the EGFR exon 20 space. We are doing that in collaboration with J&J, who has the approved Amivantamab in the space. So we are very excited by it. I think the easiest way to just, the clinical proof of concept is what they have done in the classical EGFR setting. So Amivantamab is approved with Lazertinib, very outstanding data. I think they believe that's going to be a blockbuster in the space that they're going after. Lazertinib is an EGFR inhibitor. So it's basically combining Amivantamab, which is a bispecific antibody combined with a small molecule TKI. Lazertinib is brain penetrant, so it adds a lot of value there to the Amivantamab regimen. Lazertinib is not active in EGFR exon 20. That's not something they're pursuing. It's essentially the same rationale. Instead of Lazertinib for exon 20, it's using ORIC-114 in combination with Amivantamab. I think the real question is just the dual inhibition of EGFR. Can you manage, you know, safety profile? I think we're interested in that. If it's tolerable, you know, you can believe that you can get really extended PFS and OS out of it. Yeah. Okay. Unfortunately, we're out of time. Dominic, Matt, thank you so much for joining us. And thanks everyone for listening in. Thank you.