ORIC Pharmaceuticals, Inc. (ORIC) Earnings Call Transcript & Summary

Welcome, everyone, to the JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by my Squad, Priyanka Grover, Malcolm Kuno and [ Raine ]. Our next presenting company is ORIC and presenting on behalf of the company, we have CEO, Jacob Chacko. Jacob?

Thank you, Anupam. So it's my pleasure to talk to you today about ORIC Pharmaceuticals. I'll start out by the usual disclaimers that with some forward-looking statements. You can read more about this in our SEC filings. So starting on Slide 3, ORIC stands for overcoming resistance in cancer. That in a nutshell is the mission of the company. We're primarily focused on small molecule drug development in prostate cancer and lung cancer. We have 2 agents for us that are our lead molecules. One is a brain penetrant drug for 3 different populations within lung cancer in 3 different populations that don't currently have either an approved or a late-stage agent that is able to have that brain penetrance. I'll talk to you in more detail later in the presentation about why that's so important. The second program is a PRC2 inhibitor that we're developing in metastatic castration-resistant prostate cancer in combination with multiple AR inhibitors. Those 2 programs have finished Phase I single-agent dose escalation are now in various monotherapy and combination studies with the goal that by the end of this year and early -- or early next year to have both of those programs into pivotal studies. We've built the pipeline in a unique way, and that's the combination of internal drug development. We have our own internal discovery and research capabilities. But we pair that up with targeted business development with a goal of ultimately having 1 IND candidate every 18 months. We've brought together an experienced management team that's worked together for years at a number of companies that have been named brands within the oncology space. So we've seen it and done it before. And finally, the company has got a very strong cash position with a long runway, which obviously these days is quite important. You can see in the anticipated milestones that the next 18 months are going to be busy, busy, busy for us. So we've got 7 different data milestones coming out in the next 18 months on those 2 lead programs. And that's obviously in anticipation of the pivotal program starting for both of those programs, like I said, in the second half of this year for ORIC-114 and in early 2026 for ORIC-944. On Slide 4, just a brief background on the team that we've brought together. As I mentioned, at ORIC, one of the things that's unique about the way that we've built the company is that we have both the internal discovery research capabilities to generate our own compounds in-house. Those tend to be targets that are novel targets, first-in-class targets, first-in-class opportunities, where our team has a novel biological insight but we pair that up with strategic in-licensing. And that would be in instances where we find a target where it's a validated target that another company might have a more advanced approach or a better approach than what we've come up with internally. And so we're quite open to in-licensing compounds as well. So that's been a unique aspect of the way that we've built the pipeline. We then hand that off to our clinical development regulatory team that has largely hailed from Ignyta and Aragon, which are companies that are known for their development of both lung and prostate cancer therapies. And then finally, recently, we brought on our first commercial and medical affairs capabilities as well. The pipeline, as I mentioned, is really headlined by the 2 programs, ORIC-114 in lung cancer and ORIC-944 in prostate cancer. ORIC-114 is going after 3 different targeted therapy populations within lung cancer. So namely EGFR exon 20, HER2 exon 20 and then atypical mutations in EGFR. Those 3 areas are areas that have really been underserved thus far. So amongst the -- in those areas, there is not an approved agent that has CNS activity. And the leading agents, as I mentioned, have not shown compelling CNS activity either. So we're developing this compound because it's quite potent to the order of single-digit nanomolar and low double-digit nanomolar across the variety of mutations in those 3 different populations. As I mentioned, we've completed single-agent dose escalation and now are in the expansion phase of the drug development there in a variety of monotherapy and combination indications. ORIC-944 is our prostate cancer program. As I mentioned, that's in development in combination with 2 different AR inhibitors, namely apalutamide from J&J and darolutamide from Bayer. As you can see in the clinical collaborations column, we obviously, given the combination nature of some of these therapies have struck collaborations with Johnson & Johnson and Bayer as well that have helped us with the development of those programs. We do have, as I mentioned, early discovery research programs and those capabilities internally. I won't have time to talk about those programs today, but we continue to work on novel first-in-class targets within both lung and prostate. So 2024 was a busy year. We did a lot accomplished a lot as you look at both 114 and 944. In both cases, we finished the single agent dose esalation experiences. We picked provisional RP2Ds in the case of 114 and then in the case of 114 advanced into multiple expansion cohorts, which we're enrolling right now. The goal of those expansion cohorts is obviously to make go/no-go decisions for that program later this year such that we can be in accelerated single-arm accelerated approval trials by the second half of this year. For ORIC-944, the ultimate therapeutic potential there is in prostate cancer in combination with an AR inhibitor. In 2024, we finished our single-agent dose escalation experience. We proved the good drug properties of that compound. And then have advanced that into combination drug development, which I'll talk more about shortly. We also raised money. That's the name of the game these days. We put $125 million more on the balance sheet last year, extended our cash runway. Such that we have a very strong balance sheet that enables us to advance these programs into the pivotal studies that I talked to you about. And then we also expanded our leadership team, namely in the areas of commercial and medical affairs given the later-stage development of the company. So I'm going to start by spending a little bit of time on our brain-penetrant lung program, ORIC-114, which as I mentioned, is being developed in 3 different populations within lung cancer. So as you look at the limitations of the compounds that have been either approved or in late-stage development in these 3 targeted therapy populations, they all have essentially 2 major limitations. One, being the lack of CNS activity. And the second being tolerability issues on the safety side. So on CNS activity, it like any other targeted therapy target within lung cancer, you see a high prevalence of patients who had initial presentation have CNS metastases. The important thing is even for the patients that don't have CNS metastases at initial presentation, many, many patients, in fact, the majority of patients eventually progress in the brain. And so this is why it has become dogma now within the lung space to have drugs that are brain pentrant in order to be able to treat and prevent those CNS metastases. Tolerability is a second major limitation of the drugs that have been developed for these particular targets. And that comes in 2 different flavors. So one is in the case of EGFR exon 20 compounds you often have too high of activity against EGFR wild type, which leads to either tax in the form of GI talks like diarrhea or skin talks like rash. Now we and the other next-gen inhibitors in this space have done a nice job of limiting the amount of EGFR wild-type toxicity that is seen in the patients that we've treated. But the ongoing tolerability issue for the other drugs in the space that is not an issue with ORIC-944 is off-target toxicity. So as you look at the kinome trees, you will see what are known as dirty kinome trees. So essentially hitting targets that are off-target toxicities that lead to things like QTC prolongation, anemia, liver enzyme elevations. So in other words, toxicities that you also don't want to see aside from the EGFR wild-type toxicity. With ORIC-114, we think that we've addressed these limitations. And at least in the early Phase I dose escalation data that we've presented thus far, we've already shown compelling systemic activity and intracranial activity in both EGFR exon 20 and HER2 exon 20. We've also demonstrated that CNS activity with confirmed CNS -- confirmed CNS complete response and then, again, a well-tolerated safety profile. As I mentioned, we're busy on the 114 side. So we are currently enrolling 3 different cohorts in the second-line setting for those 3 populations. We are also in the process of initiating 3 cohorts for the first-line setting for those 3 indications. With a specific focus on EGFR a typical, EGFR exon 20 monotherapy and then actually a recently announced combination with subcutaneous amivantamab from Johnson & Johnson. So for this program alone, we expect 6 data readouts between now and middle of 2026. Those data readouts are the 3 second-line cohorts and the 3 first-line cohorts that I mentioned here on this page. So why does CNS activity matter? This has been a playbook that you've seen come time and time again, whether it's [ ALK ], [ ROS ], classical EGFR mutations. You see that the best-in-class therapy in each of those areas is a CNS-active compound. The reason is because about 35% of patients at initial presentation have CNS metastases. As you get to later and later lines of therapy, that percentage grows to up to 50% or more of patients at initial presentation, having CNS metastases. The really interesting thing though is if you talk to clinicians and try to understand the importance of a brain penetrating compound. It's not just the 35% of patients that initial presentation have seen us metastases. There is also a large chunk of patients who have metastases present, but are not visible on imaging. So those are known as micro metastases. So they're there. You just don't realize they're there. And then there's finally a third group that may be legitimately does not have seen us metastases at presentation either visible or micro metastases a presentation, but will eventually develop CNS metastases if they're treated with a drug that is not brain penetrant. Where this manifests itself is in the PFS. So for example, by analogy, if you look at the ALK space alectinib, which is, by far, the largest ALK inhibitor today that's prescribed to patients obviously, very successful in terms of what it's been able to do for patients. Alectinib's ORR is not dramatically different than the first or the second approved ALK inhibitor. What's dramatically different is it's PFS. And the reason is when you look at the for these agents that are not brain-penetrant. You end up getting what you see here, which is an example that was shown by Takeda with mobocertinib, which was developed in EGFR exon 20. So one of the populations that is relevant to ORIC-944 where you see these dramatic differences in the PFS for patients with versus without brain metastases. So it's in the ability of a brain-penetrant compound to close that gap in between the patients with versus without brain metastases that you end up in the aggregate getting much longer durations with drugs that are brain penetrant. So that's why we think that 114 is so critical in these 3 populations of interest. Now why did these 3 populations of interest matter? One of the things that we -- the pendulum within small cap biotech tends to swing either hot or cold on targeted therapies. And lately, it feels like people tend to paint the target therapy area with a broad brush that the populations are "too small. As we look at the 3 target populations for ORIC-944, as I mentioned, EGFR exon 20, HER2 exon 20 and atypical EGFR mutations. Each of those -- each of them are between 2% to 3% of non-small cell lung cancer. You add up any 2 of those populations, and that's larger than non-small cell lung cancer. Obviously, long-term durability is going to be a key factor in the equation of what the long-term addressable market is in this space. But this is just to show you that from a commercial perspective, a relevance to patient's perspective, any one of these populations is actually larger than [ Ross ], larger than RET. And as I said, you put a couple of them together and you're looking at a population that's larger than oleclumab. So this is why it matters to patients and why we care so deeply about the development of this program. So Slide 11 shows you a schematic of the overall clinical development program for ORIC-114. In short, in summary, we've completed the left-hand side of this slide, which is the Phase I dose escalation. We're currently in the middle part of this slide, which is the dose expansion. We've chosen 2 different doses for provisional RP2D, so 80 milligrams daily and 120 milligrams daily to put those doses in context for you in the single-agent dose escalation experience. The first RECIST confirmed response we saw was at 40 milligrams daily. So the 2 RP2D going forward are 80 and 120 milligrams daily, which speaks to the wide therapeutic index of the compound and the good tolerability that we've seen thus far. The goal here is to continue enrolling those 2 different doses for each of the 3 cohorts for the next couple of quarters. And then by the middle to second half of this year to have picked a selected go-forward dose for each of those 3 cohorts. It doesn't have to be the same dose for each cohort, get that blessed by FDA. And then depending on the strength of the efficacy signal that we see in each of the 3 cohorts make go/no-go decisions for those. And from there, it would be the standard targeted therapy playbook, which is really starting second half this year, enroll single-agent accelerated [ ARM ] cohorts that would enable NDA filings for accelerated approval in the filings themselves taking place in the second half of 2027. We, in parallel, in a somewhat staggered fashion, would start first-line studies as well. And again, it all comes down to the strength of the signal of efficacy that we see later this year. So just as a reminder of what we've shown thus far, this is a highly synthesized summary of -- what we saw on the far right with ORIC-114 in the dose escalation experience. You can see that -- we've enrolled a dramatically different population as part of the dose escalation experience and the drugs that have come before. So 86% of these patients had a prior exon 20 therapy inhibitor -- I'm sorry, 81% had a prior exon 20 inhibitor. 86% had CNS metastases at baseline that obviously dwarfs the percentages of those patients that you've seen enrolled by our competitor compounds where really you can count on one hand, the number of patients that had enrolled with the prior exon 20 inhibitor. And in general, you see about 30% to 35% of the patients had prior CNS metastases at baseline. So obviously, a much, much harder population. And even in that much harder population, we saw multiple examples of systemic activity, multiple examples of CNS activity. And in particular, as you see on Slide 14, this is within EGFR exon 20. This is a vignette that really captures the importance of ORIC-114. So this is a patient that's 55-year-old female with EGFR exon 20 mutated non-small cell lung cancer. It was treated with chemotherapy, progressed on chemotherapy, -- she then went on to amivantamab, which is the only agent that is now approved for EGFR exon 20 non-small cell lung cancer did quite well on amivantamab for almost a year but then progressed in exactly the place that you think a patient would progress on a non-brain finishment compound, which is in the brain with 4 small lesions in the brain. She would not have qualified for any other trial in the space because you had already had a prior exon 20 inhibitor. And those patients are disallowed from those trials. A second double whammy for her was that because where brain metastases had not been treated with surgery or radiation already. She also would not have qualified for any other trial in the space. So 2 different exclusion criterias that meant that her only option was to come on to the ORIC-114 trial. And with this patient, we saw a complete response in the lungs and a complete response in the brain. And at the time of the last data update was -- she was ongoing for 9 months with the worst AE being a great to mucositis and paranoia. So this is, again, a 1 patient vignette, but really encapsulates exactly why we think that this drug is so important for its development in the lung space. Now just yesterday, we announced a collaboration with J&J, which hopefully shows that it's not just us, the things that this drug is important for development in the space. Johnson & Johnson, as I mentioned, has the only approved EGFR exon 20 inhibitor, which is amivantamab. Amivantamab is not brain penetrant. And as many of you know, Johnson & Johnson has been exploring amivantamab in combination with lazertinib in 2 different populations. One is the Mariposa studies in classical editor mutations. And then they're also studying amivantamab plus lazertinib in atypical mutations. Now lazertinib does not have potent EGFR exon 20 therapy activity. And so that's why Johnson & Johnson and ORIC decided to strike this collaboration where we're going to look at the combination of subcutaneous amivantamab with ORIC-114, specifically in EGFR exon 20. The therapeutic rationale is well understood, which is with 114 being brain penetrant, with amivantamab, able to cover the resistance mutations like MET and C797S and then with 2 exon 20 directed therapies able to get just broader and deeper coverage of the variety of exon 20 mutations. We think that this is worth studying in the clinic to see whether those 2 agents are combinable. This would obviously be really interesting if we see that they are, in fact, combinable because that would give us an interesting frontline strategy, one that in contrast to essentially the 2 traditional frontline strategies today within EGFR exon 20, which is either monotherapy or combinations with chemo. -- this would afford us the opportunity to have actually a chemo-free combination where you pair exon ORIC-114 with amivantamab. So on that last collaboration, I should have mentioned, we intend to initiate this combination trial in the first quarter this year with initial data in middle of 2026. I mentioned to you that we also had compelling activity in HER2 exon 20 at our last data update. Again, multiple different doses. We saw both systemic activity and intracranial activity. And then Slide 17 summarizes for you a pretty robust clinical development plan, again, in both the second line and the first line in these 3 different populations. Ultimately, what this road map leads to, if all goes well, is accelerated approval filings in the second half of 2027 for the second line, hopefully, one or more second-line populations and then full approval first-line NDA filings in 2028. So obviously, quite accelerated time lines, which is the case in this particular area within oncology. So I'm going to transition now to ORIC-944, which is our allosteric inhibitor of PRC2. And one of the first things we often hear from investors starting on Slide 19 is that they're not familiar with PRC2 and we always assure them they certainly are. They just know it by a different name. And so PRC2 is a complex that has 3 different subunits. The complex is probably best known because there's an approved agent for it or the part of the complex that's best known is EZH2. So EZH2 is the catalytic subunit of PRC2. There's a drug called tazemetostat that was developed by Epizyme. That's now in the hands of Ipsen, which was developed in the epithelia sarcoma and follicular lymphoma, which is an EZH2 inhibitor. Now the broader space of PRC2, whether that's EZH2 inhibitors or another subunit, EED inhibitors have been limited by a number of different things. namely drug properties. So what you tend to see in this space with these PRC2 inhibitors is poor in vitro potency, poor in vivo potency, you also have tended to see a numerous drugs with short half-life on the order of 2 hours, you've seen properties like SIP auto induction, where the drug literally induces the SIP enzymes which then metabolize the drug so you get lower exposures, the higher you dose the drug. In other words, it's just sort of a litany of things that you don't want to see in the drug properties. And so this has really limited the development of PRC2 inhibitors, whether that's in prostate cancer or other indications. With ORIC-944, we have a compound that we think has done quite nicely in terms of selectively targeting PRC2, again, through that EED subunit. It's very potent when you look at in vitro studies very potent when you look at in vivo activity. Importantly, we've already shown in the clinic as a single agent that it has excellent drug properties. So a 20-hour clinical half-life, no SIP auto induction. So essentially has just really seems to have solved some of the bad drug properties of prior compounds in PRC. This compound, as I mentioned, is being developed in combination with an AR inhibitor darolutamide from Bayer and also in combination with an AR inhibitor apalutamide from Johnson & Johnson. We just yesterday put out some preliminary combination data from that, that I'll review with you today. The goal here is to continue dose-finding work in combination with both of those AR inhibitors such that by early 2026, we can start our own Phase III pivotal program or programs for ORIC-944 in combo with one of those AR inhibitors. The target itself has been tremendously de-risked in prostate cancer by data that has been shared by Pfizer with a very similar compound in the exact same indication. And so that's why we have high confidence in the development of ORIC-944. Now as I mentioned to you, the PRC2 complex, as you can see here on Slide 20, as 3 different subunits. Most of the drugs in development thus far have targeted the catalytic subunit known as EZH2 there's been us and a few others that have targeted via allosteric inhibition going after the EED subunit, there is no difference in which of those subunits you target in terms of initial ability to inhibit the PRC2 complex. And we've looked at that through a variety of different elegant analyses, including RNA-Seq, that shows an R-square value of 0.9 when you look at the gene signatures of the genes that are activated by either EZH2 versus EED. As I mentioned, the real issue in this space has just been poor drug properties. And that's played both the EZH2 inhibitors as well as the EED inhibitors. Now why does this matter in prostate cancer? Slide 21 is a highly, highly simplified schematic for some very complex biology. But at a high level, what is happening is folks are well familiar with 3 different AR inhibitors, enzalutamide, apalutamide and darolutamide, which collectively do about $11 billion of revenue in the prostate space. Those drugs have done phenomenally well for patients. Patients have excellent clinical outcomes on those 3 drugs. But as people know, eventually, patients become resistant to those drugs. What ends up happening is that the drug is that the tumors evolve and they become AR-independent so that it no longer matters that you're using an AR inhibitor to treat the tumors. And so PRC2, what is thought is that by putting a PRC2 inhibitor in combo with an AR inhibitor, you're essentially able to push the tumor by virtue of the impact of PRC2 on a variety of different genes you're able to push the tumor back into an AR-dependent state. And so that's why it's thought that there would be synergy in combining a PRC2 inhibitor with an AR inhibitor. Now that synergy has been tested in the clinic by some prior compounds. It's failed in the clinic. And frankly, the reason for those failures, we believe, is because of the poor drug properties of those compounds. So as you look at compound from Constellation on the left side of the page here on Slide 22. Also tazemetostat, which I mentioned is approved in 2 different heme indications but it was also studied in prostate. Both of those compounds were studied in prostate in combo with AR inhibitors both of those compounds, as you can see from this schematic here, have poor cellular potency, have poor in vivo activity, have even worse drug properties in the form of, like I said, 2-hour half-life and SIP auto induction Literally, as I mentioned, in the case of one of those drugs, they've Epizyme put out data that showed with tazemetostat that as they dosed higher, they got lower exposure. And so that's obviously a suboptimal clinical experiment. Now Pfizer has a compound that they've been talking a lot about for the last 1.5 years. It's called mebrometostat. It's an EZH2 inhibitor, which, like I said, seems to have improved upon a number of the different drug properties of the first-gen compound. So with mebrometostat you have a compound that is highly potent that has good in vivo activity that has a lack of SIP auto induction. So seems to be better on that front, has a somewhat improved half-life that we estimate to be about 4 to 5 hours. So a number of different respects, has improved on the first-gen PRC2 compounds. The profile you see on the far right is for ORIC-944, which is every bit as potent on cellular potency and in vivo activity as Pfizer's compound, but in addition, has a lack of SIP auto induction has a 20-hour clinical half-life as opposed to the 4-, 5-hour clinical half-life for Pfizer's compound has less interpatient variability in the Pfizer's compound, so namely on a number of different metrics, looks as good or better than Pfizer's compound. Now the reason I'm talking so much about Pfizer's compound is because Pfizer has had put out at least in the Phase I data set, the most convincing clinical data set that shows the real promise of combining a PRC2 inhibitor with an AR inhibitor, where in 2 different prostate populations, they were able to demonstrate a PFS that was anywhere from 3.5 to 4x as long as the PFS you would expect from enzalutamide alone in that population. Preclinically, we have done experiments that seem to replicate those clinical results. As you look here on Slide 23, you can see that in this treatment refractory model, darolutamide, which does fantastically clinically, but this is a treatment refractory model. Darolutamide looks a lot like the vehicle. In the case of the orange line, which is meprometostat plus that's Pfizer's compound plus darolutamide, you can see a much longer PFS in these animal models. And then obviously, as you might expect from the better drug properties, I alluded to earlier for ORIC-944, you see even better results with the ORIC-944. And so we moved this compound in single-agent dose escalation, which we completed in the middle of last year. really the purpose of that single-agent dose escalation was to establish the better drug properties of ORIC-944. As I mentioned to you, and as you see summarized on Slide 25, with ORIC-944, you see a 20-hour clinical half-life. There is no SIP auto induction. We get very low interpatient variability. So in other words, we really check the boxes on a number of different drug properties that we wanted to see out of ORIC-944 as a single agent. We also identified 600 milligrams daily as the optimal go-forward dose, at least based on the single agent experience. And that was what we then took forward in the combination dosing, which began in the middle of 2024. Slide 26 is some new data we shared just yesterday, which was the culmination of the single-agent dosing experience with ORIC-944. As I mentioned to you, this shows you that the vast majority of AEs were Grade 1, Grade 2 AEs and really what we see is on-target PRC2 related side effects, which is namely heme tox, GI tox and some fatigue. And so I mentioned we took forward 600 milligrams daily into our combination dosing. That started in the middle of 2024. You can see here a trial schematic on Slide 27. There are 3 phenomenal AR inhibitors. Pfizer owns one of them enzalutamide, and that's what they're combining with their EZH2 inhibitor mebrometostat the other 2 phenomenal AR inhibitors are darolutamide from Bayer and apalutamide from Johnson & Johnson. And so last year, we struck collaborations with both Bayer and Johnson & Johnson. For them to give us free drug and a lot of -- a heck of a lot of input into our trial designs. They obviously see the strategic rationale here of combining an AR inhibitor with a PRC2 inhibitor given what Pfizer has already shown -- we're now doing our dose finding work in those 2 different combinations. We're actually looking at 2 different populations within the prostate space. So one is a population that's already had prior abiraterone as part of their treatment history. And then a second population, which is any prior AR inhibitor. So even in patients who've already progressed on either enzalutamide, apalutamide or darolutamide. The goal is that we will continue the dose-finding work. We anticipate that sometime in Q2 this year, we'll have our selected provisional RP2D for those combinations with apalutamide and darolutamide. We'll then spend the rest of this year enrolling more patients at those 2 provisional RP2Ds to satisfy FDA project Optimus requirements such that by the end of this year, we would have selected on go-forward RP2D. We'd also have selected on go-forward AR combo inhibitor for our combinations. And then by early 2026, have started our own Phase III program for this. Now given how much our competitor has been talking about their program, we've been getting a lot of questions about when folks can see PFS data from our ORIC-944 combinations with these AR inhibitors. We try to tell people to be patient. These combination dosing started in middle of 2024. So we're only about 2 quarters in and so long story short, we're not going to have mature PFS data of our own until probably later this year at the earliest. Otherwise, it will be first half next year, just given the long PFS that you expect to see here. Now in lieu of that, what we've tried to do here on Slide 28 is give people at least a little indication of what seems like encouraging clinical activity right out of the gates for ORIC-944 in combination with apalutamide. So, by the middle of December, we had completed the first 2 dosing cohorts of ORIC-944 at 600 milligrams and at 800 milligrams in combination with apalutamide. What you see here is best percentage change in PSA response, which as folks know, is a proxy that people use in the prostate space to try to assess early clinical activity. And as you can see here, of those 6 patients across those 2 different dosing cohorts, 3 patients achieved a PSA 50. In fact, 2 of those were PSA 90s. Now a couple of caveats. First, right off the bat. One is we continue to believe here that the right regulatory endpoint is radiographic PFS. That's the regulatory endpoint for every prostate cancer drug that's been approved. And we continue to believe that that's the regulatory endpoint for us as well in the long term. But in terms of looking at just early clinical activity, this is obviously highly encouraging, seeing these kind of PSA responses, all of these patients I urge you to look at the prior therapies at the bottom of the page, all of them have had prior abiraterone and progressed. 4 of the 6 patients had prior chemotherapy, obviously, a number of other investigational and improved therapies as well that these patients had seen. And so in light of that, seen this depth and breadth of PSA responses is quite encouraging. Now the caveats are, obviously, this is NFV. We'll see if this holds up in larger patient samples. And again, like I said, RPFS is ultimately the regulatory endpoint the question you should be asking yourself is what would apalutamide alone be able to do in this setting. And this is well documented across hundreds of patients for patients that have already progressed on abiraterone. If you give them apalutamide, you would expect that approximately 1 in every 20 of those patients would have a PSA 90 response. And then you'd expect 1 in every 5 of those patients would have a PSA 50 response. So obviously, small end, but we're already seeing quite encouraging activity in this combination. Now the darolutamide cohort, we have completed one cohort with darolutamide. We're enrolling the second cohort right now. But as you see there on the page on the bottom of Slide 28 with thus far, the preliminary clinical activity in the darolutamide combination is consistent with what you're seeing here with ORIC-944 and apalutamide. So we're encouraged, and we'll continue to develop this program. We'll continue to look at the dose finding over the next few months. and then stay tuned for the next data update for this program in fourth quarter of this year or first half next year. So with that, I think you probably have heard a lot on these 2 different programs. There's a lot of clinical activity going on. A lot of data readouts coming out in the next 18 months, 7 different data readouts in the next 18 months. the company is well funded with a long cash runway, but we're quite excited about these 2 different programs. Anupam, let me open it up for questions.

Yes. Thanks, Jacob. We have a few minutes for questions. [Operator Instructions] I just want to start on one question of my own, which is on the Phase Ib PSA response data that you shared just a few minutes ago. It's probably just a function of small numbers, and I know you're still dose escalating, but it did look like there's a little bit of an inverse dose response, like anything to comment there? Or is it just a lot of small?

Small numbers.

Got it. Okay. The question from the audience. So the portal question is -- where will the -- this is related to ORIC-114, where will the clinical trial results in the second line treatment for second line be treated at AACR or ASCO?

We have not historically specified where we plan to do it. I think the most visibility we can get right now is it will take place in the first half of this year. .

And then given amivantamab itself has shown some toxicities. What are the expectations regarding safety when you're using combination considering the safety profile observed in prior ORIC-114 studies?

Yes. So that's the whole point of doing the investigational work of 114 with amivantamab. You're not going to know whether it's tolerable to combine 2 different EGFR directed EGFR exon 20 therapies until you try that out in the clinic. Obviously, Johnson & Johnson showed with their combo with amivantamab and lazertinib in the Mariposa trials in classical EGFR mutations. And separately, amivantamab combined with lazertinib and atypical mutations. That they can achieve a tolerable profile. And so we hope that the same is true here, but we won't know until we test that in the clinic. And if for some reason, it looks like there's too much toxicity for the 2 in combination. Then obviously, we can default to 1 of the 2 traditional pads, which is either our first-line strategy being a monotherapy of 114 versus chemo or a combination with chemo versus chemo, which is exactly what all the other programs in the space have done.