Good day, and thank you for standing by. Welcome to the ORIC-944 program update call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you'll need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your host today, Dominic Piscitelli, Chief Financial Officer. Please go ahead.
Good afternoon, and welcome to the ORIC Pharmaceuticals ORIC-944 program update conference call. My name is Dominic Piscitelli, CFO. Earlier today, we issued a press release highlighting updated data from our ongoing phase I-B study of ORIC-944 in combination with apalutamide and with darolutamide in patients with metastatic CRPC. You may find the press release posted on the investor page of oricpharma.com. We have pre-recorded our prepared remarks, after which we will host a live Q&A session. Before we begin, starting on slide two, during this conference call, we will be making forward-looking statements, including forward-looking statements based on our current expectations and projections about future events and trends that may affect our business, utilizing data available to us as of May 28, 2025. ORIC's actual results may differ materially from those expressed in or indicated by such forward-looking statements.
For a description of risk factors associated with investing in ORIC, please refer to our recent filings with the SEC. ORIC specifically disclaims any obligation to update any forward-looking statements except as required by law. This presentation contains interim results based on the data from ORIC-944 clinical trials as of the cutoff date set forth on the applicable slide. During this presentation, we will not be speaking to any additional data subsequent to such date. Now, turning to slide three, during today's call, we'll discuss the preclinical rationale, phase I-B clinical data, and next steps. Finally, the prostate cancer market opportunity and potential expansion opportunities for the program, followed by Q&A. Joining me on the call today, we have Jacob Chacko, CEO, Lori Friedman, CSO, Pratik Multani, CMO, and Matt Panuwat, CBO. Now, let me turn over the call to Jacob.
Thank you, Dominic. Turning to slide four, at ORIC Pharmaceuticals, our clinical pipeline is focused on the advancement of two potentially best-in-class programs, both of which have multiple data readouts expected in 2025 and the first half of 2026, and are on a path to initiation of phase III registrational trials in 2026. The subject of today's presentation will be the first substantial readout of combination data for ORIC-944, a potential best-in-class PRC2 inhibitor, which is being studied in metastatic castration-resistant prostate cancer in combination with two different androgen receptor inhibitors, apalutamide and darolutamide. Turning to slide five, there is compelling biological rationale for combining a PRC2 inhibitor with an androgen receptor inhibitor to delay or overcome resistance that results in prostate cancers becoming AR-independent.
Unfortunately, the first-generation PRC2 inhibitor suffered from numerous limitations related to inferior potency, drug properties, and tolerability, and so were unable to demonstrate a meaningful treatment effect. ORIC-944 was rationally designed with a goal of addressing each of these limitations. Having completed single-agent dosing last year, we then initiated combination dose exploration with the support of our partners at Johnson & Johnson and Bayer to explore the activity and safety of ORIC-944 in combination with each of their AR inhibitors. Turning to slide six, the purpose of today's update is to provide an initial data set that establishes a safety and activity profile of ORIC-944 at multiple doses and with each of our combination partners that is comparable to or better than that of our competitors, with a particular eye towards another next-generation PRC2 inhibitor that has recently demonstrated meaningful clinical outcomes substantiating this therapeutic combination.
In the second half of this year, we look forward to providing additional data to support our selected Project Optimus doses, and by the end of this year or early next year, we intend to provide dose optimization data that establishes the safety, activity, and most importantly, durability underlying our selection of a final dose for ORIC-944 with our AR inhibitor of choice to take into our initial phase III trial in metastatic CRPC, which is slated to initiate in the first half of next year. Turning to slide seven, I previously referenced a competitor next-generation PRC2 inhibitor that is being developed by Pfizer in multiple phase III studies. In a randomized control trial, that PRC2 inhibitor in combination with an AR inhibitor demonstrated substantially better PSA activity and ultimately median radiographic PFS in comparison to enzalutamide monotherapy.
As we will discuss in more detail later in this presentation, our initial experience with ORIC-944 in combination with either apalutamide or with darolutamide has yielded strong results with a safety profile and activity as measured by PSA50 and PSA90 response rates that compare quite favorably to the mevrometastat plus enzalutamide combination data. With that, let me now hand the call over to Lori to provide an overview of the preclinical rationale underlying PRC2 inhibition before Pratik walks us through the early clinical combination data. Lori?
Thanks, Jacob. It's my pleasure to talk about PRC2 and our excitement for developing ORIC-944 in prostate cancer. Turning to slide nine, I'll take a deep dive into the function of PRC2. As shown in the diagram on the left, the PRC2 complex functions as a transcriptional repressor by modifying histones to regulate gene expression. ORIC-944 is an allosteric inhibitor of EED and blocks the function of the entire PRC2 complex. PRC2 is dysregulated in several cancers, with data implicating its role in cell fate and differentiation. In patients with prostate cancer, the expression of PRC2 target genes is associated with poor prognosis. Recent randomized clinical data in metastatic castration-resistant prostate cancer demonstrated a significant progression-free survival improvement for the combination of a PRC2 inhibitor with an AR inhibitor versus standard of care.
Now, turning to slide 10, with this strong biology behind it, PRC2 has been a target of interest for many years. However, the first-generation inhibitors, such as CPI-1205 and tazemetastat, had multiple shortcomings, as shown in the left half of the table. Mevrometastat, a second-generation inhibitor, addressed some of these issues, including cell potency and CYP autoinduction, yet falls short in other drug properties such as solubility and half-life. ORIC-944 shows improved drug properties in all categories, thus has potential as a best-in-class PRC2 inhibitor that addresses all the limitations of earlier-generation inhibitors. On slide 11 are two examples of preclinical in vitro data demonstrating the superior potency of ORIC-944 to first-generation PRC2 inhibitors. In these dose-ranging studies, AR-positive prostate cancer cell lines were treated head-to-head with four different drugs and assayed for effects on cell growth and viability.
The cell potency for the first-generation inhibitors, shown in black and dark blue curves, is right-shifted due to their weaker potency. ORIC-944 demonstrates comparable potency to mevrometastat in prostate cancer cell lines, and ORIC-944 is superior to the first-generation inhibitors. The graphic on slide 12 summarizes how therapeutically targeting PRC2 reverses the natural evolution of prostate cancer. As prostate cancers are treated with hormone blockade or with AR-targeted therapies, they evolve to evade these therapies. Going from left to right, the graphic shows prostate tumors progressing from castration-sensitive to insensitive and from AR-dependent to AR-independent. Epigenetic reprogramming is the mechanism by which prostate cancer cells transition to change their cell state, evolving away from a differentiated cell state in primary prostate tissue.
PRC2 inhibition can delay or reverse this process so that prostate cancer cells regain the luminal cell state that reflects the tissue of origin and thus regain their AR dependency. This mechanistic rationale supports the combination of PRC2 inhibitors with AR inhibitors and suggests that the therapeutic potential of ORIC-944 in prostate cancer will be maximized in combination with AR inhibition. On slide 13 is an example of preclinical data supporting this mechanism of ORIC-944 sensitizing prostate cancers to AR inhibition. In the experiment shown on the left, prostate cancer xenografts were treated with either ORIC-944 or the vehicle control, and tumors were then assessed for transcriptional changes using RNA sequencing. Two consistent changes were observed: a significant increase in AR signaling and a significant increase in luminal cell state markers. These transcriptional shifts result in the prostate tumors having an increased dependency on the androgen receptor.
To confirm this mechanism of ORIC-944 treatment restoring a cell state that has enhanced sensitivity to AR inhibition, we assessed synergy for this combination, as shown on the right. Prostate cancer cells were treated with dose-ranging concentrations of enzalutamide and a PRC2 inhibitor alone and in combination. The impact on cell viability was then analyzed for synergy potential, and the thermometer summarizes the results. A synergy score of 10 or higher denotes strong synergy of two drugs. The combination of enzalutamide with ORIC-944 demonstrated a strong synergy score of 15.8. Head-to-head experiments for the enzalutamide combination with mevrometastat produced a similar result to ORIC-944. Carrying this combination forward into in vivo prostate cancer models, on slide 14 is an example of a study where we treated AR-inhibitor-resistant prostate cancer xenografts with darolutamide with and without PRC2 inhibitors.
The combination of ORIC-944 with darolutamide impressively improved progression-free survival in this castration-resistant prostate cancer setting. Thus, ORIC-944 has been shown to reverse AR inhibitor resistance in prostate cancer to improve PFS, and importantly, with ORIC-944's improved drug properties, it stands out as a best-in-class PRC2 inhibitor. We're excited to assess these AR inhibitor combinations in the clinic, as Pratik will tell you about.
Thank you, Lori. Turning to slide 16, I will now provide a comprehensive update of our ongoing phase I-B trial of ORIC-944 in patients with metastatic castration-resistant prostate cancer, or mCRPC. This first study explored ORIC-944 as a single agent in patients with mCRPC who had progressed after at least one AR inhibitor and had received up to two prior chemotherapy regimens. Through an i3+3 design, we demonstrated the strong pharmaceutical properties of ORIC-944, specifically its long clinical half-life with dose-proportional exposure and no evidence of CYP autoinduction, which supports once-daily administration. We also demonstrated robust target engagement through measurement of H3K27 methylation status in peripheral blood cells. ORIC-944 as a single agent exhibited an overall well-tolerated safety profile, making it highly suitable for drug combinations. Collectively, these properties differentiate ORIC-944 from other PRC2 inhibitors and position it as a potential best-in-class molecule.
Turning to slide 17, you can see the PK curves from the single-agent dose escalation, ranging from 100 mgs up to 900 mgs once daily. You see nice dose proportionality as we went up in dose and can derive the approximately 20-hour half-life, which is compatible with once-daily dosing. Comparing the ORIC-944 PK curves to target efficacy thresholds, you can see that doses as low as 200 mgs achieve concentrations associated with efficacy in preclinical models of prostate cancer, which affords us a broad, potentially efficacious dosing range for ORIC-944 in the clinic. Slide 18 shows the safety profile of single-agent ORIC-944 across our dose escalation experience. ORIC-944 was generally well tolerated at doses up to 900 mgs, well above the efficacious dose projections I described on the previous slide.
The main classes of toxicity expected with a PRC2 inhibitor are hematologic and GI, and the ORIC-944 adverse event profile is consistent with that. Almost all events were grade 1 or 2, and as expected, we did see a few grade 3 hematologic adverse events at the highest dose levels tested. We saw no grade 3 diarrhea and no grade 4 or 5 events. Taking the PK curves from the previous slide and the safety from this slide, we have a wide therapeutic window in which to study ORIC-944 and optimize its performance. In general, doses between 400-800 mgs once daily reach exposures compatible with potential efficacy while still having a favorable safety profile. Slide 19 highlights the key differences in pharmaceutical properties of ORIC-944 compared with other PRC2 inhibitors.
In particular, 944 stands apart even from mevrometastat with its long clinical half-life of approximately 20 hours compared to 4 hours or shorter for other PRC2 inhibitors. Turning to slide 20, with the completion of single-agent dose escalation, we proceeded to dose exploration in combination with apalutamide and with darolutamide. In this ongoing part of the study, patients are eligible if they have received prior treatment with an androgen receptor pathway inhibitor. Patients are also allowed but not required to have up to one prior chemotherapy. We started initially with post-abiraterone patients. More recently, we've just started enrolling post-AR inhibitor patients, that is, patients post enzalutamide, apalutamide, or darolutamide. Today, we'll focus on the post-abiraterone treated patients.
The combination dose exploration is being carried out in two distinct cohorts: one with various doses of ORIC-944 in combination with the standard dose of apalutamide, and the other with various doses of ORIC-944 in combination with the standard dose of darolutamide. Once dose exploration is completed for each of these combinations, two candidate RP2Ds would then be carried forward for each combination to satisfy project optimist requirements. This optimization for each combination would be conducted in the two distinct patient populations I outlined earlier, one with only prior abiraterone exposure and the other with only one prior AR inhibitor exposure. Based on the results of these dose optimization cohorts, we would then select the appropriate combination dose of ORIC-944 for each of the two potential AR inhibitors of interest, apalutamide and darolutamide. We would then carry one of these combinations forward into our first phase III trial.
Turning to slide 21, let me present the initial data we've generated. We have compiled safety and initial efficacy data from 17 patients with mCRPC after prior abiraterone treatment enrolled into our dose exploration of ORIC-944 with either apalutamide or darolutamide. On this slide, we have the baseline characteristics of the 17 patients. Of note, these patients had a median of three prior lines of therapy, excluding ADT therapy, which is not counted in this median. Since these patients are all post-abiraterone, which accounts for one prior line, you can see that patients had also received a variety of other approved and investigational prostate cancer therapies, including immunotherapy in 41% and chemotherapy in 29%. Slide 22 depicts a waterfall plot of the best percent change in PSA from baseline in these 17 patients as of a data cutoff of May 9th.
The bars represent individual patients and are color-coded by ORIC-944 dose, 400, 600, or 800 mgs once daily. Overall, there was a 59% rate of PSA50 response. Nearly all patients with a PSA50 were confirmed one month later for a confirmed PSA50 rate of 47%, which does not include one additional PSA response pending confirmation. There was also a 24% rate of PSA90 response, all of which confirmed one month later. Of note, PSA responses were observed across all ORIC-944 dose levels and were also observed at comparable rates with both apalutamide and with darolutamide. The majority of these patients are still ongoing with multiple approaching one year or beyond.
Further dose exploration remains ongoing in both combination cohorts, but even with this preliminary look at efficacy, there appears to be a strong clinical effect with doses of ORIC-944 as low as 400 mgs once daily, confirming the broad therapeutic window we had expected from our single-agent work. With that in mind, let's turn to slide 23, which depicts the safety profile of the 17 patients who received combination therapy with either apalutamide or darolutamide. Here we have the treatment emergent adverse events attributed to either ORIC-944 or the AR inhibitor that were seen in 15% or more of patients. You can see that almost all events are grade 1 or 2 in severity. In fact, most were grade 1 and consist largely of mild GI-related toxicity with very little grade 3 toxicity and no related grade 4 or 5 events.
Diarrhea was the most common treatment-related event occurring in 53% of patients across all dose levels, with only one instance that was grade 3. Coupled with the PSA efficacy data on the previous slide, these safety data show that we have a wide therapeutic window as we continue dose exploration to identify the optimal doses of ORIC-944 for each of our combinations with an AR inhibitor. Turning to slide 24, you can see our PSA50 and PSA90 response rates, as well as our safety profile to date for the combination of ORIC-944 with either apalutamide or darolutamide, alongside the same reported outcomes from the mevrometastat randomized data, both for the combination arm with enzalutamide as well as the single-agent enzalutamide control arm.
Although all patients on this slide are post-abiraterone, as I described earlier, the ORIC-944 patient population had a median of two additional prior therapies, while for the mevrometastat population, the only additional prior therapy was chemotherapy in about 45% of patients. With that said, you can see that single-agent enzalutamide gives you the expected low PSA50 rate with just single-digit PSA90. When combined with mevrometastat, this rate approximately doubles, which translated into a more than doubling of the radiographic progression-free survival from 6.2 months to 14.3 months. Although our data are too early to report on PFS, the PSA response rates we've seen so far, both PSA50 and PSA90, with the combination of ORIC-944 with AR inhibitor, compares favorably with the mevrometastat combination data.
Looking at safety, you can see that enzalutamide alone has a modest but measurable rate of adverse events, with fatigue in about half of patients and nausea, anemia, diarrhea, and decreased appetite occurring in approximately 20%-25% of patients, all grade 1 or 2. With the addition of mevrometastat, these adverse events increase in rate and severity, with now almost 80% experiencing diarrhea, grade 3 in 18%. Similarly, decreased appetite and fatigue, along with dysgeusia, now occur in almost 60% of patients. Anemia is seen in about half of patients, and we don't know the mevrometastat adverse events that occur at rates below 30% since they were not disclosed. The combination of ORIC-944 with an AR inhibitor does lead to the expected adverse event of diarrhea, but in about half of patients, of which 6% have reported grade 3.
Fatigue and nausea come in at about 35%-40%, and other AEs are below 30% incidence, so we can't make a comparison to the mevrometastat data, but we haven't seen comparable rates of anemia and certainly no alopecia. Overall, we feel we are in a strong position with these initial ORIC-944 combination data, both in terms of early measures of efficacy through PSA50 and PSA90 rates and with a safety profile compatible with long-term dosing and a convenient once-daily regimen. These data position ORIC-944 as a potential best-in-class PRC2 inhibitor that could benefit a broad range of patients with prostate cancer. Finally, on slide 25, we've outlined our next steps to phase III. First and foremost is completion of dose exploration with both apalutamide and with darolutamide to identify the candidate RP2Ds for each combination. We expect to complete this in the first half of this year.
Following that, in the second half of this year, we would proceed to dose optimization to identify the final RP2D for each combination. We would then also determine which combination we take forward into our first phase III trial. Finally, in the first half of 2026, we expect to finalize the phase III trial's design, get the necessary input from multiple regulatory authorities, and initiate our first global phase III study. Now I'll turn it over to Matt to provide an overview of the commercial opportunity for ORIC-944 in various settings of prostate cancer in which we may choose to focus our future phase III development plans. Matt.
Thank you, Pratik. As a quick reminder, starting with slide 27, ARPIs have become the foundational class of therapy in prostate cancer and are widely used across the treatment continuum.
Although initially approved for patients with metastatic castration-resistant prostate cancer, ARPIs have gained multiple approvals and are recommended by NCCN guidelines for use in earlier lines of therapy in disease states, including in non-metastatic and hormone-sensitive disease. This therapeutic class has transformed the standard of care across the spectrum of prostate cancer. The widespread use of ARPIs represents a significant commercial opportunity for PRC2 inhibitors, given the potential to reverse or delay resistance to ARPIs and further improve outcomes for patients with prostate cancer. Turning to slide 28, widespread usage of ARPIs has created a substantial therapeutic class that could become even larger through extended durability enabled by combinations with PRC2 inhibitors. Last year, worldwide sales of AR inhibitors reached approximately $11 billion.
While Xtandi was first approved in 2012 and is the market-leading AR inhibitor, the subsequent Erleada launch in 2018 and Nubeqa launch in 2019 have helped expand the ARPI market, with each product easily reaching blockbuster status. Even with the success of these three blockbuster therapies totaling $11 billion in annual sales, this only accounts for approximately half of the global prostate cancer market for ARPIs, since branded and generic abiraterone still represents approximately 50% of the market by patient share, further illustrating the commercial potential for therapies like PRC2 inhibitors that can easily combine with ARPIs to extend their durability. Turning to slide 29, beyond the opportunity to combine PRC2 inhibitors wherever AR inhibitors are used de novo, PRC2 inhibitors can also be combined with AR inhibitors to enable more meaningful clinical outcomes from the already common practice of ARPI switching.
Unfortunately, for patients who progress on ARPIs, there are limited therapeutic options that provide good efficacy with tolerability that physicians and patients find acceptable. As a result, ARPIs are frequently sequenced one after another despite limited clinical benefit. U.S. real-world data shows that ARPI use has grown to about 70% in metastatic castration-sensitive disease, and about half of that ARPI use is abiraterone, and the other half is comprised of the three branded AR inhibitors. Upon progression to metastatic castration-resistant disease, up to 50% of these ARPI-treated patients will receive a different sequential ARPI rather than other therapeutic interventions like chemotherapy. This ARPI sequencing decision is often driven by factors like patient tolerability, treatment access, and a preference for convenient and well-tolerated oral regimens, despite the suboptimal efficacy, which ranges from between three to six months of radiographic PFS.
If PRC2 inhibitors enable ARPI switching to achieve extended durability, this already common practice could become even more widespread. Finally, on slide 30, this is a summary of the U.S. prostate cancer market landscape, detailing the various treatable patient populations and current approved therapy efficacy parameters across disease states. In metastatic CRPC, we estimate about 37,000 patients will have been treated with either abiraterone or an AR inhibitor, and based on available PRC2 and AR inhibitor combination data to date, we believe this regimen could significantly improve radiographic progression-free survival meaningfully from three-six months to 12-14 months, and this is where we initially intend to develop and commercialize ORIC-944. This ARPI-treated mCRPC patient population alone represents an addressable market opportunity of over $7 billion in the U.S. annually.
Given ORIC-944's synergy with AR inhibitors, we may have the opportunity to target ARPI naive mCRPC or earlier disease stages that have even larger patient populations, with the potential of establishing a new all-oral, well-tolerated PRC2 inhibitor combination standard of care regimen and improved patient outcomes across the disease landscape. Now let me turn it over to Lori to discuss potential expansion opportunities for the development of ORIC-944.
Thank you, Matt. We have shown mechanistic data in castration-resistant prostate cancer models that epigenetic changes drive invasion from AR-directed therapeutics, and this resistance can be reversed with a PRC2 inhibitor combination. As highlighted on slide 32, it is notable that additional research has shown that lineage change occurs in a spectrum of different cancers, opening the potential for ORIC-944 in additional indications and combinations.
Recent studies have demonstrated that there's a shared reliance on the PRC2 mechanism in cancer evolution, which stimulated interest to explore the combination of PRC2 inhibitors with oncogene-directed therapies across prostate, breast, lung, and colon cancers. We've now begun experiments to investigate these indications for their future potential, and I'll share a few highlights with you today. First, on slide 33, we assessed castration-sensitive prostate cancer to confirm that ORIC-944 had the same mechanism and synergy that we'd previously seen in the castration-resistant setting. Importantly, we found that ORIC-944 effects in castration-sensitive cells were comparable to the studies in castration-resistant prostate cancer cells. On the left, ORIC-944 increases AR signaling and luminal markers in castration-sensitive prostate cancer cells to then produce synergy when combined with an AR inhibitor.
On the right, the strong synergistic effect on cell growth was observed for enzalutamide combined with either ORIC-944 or mevrometastat in these castration-sensitive prostate cancer cell models. We then proceeded to in vivo assessment, shown on slide 34. This castration-sensitive prostate cancer model responds to the AR inhibitor, darolutamide, but importantly, the ORIC-944 combination prolongs progression-free survival in these CSPC xenografts, providing proof of concept in supportive development in earlier prostate cancer settings. On slide 35, we expanded the prostate cancer combination synergy into hormone-positive breast cancer, which has parallel biology to AR-positive prostate cancer, with hormone signaling being a key tumor dependency in both cancers. In ER-positive breast cancer, antagonist or degraders such as fulvestrant are standard of care and are efficacious. The addition of ORIC-944 to fulvestrant improves the progression-free survival in ER-positive breast cancer xenografts, supporting development in this indication.
Finally, on slide 36, recent literature published in the journal Cancer Discovery noted the role of PRC2 lineage change in colorectal cancer, driving combination benefit for PRC2 inhibition with KRAS inhibition. We assessed this possibility for ORIC-944 in KRAS G12C mutant xenografts in both colon cancer and lung cancer models and found that ORIC-944 drives tumor regressions when combined with the KRAS G12C inhibitor at aggressive, supporting development in these indications. Thus, there are multiple potential indications supported by strong preclinical results. Jacob will now summarize expansion opportunities and next steps.
Thank you, Lori. Turning to slide 38, we have outlined the next steps for ORIC-944 beyond its initial development in metastatic CRPC. Building on these data, we intend to evaluate earlier stages of the disease, including in the ARPI naive setting and the castration-sensitive setting.
There is also the potential to study ORIC-944 in combination after prior AR inhibitor therapy, which, as you saw, represents a substantial opportunity. Based upon our analysis and additional preclinical data, we intend to design and launch a second phase III trial in one of these prostate cancer indications. As you heard from Lori, the potential for the biology of PRC2 inhibition and for ORIC-944 in particular extends into multiple other common solid tumor types, such as breast, non-small cell lung, and colorectal cancer. Therefore, alongside our prostate cancer phase III program, we intend to design and initiate proof of concept clinical development in one or more of these additional solid tumor indications to fully demonstrate the potential of ORIC-944 in cancer. We'll wrap up our prepared remarks on slide 39.
We continue to be excited about the development prospects for both our clinical programs, with numerous upcoming data readouts that should set the stage for the initiation of phase III registrational trials in 2026. Within prostate cancer, we believe the initial combination data presented today helped build a strong case for the potential best-in-class profile of ORIC-944 in combination with apalutamide and with darolutamide. Concurrent with the data readout today, we also announced the successful completion of a $125 million pipe financing by healthcare specialist investors, which has extended our cash runway into the second half of 2027 and, importantly, beyond the projected mid-2027 data readout from our first phase III metastatic CRPC study. Before we begin Q&A, I'd like to thank our investigators, as well as the entire ORIC team who worked diligently to tackle our mission on behalf of patients.
Most importantly, I want to thank our patients and their families, whom we hope to help overcome resistance in cancer. With that, let's open it up for Q&A.
As a reminder, if you'd like to ask a question at this time, please press star one, one on your telephone and wait for your name to be announced. To withdraw your question, please press star one, one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Maury Raycroft with Jefferies.
Hi, congrats on the data update, and thanks for taking my questions. I'm wondering if we can talk more about how these patients in your study compared to Pfizer's mevrometastat phase II population. It looks like you have fewer chemo or docetaxel treated patients in your study at 29% versus Pfizer's 45%.
Wondering if you saw a higher PSA response in the chemo naive patients or if you could talk more about that.
Pardon me, you may still be on mute.
Can you hear me, or?
Yeah, we can hear you, Maury. Can you hear us?
No, we can't hear you. I can hear you now.
Hey, can you hear us now?
Yeah. Yeah, I can hear you now. Yeah.
Okay. Sorry, don't know what happened there. I'm not sure which parts you caught, Maury. This is Jacob. Again, thanks for your questions. Pratik, our CMO, is going to restart answering your questions since apparently we cut out. Go ahead, Pratik.
Sure. I'll answer your two questions sequentially. In terms of the overall comparison of the patient populations, based on the information that Pfizer disclosed at ASCO GU, the patients in our study were more heavily pretreated.
The mevrometastat study required prior abiraterone, as do we. They also required or they also permitted up to one prior chemotherapy, as do we. The mevrometastat study did not allow any other prior treatments, whereas we did. We had a median of three prior therapies in our patients. Many of our patients on top of prior AbbVie and possibly chemotherapy also got immunotherapy, PARP inhibitors, and other agents. You can see that in the baseline characteristics slide in the presentation. Pfizer did not disclose the median number of prior therapies for their population, but you can basically calculate it from their inclusion and exclusion criteria. They all had prior AbbVie, and 45% of patients had prior chemo. Technically, actually, their median prior therapies is one.
In terms of the chemotherapy, yeah, we had 29% of our patients have prior chemotherapy in this cut versus Pfizer's 44%. If we look at the PSA50 response rates in the chemo pretreated and the chemo naive patients in our data set, they were identical. We do not see prior chemo as having an impact on the ability to achieve a clinical effect in our study.
Got it. Okay. That's helpful. Maybe another question just for the four PSA90 patients. What does deepening from PSA50 to PSA90 look like? Do you anticipate that a proportion of the PSA50 patients will convert to PSA90, or is this a relatively mature snapshot of PSA responses?
For the PSA50s and the PSA90s, the PSA50s certainly could evolve over time. We have many patients still on trial.
The majority of our patients are still on study. I can't comment on sort of the pace or the frequency of 50s going to 90s. It could still evolve, certainly.
Got it. Okay. Thanks for taking my questions. I'll hop back in the queue.
Thanks, Maury.
Our next question comes from Anupam Rama with JP Morgan.
Hey, guys. Thanks so much for taking the question, and congrats on the data. Just two quick ones from me. Look, I know it's super early right now, but any qualitative commentary on durability here or how we should think about durability? Second question, have you or do you plan on looking at any other correlative responses like resist responses or ctDNA? Thanks so much, guys.
Thanks, Anupam. Pratik will take those as well.
Okay. We're still in combination dose exploration.
As Jacob said at the front of the call, our objectives with this disclosure were to give an initial read on combination safety and clinical activity across multiple doses and with both apalutamide and darolutamide. I think we were able to achieve that today. Given that we're in a dose exploration data set, we have cohorts of patients on apalutamide and darolutamide with widely different start dates. We have some cohorts where patients have been on study, as I said, close to a year or more, and other cohorts that are very fresh with much less follow-up. Here's what I can say about durability at this point. Nearly every observed PSA50 response that we saw was confirmed one month later, and every PSA90 response that we've seen was confirmed one month later.
This is in contrast with what Pfizer's recent data set showed, where they had a drop-off from 54% to 34% on PSA50s from unconfirmed to confirmed, and 17% to 12% on PSA90s unconfirmed to confirmed from their mevrometastat data set. The majority of our patients, as I said a little while ago, are still on drug. We have a patient with a PSA90 out past a year and multiple patients approaching a year or greater. That is what I can give you right now. For a more detailed read on durability, we are going to use our dose optimization data set. Here, we will have a good robust set of patients at just two dose levels. The expectation is that we will have a readout on durability as well as safety and such in the fourth quarter of this year, first quarter of next year.
Your second question was correlative measures like RECIST or ctDNA. Most patients with advanced prostate cancer have bone-only disease, and most of the soft tissue disease that they have are non-target. The majority of patients with prostate cancer and on our study are not evaluable for RECIST response. For us, we just need to have a larger N to get some of these patients to get any kind of true read on RECIST response rate. We did, though, look at ctDNA and measure it in all our patients. I'm happy to say it's not in the main presentation, but the vast majority of patients had a substantial decrease in ctDNA with complete molecular clearance in many of these patients. This gives us really another read and assurance on our clinical activity. We'll probably share these data in a future update.
Congrats again on the update, guys.
Thanks, Anupam.
Our next question comes from Prakhar Agarwal with Cantor Fitzgerald.
Hi. Thanks for taking my questions and congratulations on the data as well. Maybe firstly, what do you expect will be our RP2D for ORIC-944 with apalutamide and with darolutamide? There seems to be some signs of dose response on PSA50 confirmed, but 800 mg dose also had 80% grade 1-2 diarrhea. Also, could you confirm the rates of cytopenias? Finally, how will you decide which AR inhibitor to combine with for phase III trials? Thank you.
Sure. In terms of the RP2D for the apalutamide and darolutamide combination, first, you have to sort of keep in mind that enzalutamide and apalutamide are both CYP inducers.
They will push down the exposure of mevrometastat in the Pfizer combination with enzalutamide and ORIC-944 for our combination with apalutamide. Darolutamide doesn't have this CYP induction effect, so you wouldn't expect a drug-drug interaction. We have to take into account these potential interactions or lack thereof when we think about the appropriate dose for darolutamide and apalutamide. In terms of what we think the RP2D will be for, say, first darolutamide, most certainly, I think we're going to be optimizing 400 of ORIC-944 versus 600. As you saw from the single agent part of the presentation, we see great target coverage at 200 mgs, as low as 200 mgs. We have great safety at 400. We're seeing clinical activity. So 4 and 6 with darolutamide seems like the path forward for us.
We'll then suss out which is the one we take as the nominated as the RP2D. For apalutamide, we have to go with higher doses to account for the CYP induction. Right now, it's looking like maybe 600 versus 800. The safety with apalutamide looks really good. We are actually looking now at 1,200 mgs of ORIC-944 with apalutamide. That still needs to read out. That could be a contender for one of the dose optimization cohorts. That has yet to be determined. Another question was around cytopenias. You saw we don't see cytopenias at a high rate. Our cutoff for adverse events in this presentation was 15% or higher. You saw that no cytopenias made it on that list. We only had one event of anemia and one event of neutropenia.
It's very low in the population across the dose levels that we've tested. I would contrast that with close to the 50% anemia rate that Pfizer saw in their experience. We're not seeing high rates of cytopenia at all at the dose levels we're looking, despite the fact that we're seeing good clinical activity.
Pratik, I'll take your last question just in terms of how we decide which AR inhibitor we're going to take forward into phase III, or at least the initial phase III study. I mean, obviously, apalutamide and darolutamide are both great drugs. We've been well supported by both of our partners at J & J and Bayer. Those two drugs have done phenomenally well for patients with fantastic efficacy that's really indistinguishable from that of enzalutamide as monotherapies, but clearly safety profiles for both apalutamide and darolutamide that do distinguish from enzalutamide.
We see really compelling efficacy as Pratik walked through with you today and also good safety with both apalutamide and darolutamide in combination with 944. From a clinical perspective, there has been no reason thus far that we would prefer one over the other. As folks know, we are imminently going to kick off dose optimization of 944 with both combination regimens. That will give us additional insight into safety, efficacy, and importantly, durability of each combo regimen in larger numbers of patients at provisional RP2D doses. Again, to reiterate, we have not seen differences in our clinical experience thus far. There is no reason mechanistically why the two drugs would behave differently, the two combo agents would behave differently from one another.
Ultimately, the decision on which AR inhibitor we select for the first phase III study is going to be based on the overall data. Probably just as important, if not more important, it'll be based on a variety of strategic considerations.
Our next question comes from Colleen Kusy with Baird.
Great. Good afternoon. Thanks for taking our questions, and congrats on the data today. Your competitor's combo uses enzalutamide. Your data is obviously in combo with darolutamide or apalutamide. We have some monotherapy data for enzalutamide alone. Are there any good data for apalutamide and darolutamide single agents in this patient population? Just trying to figure out the better PSA responses that you're seeing, whether that could be attributable to the better combination partner.
Sure. Pratik, you can take that, Colleen.
Sure.
All three of these agents, enzalutamide, apalutamide, and darolutamide, have been studied in a bunch of different indications. When you look at an indication where they all have run trials and you line up the outcomes in those studies, PSA response, radiographic PFS, overall survival, the results are nearly identical. There is really no evidence that they would behave any differently from each other in the post-abiraterone mCRPC population. Now, enzalutamide has a label in that indication, so you can look at their phase III study. The other two have done studies in that indication as well. Again, the outcomes are identical. We do not think there is really any meaningful effect coming from sort of a difference in the AR inhibitor we are using.
Great. That is helpful. Thank you. From a higher level, obviously, Pfizer is roughly two years ahead of you. How do you think about how this profile will shake out relative to mevrometastat? Do you think you need to be better than them to be competitive or as good given the delay in timelines?
Yeah. Colleen, thanks for the question. It's Jacob. I can take that. The short answer is we do not think that we need to be better than them. Obviously, you've seen today some hints of why we may, in fact, end up being better than them. Maybe the longer answer, if I could expound on it, would be the perfect analogy, I think, is staring folks in the face, which is if you look at the androgen receptor inhibitors. Obviously, the three big AR inhibitors, as we reviewed today, are enzalutamide, apalutamide, and darolutamide.
As we've said today on the call, and as folks know from empirical experience, those three drugs are indistinguishable in terms of efficacy in all the populations in which the three drugs have been studied. Where there is some slight difference is that while enzalutamide is not a particularly poorly tolerated drug, certainly apalutamide is better tolerated than enzalutamide, and darolutamide is also better tolerated than enzalutamide by patients. There is some slight benefit there for apalutamide and for darolutamide. The reason I give you that background context is, as we reviewed today, enzalutamide does over $6 billion of sales globally each year, still growing double digits, and was approved in 2012. Six years later, apalutamide came to market as the second entrant, and darolutamide even after that as the third entrant. Obviously, both of those drugs are blockbuster drugs many times over, growing significantly.
Point being that in a population as large as prostate cancer, really even the second or third entrants that is fairly indistinguishable from the first still lands itself in blockbuster status. That is why I say that for us, if the base case here is that we end up as good as Pfizer in terms of the combo regimen, both in terms of efficacy and safety, and just keep that timeline gap as short as possible, we feel quite comfortable with that profile being extremely competitive and obviously commercially attractive.
As we touched on today, from an early read on efficacy as measured by the PSA activity, PSA50s, PSA90s, just the overall rate of how much of that PSA activity ends up confirming, and then obviously the safety profile, we think there's several reasons why we may, in fact, end up better with our combination agent, whether that's a combo with apalutamide or darolutamide, may end up better than the mevrometastat combo.
Yep. That's great. Thanks so much for taking our questions, and congrats again.
Thank you.
Our next question comes from Matthew Biegler with Oppenheimer.
Hey, guys. Thanks for the question. Our congrats as well. I wanted to first ask about the GI side effects, nausea, diarrhea, etc. Seems to be on target. I think Pfizer's arguing that with food, the side effects were more manageable.
Have you guys studied food effects, and can you comment on how you stack up so far? I just had a question on broader strategy. I think you mentioned expanding into castration-sensitive. I was just curious how supportive you think these data today are in terms of translating from castration-resistant to castration-sensitive. Thanks.
Thanks, Matt. I'll ask Pratik to take the first one. Lori, our CSO, can take the second one.
Sure. We do not have an appreciable food effect. Pfizer did their food effect study to look whether food improved the safety profile. We are not in a position yet that we need to ask that question of our molecule and our combination. As you saw, these are doses that are clinically active. We are not still at low doses where the safety profile is sort of not informative.
This safety profile is informative because we are seeing PSA response rates. We are seeing low rates of GI tox. If we need to, we would, but we do not right now feel the need to look at a food effect to try to ameliorate safety.
Yeah. Matt, with regard to CSPC, I'll ask Lori to just sort of talk about some of the translatability you asked about in terms of what we're seeing preclinically and clinically in CRPC. Maybe just at a high level from a strategic point of view, we are highly interested in CSPC as an indication. Obviously, Matt talked you through the overall prostate landscape and the fact that any single indication within CRPC that we were to pursue as our initial phase III study is a multi-billion dollar TAM in the U.S. alone. Obviously, CSPC is multiples of that.
With the profile as clean as what we've seen on the safety side of things thus far with our both 944 combo regimens, CSPC is high, high in our list of future additional phase III studies and indications that we'd like to go after. Maybe Lori can comment specifically on just translatability.
Yeah. Thank you for the question. We have extensive preclinical data sets in CRPC and CSPC models. And the mechanism in prostate cancer translates perfectly between that castration-resistant setting and the castration-sensitive prostate cancer models. ORIC-944 enhanced the AR signaling and luminal cell state in both settings, which leads to synergy and improved survival in xenografts in both contexts. Additionally, when you're thinking about different lines of therapy in prostate cancer, in the earlier lines of patients, there's less tumor heterogeneity.
That's a greater proportion of patients who have AR-driven disease that would benefit from ORIC-944 and an AR inhibitor combination.
Thanks again. Appreciate it.
Thank you, Matt.
Our next question comes from Michael Schmidt with Guggenheim.
Oh, hey, guys. Thanks for taking my question. I may have missed it earlier, but just on the PSA response rate, were there any differences between combination with apalutamide or darolutamide? Just curious. I know it seems like some of the dose range for 944 may be different for either one of those. And then just another bigger picture question on your sort of planned registration study and longer-term expansion plans. Is the idea sort of to replicate essentially the ongoing Pfizer phase III trials just with your drug, obviously, and then one of the two AR inhibitors?
Is there perhaps opportunity to do different trials, be different combinations, or perhaps going earlier into the HSPC setting to sort of leapfrog them? Thanks.
Yeah. Thanks, Michael. To answer your questions, no difference that we're seeing really in any aspects of the profile between the apalutamide combination and the darolutamide combination with 944. That applies to safety, but it also applies to the PSA activities, PSA50s, PSA90s, rate of PSA50s, rate of PSA90s, I should say, and the durability that we're seeing between the two. Although obviously, we've had just a longer follow-up with the apalutamide patients who started earlier than the darolutamide patients. In terms of the future development plan, we touched on several areas within CRPC today, but also the broader prostate landscape that we'd be interested in pursuing.
Some may overlap with Pfizer's various phase III studies. I think they've outlined three phase III studies to date, two of which they've started and one which sounds like it may start imminently. We may overlap in some of those, but we also may go our own way in some of those because obviously, the prostate landscape is incredibly large. That very well could be the case that we'll have some overlap, but also some areas that are unto ourselves.
Thank you.
Our next question comes from Yigal Nochomovitz with Citi.
Hi. Congrats on the strong data. I had a question regarding the phase III. Do you need to see PFS, even early signal on PFS, before making a determination with respect to apalutamide versus darolutamide?
You mentioned the first phase III will be one of those partners, but is there a potential for a second phase III that would be the other one, or that's not the intention? Thanks. Yeah.
Thanks, Yigal. Short answer is we do not need to see mature PFS data from the current dose optimization work before starting our first phase III study. We intend to start the first phase III study first half of next year. In fact, we will not have mature PFS data. Obviously, what we will have, as Pratik said, is with dose optimization starting imminently with both combo regimens, both combo partners, we will have a substantial number of patients at provisional RP2Ds that will have been followed up. Certainly, several of them will have been followed up for six-plus months by the end of this year or early next year.
Clearly, we can do landmark analyses based on what % of patients are still ongoing at various points in time, four-plus months, six-plus months, whatever that might be. Those can be via statistics translated into what PFS might look like. Really, the point here, Yigal, is if we were to be as conservative as we possibly could be on a development plan, it also means that we would just be unnecessarily, I think, pushing out the start of the phase III timing. Given the strength of the results that we've seen to date that we presented today, and obviously, the strength of the results we've seen in a randomized setting from Pfizer, we think it behooves us to move as quickly as possible into that first phase III beginning of next year.
In terms of taking one of those combo regimens into the first phase III study, it obviously does not hamstring us from what we would do for future phase III studies. I guess we would just keep an open mind as to which agent we would take into which subsequent studies.
Okay. Obviously, given your comments today, it seems like things are looking, at least from this early data set, very similar between the two. As you pointed out, there are some differences with respect to the DDIs. Assuming everything continues to look essentially equivalent between the two choices, what is going to tip the balance in terms of which one you decide to go forward with first?
Yeah.
I think as I alluded to in one of the earlier questions, Yigal, I think that because we don't see a difference thus far clinically between the two agents, because they're both great agents, and because both J&J and Bayer have thus far been great partners to us in the work thus far, we also because there's not a mechanistic reason to see a difference between the two agents, I think it'll come down to strategic considerations, frankly, as to which of those we take forward into the first phase III study or into subsequent phase III studies. There's a whole host of things that go under the rubric of strategic considerations, which I probably shouldn't enumerate today on the call.
Certainly, even a buy-in on a broader development plan and thinking about unlocking future opportunities like CSPC, those are things that are going to be quite important to us as we think about just what's the right path forward with the right combo agent from the right partner. It is really likely to come down to strategic considerations. As we think about the future development plan, we talked about CSPC today, but obviously, even before getting to something like CSPC, folks know that we have just recently started dosing patients, very recently started dosing patients that are post-AR inhibitor. Obviously, the results today we talked about were in patients that were the 17 patients that were post-abiraterone that we reviewed with you today.
Very recently, as in less than half a dozen patients under our belt in the last couple of months, we've started dosing patients who are being treated after having progressed on an AR inhibitor. Even in that small data set, less than half a dozen patients, there are reasons to believe that we've seen already that the drug and the regimen will work, for example, post-enzalutamide. That obviously generating more data in that particular patient population in the coming months and quarters is going to be quite important as we factor in in terms of what the future phase III development strategies might look like. In addition to post-abiraterone, maybe a post-AR inhibitor or a broader post-ARPI study, any of the above might be on the table.
Right. Got it. Thanks very much.
Our next question comes from Derek Argila with Wells Fargo.
Hi. This is Evon for Derek. Thanks for taking our questions and congrats on the data. A couple from us. First, can you provide a bit more color on what data can we expect in the update later this year and whether it's possible we get any insights, early insights on PFS? The second question is, how are you thinking about financing development beyond CRPC? Is this something you plan doing internally, or are you open to larger collaborations? Does your cash guidance include any proof of concept studies for other tumor types or other prostate cancer patients?
Thanks. Yeah. Dominic, I'll take those.
Yeah. With regards to your first question, the guidance for the second half of this year that we provided earlier this year was to provide about 20-25 patients' worth of data.
Again, that will be from the dose optimization portion of the study. The focus there will be again, I'm sorry, that'll be from the dose escalation portion of the study. The focus there will be obviously focused on PSA and safety. One thing to note here, as you saw today, the original guidance was 10-12 patients. We actually had 12 patients' worth of data. The reason for that is enrollment definitely picked up post the ASCO GU. We may be on the higher end of that guidance for the second half of the year. With regards to the durability there, I think the answer there is the focus there is going to be more on the dose optimization portion of the study, which would be in Q4 of this year or Q1 of next year.
From a cash perspective, taking into account the current financing of $125 million, the pro forma cash balance as of end of March is $349 million. That does extend our cash runway into the second half of 2027. Importantly, that does take us past the anticipated data readout for the first phase III study for ORIC-944. Lastly, your question on what's included in that, that is a fully burdened number. That does assume we're starting a phase III study, obviously, for 944 in the first half of 2026. We're also starting a phase III study for ORIC-114 in 2026. That does assume pretty much all the costs associated with that, including the CMC-related cost.
There's nothing factored in there in terms of future BD activity or strategic collaborations. Obviously, for the sake of conservatism, that's the way we've budgeted that. But also, obviously, we're quite open to considering strategic collaborations at the right time and on the right terms.
Our next question comes from Soumit Roy with Jones Trading.
Afternoon, everyone. And congrats on the data again. If you could just elaborate a tiny bit on the kinetics of the PSA drop, is it you're seeing it coming down in the first two weeks, 50%-90%, or it's taking longer but staying more stable? The second is, beyond prostate cancer, should we continue to expect some initial data from the 114 EGFR mutant programs in the second half of the year?
Yeah. Let me take your second question first, which is, yes, you should continue to expect the public milestone that we promised in the second half of this year for the lung program is continued to be on track for the second half of this year. Nothing's changed from that. Pratik will take your question on PSA kinetics.
Yeah. I mean, I think we've seen all the above, rapid decreases and then sort of partial decreases that then improve over time. As I said earlier, we have multiple patients. The majority of our patients are on study. Their PSA responses are evolving. I can't give you sort of a definitive read on the kinetics, but we're seeing different patterns.
Got it. Is there any heavy concomitant usage of steroid for these patients, or it's within your range?
No, no. There isn't any.
Okay. Thank you so much.
Our next question comes from Stephen Willey with Stifel.
Yeah. Thanks for taking my questions. Congratulations on the data. Just wondering if there's anything that you can say about baseline PSA.
I know it's small patient numbers, but just curious as to how the baseline PSA here compares to what was observed in the baseline of the Pfizer study. Thanks.
Thanks, Stephen. Pratik will take that.
Sure. You referenced the Pfizer study, but they actually didn't say in their randomized study what the baseline PSA was. So we didn't say that here either. I can tell you, though, that our median baseline PSA in the patients that we presented today is well within the range of precedent phase III studies. If you look at these studies in enrolled patients post-ARPI, mCRPC like PSMA4, SPLASH, CONTACT2, TRITON3, if you look at their baseline PSAs, we're right in there. Sort of just to add to that, we're definitely not, or it's meaningfully higher than the baseline PSA for the phase II tazemetastat study, CELLO-1. That was in chemo naive patients.
They had a baseline PSA in the mid-single digits. We're meaningfully higher than that and really sort of in the ballpark of all these phase IIIs. It is a representative population. I can't comment on the Pfizer one because they didn't disclose theirs.
Understood. Appreciate the context. Thank you.
Thanks, Stephen.
There are only no further questions in queue at this time. This concludes today's conference call. Thank you for participating. You may now disconnect.