Oric Pharmaceuticals (NASDAQ:ORIC) detailed new dose-optimization results for its PRC2 inhibitor rinzimetostat and outlined plans to begin its first phase III registrational study in metastatic castration-resistant prostate cancer (mCRPC), emphasizing a combination regimen intended to deliver competitive early efficacy with a differentiated tolerability profile.
Company highlights rinzimetostat and PRC2 inhibitor landscape
CEO Jacob Chacko said ORIC’s late-stage pipeline is centered on two programs: rinzimetostat, a PRC2 inhibitor being developed in prostate cancer “in collaboration with our partners at Bayer and Johnson & Johnson,” and enozertinib, a brain-penetrant EGFR inhibitor in development for non-small cell lung cancer with Johnson & Johnson.
Preclinical rationale: next-generation PRC2 inhibitor design
Chief Scientific Officer Lori Friedman said first-generation PRC2 inhibitors (including CPI-1205 and tazemetostat) had “multiple shortcomings,” while second-generation mevrometostat improved some properties but “falls short in other drug properties such as solubility and half-life.” Friedman said rinzimetostat shows improvements across categories and has “a 20-hour half-life in the clinic,” positioning it as a potential best-in-class PRC2 inhibitor.
Friedman described preclinical work supporting combining PRC2 inhibition with AR inhibition, arguing that epigenetic reprogramming enables prostate tumors to evade therapy and that PRC2 inhibition can reverse or prevent lineage escape. She highlighted xenograft studies where adding rinzimetostat to darolutamide improved progression-free survival in both castration-resistant and castration-sensitive models.
Phase Ib dose optimization supports 400 mg once daily with darolutamide
Chief Medical Officer Pratik Multani reviewed ORIC’s phase Ib experience, stating that single-agent dosing from 100 mg to 900 mg once daily demonstrated “dose proportional exposure,” “no evidence of CYP autoinduction,” and a 20-hour half-life enabling once-daily dosing. He said robust target engagement was seen at doses as low as 200 mg and that the single-agent maximal tolerated dose was 800 mg, supporting combination development.
Multani said ORIC conducted combination dose finding with darolutamide and apalutamide and then randomized patients into dose-optimization cohorts. The update focused on post-abiraterone mCRPC patients receiving rinzimetostat 400 mg or 600 mg once daily with darolutamide.
Multani emphasized pharmacokinetic and pharmacodynamic support for both doses: both 400 mg and 600 mg covered target exposure over 24 hours, and H3K27 trimethylation changes in PBMCs showed a maximized pharmacodynamic signal at both doses. However, he said exposure-response analyses performed in line with FDA’s Project Optimus found “comparable efficacy” between 400 mg and 600 mg, but statistically significant relationships between higher exposure and clinically meaningful toxicities and treatment modifications.
“The definitive conclusion from this work is that 400 milligrams is the preferred RP3D for rinzimetostat in combination with darolutamide,” Multani said.
Efficacy and safety signals and comparator context
In the post-abiraterone 400 mg cohort, Multani presented early activity metrics including a PSA waterfall showing a 47% unconfirmed and 33% confirmed PSA50 response rate among 15 evaluable patients. ORIC also highlighted ctDNA reductions: 71% of patients had a 50% ctDNA reduction and 29% had a 90% reduction.
Friedman said ctDNA reduction may be a more direct readout of tumor burden than PSA for PRC2 inhibition, and contextualized ORIC’s 71% molecular response rate against other studies. She cited molecular response rates of 28% and 44% in the AMBASSADOR-250 and COMRADE studies assessing AR inhibition and radium-223, and said treatment-naïve mCRPC populations receiving standard of care have reported molecular response rates of 65%–78%.
On durability, Multani described landmark rPFS in the post-abiraterone 400 mg cohort with a median follow-up of 4.9 months: 93% progression-free at three months and 84% at four and five months. He also provided an early look at post-AR inhibitor mCRPC patients treated at 400 mg, reporting 93% progression-free at three months and 85% at four and five months with a median follow-up of 4.8 months.
Safety was a focal point of the call. Multani said that across 33 patients at both dose levels, there was “only one grade 3 event” and “no grade 4 or 5 treatment-related adverse events.” He said the most frequent adverse events included fatigue and gastrointestinal toxicities, with a trend toward more grade 2 diarrhea and nausea at 600 mg versus 400 mg. In a broader dataset including post-AR inhibitor cohorts, he highlighted diarrhea rates of 19% at 400 mg versus 37% at 600 mg and noted nausea was lower at 400 mg and entirely grade 1.
When asked about cytopenias and alopecia, Multani said neutropenia and thrombocytopenia occurred at a low rate “less than 5%,” and ORIC observed “a grand total of one” grade 1 treatment-related alopecia event at 600 mg. He attributed creatinine increases largely to dehydration associated with GI events, saying they “resolve easily with hydration.”
Himalayas-1 phase III trial design and timing
Multani unveiled the phase III trial design for Himalayas-1, which will enroll mCRPC patients previously treated with abiraterone and with up to one prior chemotherapy in the metastatic castration-sensitive setting. Patients will be randomized 1:1 to rinzimetostat plus darolutamide versus physician’s choice of an AR inhibitor or chemotherapy. The primary endpoint is rPFS, with overall survival as a key secondary endpoint.
ORIC said it has selected more than 250 sites in over 20 countries and formed a steering committee chaired by Matthew Smith of Massachusetts General Hospital and vice-chaired by Karim Fizazi of Gustave Roussy, with additional members from institutions including The Royal Marsden, Peter MacCallum Cancer Centre, Mayo Clinic, UCSF, and Memorial Sloan Kettering.
On regulatory interactions, Multani said ORIC plans an end-of-phase I meeting with the FDA in Q2 to obtain “final sign-off” on the 400 mg RP3D and the final phase III protocol design, and reiterated the company’s expectation to start the trial in the second quarter.
Regarding timing, Multani said ORIC expects top-line data in “late 2027 or early 2028,” assuming about 16 months to fully enroll the study plus time to reach the required number of PFS events.
Commercial framing and market research
SVP Keith Lui said ORIC estimates roughly 17,000 U.S. patients annually with mCRPC previously treated with abiraterone, and—using an estimated treatment duration of about 14 months and current pricing—pegged the U.S. addressable market at “over $3.5 billion” and the global market at “around $7 billion” for the initial indication.
Lui also described blinded market research comparing target product profiles for rinzimetostat plus darolutamide versus a competitor PRC2 inhibitor plus enzalutamide in post-abiraterone mCRPC, with similar efficacy but more favorable safety for the rinzimetostat profile. He said physicians indicated they would ascribe the rinzimetostat profile “80% share of the PRC2 class,” suggesting safety differentiation alone could drive prescribing decisions.
In Q&A, Lui addressed anecdotal reports of declining abiraterone use, saying ORIC triangulated multiple sources—including third-party prescription data, market research, and conversations with academic and community clinicians—and continues to hear abiraterone use is “highly sticky,” citing physician familiarity, payer preference because it is generic, and evidence-based sequencing considerations.
Chacko closed by reiterating ORIC’s view that the dose-optimization results support rinzimetostat plus darolutamide as a potential all-oral option with a competitive efficacy trajectory and improved tolerability as it moves into the Himalayas-1 registrational study.
About Oric Pharmaceuticals (NASDAQ:ORIC)
Oric Pharmaceuticals, Inc is a clinical-stage biopharmaceutical company headquartered in South San Francisco, California. The firm is dedicated to discovering and developing small molecule therapeutics designed to overcome resistance mechanisms in solid tumor oncology. Its research efforts focus on identifying novel targets and advancing precision medicines that can restore or enhance patient response when standard therapies fail.
The company’s pipeline features lead candidates such as ORIC-101, a selective, orally available antagonist of the glucocorticoid receptor currently being evaluated in Phase 1/2 trials for patients with solid tumors who have acquired resistance to chemotherapy and hormonal agents.
