Topline efficacy from ORIC’s Phase 1b mCRPC study shows a 55% PSA50 response rate (11/20) with 40% confirmed (8/20), and a 20% PSA90 response rate (4/20, all confirmed). Among patients with baseline ctDNA, 76% (13/17) achieved greater than 50% reductions, and 59% (10/17) achieved ctDNA clearance. Safety remained favorable: the vast majority of treatment-related AEs were Grade 1–2, with a single Grade 3 event and no Grade 4–5 events attributed to study drugs as of the September 22, 2025, cutoff.
The update centers on ORIC-944, an allosteric PRC2 (EED) inhibitor, given once daily across 400–1,200 mg dose levels in combination with apalutamide or darolutamide in patients with metastatic castration-resistant prostate cancer previously treated with an ARPI and up to one chemotherapy (median three prior lines overall). Activity signals were seen across dose levels and with both AR backbones. On the back of these data, ORIC has set provisional RP2Ds by regimen, advanced the trial into a dose optimization phase, and outlined plans to initiate a first global Phase 3 registrational study in the first half of 2026, with additional Phase 1b optimization data targeted for the first quarter of 2026.
Strategically, ORIC is moving quickly to convert early biological and PSA signals into a registrational path, betting that PRC2 inhibition can reverse or blunt AR resistance and extend the utility of oral AR inhibitors without adding significant toxicity. Dual development with both apalutamide and darolutamide hedges against partner, geography, and label variability, and creates optionality on the registrational backbone. The prominent use of ctDNA to demonstrate depth of response is notable: clearance rates exceed benchmarks reported for standard agents in comparable settings, though cross-trial comparisons are inherently limited. Regulators will likely view ctDNA as supportive rather than primary evidence, putting pressure on ORIC to deliver durable radiographic benefit and survival signals in the next phase.
For sites and CROs, the operational profile is attractive: oral-plus-oral regimens, manageable AE burden, and no inpatient procedures. The trade-off is intensified biomarker logistics if serial ctDNA and AR mutation tracking are embedded into dose optimization and Phase 3 stratification; central lab coordination and rapid processing windows will matter. Sponsors running competing mCRPC programs should expect heightened enrollment competition in a post-ARPI population already targeted by PARP combinations, radioligand therapies, and AKT/PI3K pathway agents. Choice of control will be scrutinized: combining with continued AR blockade post-ARPI requires careful justification, as practice patterns vary on continuing the same ARPI beyond progression. For payers, the commercial case will hinge on demonstrable rPFS and OS gains relative to ARPI alone or to accepted post-ARPI standards in the chosen line of therapy.
Key watch items over the next two quarters include durability of PSA and ctDNA responses, emerging radiographic endpoints from the Phase 1b optimization cohort, and clarity on the Phase 3 design: primary endpoint selection (likely rPFS), comparator strategy, and whether ORIC commits to one AR inhibitor backbone or runs parallel programs. Pharmacokinetic interplay with apalutamide and darolutamide appears to be guiding dose selection and will need to hold under global, real-world co-medication patterns. Also worth tracking are the contours of drug supply and collaboration agreements with the AR inhibitor owners, site activation pacing in a crowded mCRPC landscape, and any late-emerging hematologic or epigenetic-class toxicities with longer exposure. The core question is whether the ctDNA and PSA depth observed in a small dataset will translate into a clinically decisive, durable benefit at Phase 3 scale.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
