ORIC Pharmaceuticals announced completion of the dose exploration portion of its Phase 1b trial evaluating ORIC-944, an allosteric inhibitor of polycomb repressive complex 2 (PRC2), in combination with androgen receptor (AR) inhibitors for patients with metastatic castration-resistant prostate cancer (mCRPC). The results demonstrate promising efficacy signals and a favorable safety profile that supports advancement to Phase 3 development.
Strong PSA Response Rates Across Dose Levels
The trial enrolled patients previously treated with a median of three prior lines of therapy, including abiraterone acetate and up to one prior line of chemotherapy. Patients received once-daily ORIC-944 at doses of 400 mg, 600 mg, 800 mg, or 1,200 mg in combination with either 240 mg apalutamide once daily or 600 mg darolutamide twice daily.
Among 20 patients with mCRPC, 55% achieved a PSA50 response, with 40% showing confirmed responses. Additionally, 20% of patients achieved a PSA90 response, with all responses confirmed. These response rates were observed across all ORIC-944 dose levels and at comparable rates in both combination regimens.
"We continue to be encouraged by ORIC-944 combination data, which further demonstrate its potential as a best-in-class PRC2 inhibitor that may benefit a broad range of patients with prostate cancer," said Jacob M. Chacko, M.D., president and chief executive officer.
Significant ctDNA Reductions Signal Potential Long-term Benefit
Circulating tumor DNA (ctDNA) analysis provided additional evidence of therapeutic activity. Among 17 patients with available ctDNA samples, 88% had detectable ctDNA at baseline, which is higher than precedent trials with standard of care agents in comparable mCRPC patient populations.
ORIC-944 combinations demonstrated rapid and deep ctDNA responses, with 76% of patients achieving greater than 50% ctDNA reduction. Notably, 59% of patients achieved complete ctDNA clearance, which exceeds clearance rates observed in precedent trials with standard of care agents in similar patient populations. ctDNA serves as a useful biomarker to predict duration of treatment benefit and survival in prostate cancer.
Favorable Safety Profile Supports Long-term Dosing
Both combination regimens demonstrated safety profiles compatible with long-term dosing. The vast majority of treatment-related adverse events were Grade 1 or 2 in severity and consistent with PRC2 and AR inhibition. As of the September 22, 2025 cutoff date, only one patient experienced a Grade 3 treatment-related adverse event, with no Grade 4 or Grade 5 adverse events attributed to the study drugs.
Preclinical Data Supports Best-in-Class Potential
Complementing the clinical results, preclinical data presented at the 2025 EORTC-NCI-AACR International Conference demonstrated ORIC-944's potential beyond prostate cancer. In castration-sensitive prostate cancer models, ORIC-944 combined with AR inhibitors synergistically impaired tumor growth, significantly improved survival, and extended duration of response by restricting cellular plasticity and delaying tumor adaptation.
The preclinical studies also showed promise in KRAS-mutant cancers. ORIC-944 combined with KRAS inhibitor adagrasib regressed 100% of tumors in KRAS-mutant non-small cell lung cancer xenograft models and prevented tumor relapse while extending progression-free survival.
"These preclinical data underscore the potential of ORIC-944 to overcome resistance not only in prostate cancer but in other solid tumors," said Lori Friedman, PhD, chief scientific officer.
Path Forward to Phase 3 Development
Based on the efficacy and safety results, ORIC has selected provisional recommended Phase 2 doses for the dose optimization portion of the trial. These include 400 mg and 600 mg once daily of ORIC-944 with darolutamide, and 600 mg, 800 mg, and 1,200 mg once daily of ORIC-944 with apalutamide.
The company plans to announce preliminary dose optimization data in the first quarter of 2026, which will inform the choice of ORIC-944 dose for the first global Phase 3 registrational trial in mCRPC expected to initiate in the first half of 2026.
