ORIC-944 shows promise in combination with ARPIs for mCRPC

The PRC2 inhibitor ORIC-944 demonstrated encouraging anti-tumor activity with favorable tolerability in combination with androgen receptor pathway inhibitors (ARPIs) in patients with metastatic castration-resistant prostate cancer (mCRPC), according to updated results from a phase 1b trial (NCT05413421) of the regimens.¹

“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, MD, president and chief executive officer of ORIC Pharmaceuticals, in a news release from the company.¹

Overall, the open-label, multicenter, phase 1b study enrolled patients with mCRPC who had received a median of 3 prior line of therapy. Participants in the study received ORIC-944 once daily at a dose level of 400 mg, 600 mg, 800 mg, or 1200 mg in combination with either 240 mg of apalutamide (Erleada) once daily or 600 mg darolutamide (Nubeqa) twice daily. At the time of data report, results were available for 20 patients in the prostate-specific antigen (PSA) data analysis and 17 patients in the ctDNA analysis.

PSA responses and ctDNA reductions were observed across all dose levels of ORIC-944. These responses were comparable across patients who received ORIC-944 in combination with apalutamide or with darolutamide, according to ORIC.

A PSA reduction of at least 50% (PSA50) was achieved in 55% of patients (11 of 20), with a confirmed PSA50 response rate of 40% (8 of 20). Further, 20% of patients (4 of 20) achieved a PSA reduction of at least 90%, of which all were confirmed.

The investigators also assessed ctDNA activity. In the trial, 88% of patients had detectable ctDNA at baseline. Overall, 76% of patients (13 of 17) achieved a ctDNA reduction of at least 50%, and 59% of patients achieved ctDNA clearance. According to ORIC, this rate is “greater than clearance rates observed in precedent trials with standard of care agents in comparable mCRPC patient populations.”

Safety data showed that ORIC-944 was tolerable both in combination with apalutamide and with darolutamide. According to the company, the safety profiles for each combination regimen were compatible with long-term dosing. In the study, treatment-related adverse events (TRAEs) were generally grade 1 or 2 in severity and were consistent with the known adverse effects of PRC2 and AR inhibition. One patient experienced a grade 3 TRAE, and no grade 4 or 5 TRAEs were reported.

Based on these findings, ORIC plans to proceed with the dose optimization portion of the trial. The study will continue to assess ORIC-944 at the recommended dose levels of 400 mg and 600 mg once daily in combination with 600 mg twice daily with darolutamide as well as at 600 mg, 800 mg, and 1200 mg once daily in combination with apalutamide. Enrollment in the dose optimization portion of the trial is ongoing, with preliminary data expected in the first quarter of 2026.

Results from the dose optimization study will inform the dose level selected for a phase 3 registrational trial in mCRPC, which the company plans to launch in the first half of 2026.

Chacko concluded, “The tolerability and efficacy data to date provide compelling validation for the doses we’ve selected for the dose optimization portion of the phase 1b trial. We look forward to sharing dose optimization data in 1Q 2026 ahead of initiating our first global phase 3 registrational trial in mCRPC in the first half of next year.”

REFERENCE

1. ORIC Pharmaceuticals announces completion of dose exploration portion of ORIC-944 phase 1b clinical trial and continues to demonstrate potential best-in-class efficacy and safety. News release. ORIC Pharmaceuticals. November 13, 2025. Accessed November 14, 2025. https://www.globenewswire.com/news-release/2025/11/13/3187843/0/en/ORIC-Pharmaceuticals-Announces-Completion-of-Dose-Exploration-Portion-of-ORIC-944-Phase-1b-Clinical-Trial-and-Continues-to-Demonstrate-Potential-Best-in-Class-Efficacy-and-Safety.html