ORIC-944 shows promise in combination with AR inhibitors in mCRPC

Data from a phase 1b dose escalation study (NCT05413421) showed that ORIC-944, in combination with androgen receptor (AR) inhibitors, elicited promising antitumor activity in patients with metastatic castration-resistant prostate cancer (mCRPC).¹

Final completion of the phase 1b trial is expected in mid-2025.

ORIC-944 is a “potent and selective allosteric inhibitor of the polycomb repressive complex 2 (PRC2) via the embryonic ectoderm development (EED) subunit,” according to ORIC Pharmaceuticals. The agent is currently being assessed in combination with the AR inhibitors apalutamide (Erleada) and darolutamide (Nubeqa).

“These ORIC-944 combination data demonstrate substantial clinical activity with both AR inhibitors, apalutamide and darolutamide, through early measures of efficacy (PSA50 and PSA90 response rates) and a safety profile consisting almost entirely of mild to moderate GI related adverse events, making it highly suitable for potential long-term dosing,” said Pratik S. Multani, MD, chief medical officer of ORIC Pharmaceuticals, in a news release from the company.¹

In total, the open-label study enrolled 17 patients with mCRPC across clinical trial sites in the US, Australia, Spain, and the UK.² Participants were eligible for the trial if they had received prior treatment with an AR pathway inhibitor and up to 1 prior chemotherapy. Those enrolled in the study had received a median of 3 lines of prior therapy.

For the study, patients received 800 mg of ORIC-944 in combination with either 240 mg of apalutamide once daily or 600 mg of darolutamide twice daily.

Overall, 59% of patients (10 of 17) achieved at least a 50% decline in prostate-specific antigen (PSA) level (PSA50). The confirmed PSA50 response rate was 47% (8 of 17). At the time of data report, there was 1 response still pending confirmation.

Further, 24% of patients (4 of 17) achieved at least a 90% decline in PSA level (PSA90). All of these have been confirmed responses.

ORIC Therapeutics also noted, “PSA responses were observed across all ORIC-944 dose levels and were also observed at comparable rates in combination with apalutamide or with darolutamide.”

The majority of patients remain on trial, with many having been on therapy for nearly 1 year.

Treatment has been generally well-tolerated, according to the company, with the majority of adverse events (AEs) being grade 1 or 2. AEs have been consistent with what is expected with PRC2 and AR inhibition. The most common treatment-related AE to date is diarrhea, which has been reported in 53% of patients (9 of 17) across all dose levels.

There has been 1 grade 3 AE in the trial. No grade 4 or 5 treatment-related AEs have been reported.

Final completion of the phase 1b trial is expected in mid-2025, the company noted. A recommended phase 2 dose level for ORIC-944 will be evaluated with both apalutamide and darolutamide for the dose optimalization portion of the trial, expected to launch in the second half of 2025.

According to ORIC, “Data from the dose optimization portion of the trial will inform the choice of ORIC-944 dose to advance in combination with apalutamide or with darolutamide in the first global phase 3 registrational trial in mCRPC that the company expects to initiate in 1H 2026.”

“The data generated to date continue to demonstrate the potential of ORIC-944 to be a best-in-class PRC2 inhibitor that may benefit a broad range of patients with prostate cancer,” concluded Jacob M. Chacko, MD, president and CEO of ORIC Pharmaceuticals, in the news release.¹ “The efficacy and safety data presented today compare favorably to other PRC2 inhibitor data presented earlier this year. We look forward to subsequent updates from the dose exploration and dose optimization portion of the phase 1b trial over the next 3 quarters as we move towards initiating our first global registrational trial in 1H 2026.”

REFERENCES

1. ORIC Pharmaceuticals announces potentially best-in-class preliminary efficacy and safety data from ongoing phase 1b trial of ORIC-944 in combination with AR inhibitors for the treatment of patients with mCRPC. News release. ORIC Pharmaceuticals, Inc. May 28, 2025. Accessed May 30, 2025. https://investors.oricpharma.com/news-releases/news-release-details/oricr-pharmaceuticals-announces-potentially-best-class

2. Study of ORIC-944 in patients with metastatic prostate cancer. ClinicalTrials.gov. Last updated March 20, 2025. Accessed May 30, 2025. https://clinicaltrials.gov/study/NCT05413421