ORIC-944 Plus AR Inhibition Yields PSA Responses in mCRPC

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Credit: © Sebastian Kaulitzki
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Treatment with the combination of the potent and selective PRC2 inhibitor ORIC-944 and an androgen receptor (AR) pathway inhibitor produced prostate-specific antigen (PSA) responses and was safe in patients with metastatic castration-resistant prostate cancer (mCRPC), according to preliminary data from a phase 1b trial (NCT05413421).1

Findings announced by ORIC Pharmaceuticals showed that evaluable patients treated with ORIC-944 plus an AR pathway inhibitor (n = 17) achieved a PSA50 response rate of 59%. One month later, the confirmed PSA50 response rate was 47%, which did not account for 1 patient awaiting confirmation of response. Notably, the confirmed PSA90 response rate was 24%. PSA responses occurred across all dose levels of ORIC-944 and irrespective of whether patients underwent AR inhibition with apalutamide (Erleada) or darolutamide (Nubeqa).

Regarding safety, most adverse effects (AEs) were grade 1 or 2, and AEs were consistent with PRC2 and AR inhibition. No grade 4 or 5 treatment-related AEs (TRAEs) attributed to ORIC-944 were reported; the most common any-grade TRAE was diarrhea (53%), including a grade 3 instance in 1 patient.

“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 gastrointestinal-related AEs, making it highly suitable for potential long-term dosing,” Pratik S. Multani, MD, chief medical officer, of ORIC Pharmaceuticals, stated in a news release.

The first-in-human, open-label, multicenter, dose-escalation phase 1 study enrolled patients with metastatic prostate cancer who previously underwent bilateral orchiectomy or were willing to continue treatment with a GnRH analogue or antagonist to maintain castrate levels of testosterone.2 In part 1, which evaluated ORIC-944 monotherapy, any number of prior lines of therapy were permitted; however, disease progression after at least 1 line containing an AR pathway inhibitor was required, and no more than 2 chemotherapy regimens were allowed in the mCRPC setting. In part 2, which evaluated ORIC-944 in combination with an AR pathway inhibitor, 1 prior line of treatment with an AR pathway inhibitor was required, and up to 1 prior line of chemotherapy in the castration-sensitive setting was allowed. In part 3, which is serving as the dose optimization portion for the combination, criteria mirror part 2, although patients are being assigned based on prior AR inhibitor exposure; those who received prior abiraterone acetate (Zytiga) are being assigned to cohorts A and B, and patients previously treated with apalutamide, darolutamide, or enzalutamide (Xtandi) are being enrolled in cohorts C and D.

Other key inclusion criteria comprised evidence of progressive disease, measurable and/or evaluable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function.

Patients with a history or presence of central nervous system metastases were excluded unless they were previously treated and stable. A history of class III/IV congestive heart failure, or severe nonischemic cardiomyopathy, unstable or poorly controlled angina, myocardial infarction, or ventricular arrhythmia within 6 months of enrollment also precluded patients from participating.

During part 1 of dose-escalation, ORIC-944 was administered as a single agent in oral, once-daily doses in 28-day cycles. In part 2, patients received escalating doses of daily ORIC-944 at 400 mg, 600 mg, or 800 mg in combination with apalutamide at 240 mg once daily or darolutamide at 600 mg twice daily.1 In part 3, the optimal dose of ORIC-944 is being further evaluated with in combination with apalutamide in cohorts A and C, and in combination with darolutamide in cohorts B and D.2

The study’s primary end points were determining the recommended phase 2 dose of ORIC-944 and pharmacokinetics. Clinical benefit rate, objective response rate, duration of response, progression-free survival, and changes in PSA levels served as secondary end points.

Among the 17 patients to receive ORIC-944 in combination with an AR pathway inhibitor, the median number of prior lines of therapy was 3, which included abiraterone acetate.1 Patients also received up to 1 line of chemotherapy and other approved and investigational agents.

“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,” Jacob M. Chacko, MD, president and chief executive officer of ORIC Pharmaceuticals, added in a news release. “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 the first half of 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. May 28, 2025. Accessed May 29, 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. Updated March 20, 2025. Accessed May 29, 2025. https://clinicaltrials.gov/study/NCT05413421