ORIC-944 is a potent and selective allosteric inhibitor of the polycomb repressive complex 2 (PRC2), specifically targeting the embryonic ectoderm development (EED) subunit. This novel agent is showing early promise in treating metastatic castration-resistant prostate cancer (mCRPC), with ongoing clinical trials exploring its potential in combination with androgen receptor (AR) inhibitors.

The Phase 1b trial of ORIC-944 is currently underway, focusing on its use in combination with the AR inhibitors apalutamide and darolutamide. Dosing began in mid-2024, with dose escalation cohorts established for both combinations.

Early results from the apalutamide combination cohort highlight deep reductions in prostate-specific antigen (PSA) levels, a key marker for prostate cancer activity. Among the six patients in the first two dose cohorts (600 mg and 800 mg of ORIC-944), three achieved confirmed PSA50 responses (a ≥50% reduction in PSA levels), with two of these showing PSA90 responses (a ≥90% reduction).
Notably, these PSA responses were sustained for at least 12 weeks, with one durable PSA90 response ongoing at 38 weeks.

The combination of ORIC-944 with apalutamide has demonstrated a manageable safety profile, with treatment-related adverse events (TRAEs) predominantly limited to Grade 1 and Grade 2. Only one Grade 3 TRAE of fatigue was reported, and the patient remained on treatment without dose modification. No dose-limiting toxicities or treatment discontinuations due to safety concerns were observed in these early cohorts.

Parallel progress is being made with the darolutamide combination cohort, where dose escalation is ongoing. Preliminary clinical activity in this group aligns with the findings from the apalutamide cohort, reinforcing the potential of ORIC-944 to enhance the effectiveness of AR inhibitors.

Single-agent data from the initial Phase 1b study supported the advancement of ORIC-944 into combination therapies.

Looking ahead these results suggest a potential initiation of registrational trials planned for early 2026.

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