Oric Pharmaceuticals (ORIC) Study update summary

Key study findings and dose optimization

• Rinzimetostat, a next-generation PRC2 inhibitor, demonstrated strong efficacy and a highly differentiated safety profile in metastatic castration-resistant prostate cancer (mCRPC) when combined with darolutamide, supporting the selection of 400 mg once daily as the recommended phase III dose (RP3D).

• The 400 mg dose showed comparable efficacy to 600 mg but with significantly fewer Grade 2 adverse events, lower rates of diarrhea and nausea, and fewer treatment modifications, making it preferable for long-term use.

• Exposure-response analysis confirmed no efficacy advantage at higher doses but a clear safety benefit at 400 mg, aligning with FDA Project Optimus guidance.

• The safety profile was markedly cleaner than competitor regimens, with most adverse events being Grade 1 or 2 and only one Grade 3 event across all patients at both dose levels; no Grade 4 or 5 events were attributed to the combination.

• Rinzimetostat’s safety and efficacy profile positions it as a potential best-in-class therapy for mCRPC.

Clinical efficacy and biomarker response

• In the dose optimization cohort, rinzimetostat plus darolutamide achieved a 47% unconfirmed and 33% confirmed PSA50 response rate, with multiple patients remaining on treatment.

• 71% of patients had a 50% reduction in circulating tumor DNA (ctDNA), and 29% had a 90% reduction, outperforming other therapies in similar populations.

• Landmark radiographic progression-free survival (RPFS) at three, four, and five months was 93%, 84%, and 84%, respectively, exceeding benchmarks from ARPI monotherapy and matching competitor PRC2 inhibitor combinations.

• The efficacy was notable given the more heavily pretreated and higher-risk patient population compared to competitor studies.

• RECIST responses were observed in all evaluable patients with measurable disease, and ctDNA reduction correlated with long-term durability.

Comparative safety and tolerability

• Rinzimetostat at 400 mg had lower rates of Grade 3 adverse events, serious related adverse events, dose reductions, and discontinuations compared to competitor PRC2 inhibitor regimens.

• Adverse events such as cytopenias and alopecia were rare and mild, and blood creatinine increases were mostly Grade 1 and reversible with hydration.

• The safety profile remained consistent across both post-abiraterone and post-AR inhibitor populations, supporting broad applicability.

• Minimal food effect was observed, allowing for flexible dosing with darolutamide; food effect studies indicate no significant impact on efficacy or safety.

• The differentiated safety profile is expected to drive strong physician preference and patient adherence.