Phase 3 Trial Initiated for Rinzimetostat Plus Darolutamide in mCRPC

A phase 3 trial evaluating rinzimetostat (ORIC-944) in combination with darolutamide (Nubeqa) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with abiraterone (Zytiga) has been initiated, according to a news release from ORIC Pharmaceuticals.¹

Previous dose optimization data showed favorable efficacy and safety profiles, leading to the selection of a phase 3 dose and opening of the phase 3 Himalayas-1 trial to investigate rinzimetostat in a setting where standard-of-care options have poor outcomes.²

“Given the significant unmet need in prostate cancer and the potential best-in-disease clinical profile that rinzimetostat has continued to demonstrate, the initiation of our Himalayas-1 Phase 3 trial represents an important milestone,” Jacob M. Chacko, MD, president and chief executive officer of ORIC, stated in the news release.¹

Phase 3 Study Plan

Himalayas-1 is expected to enroll approximately 600 patients across more than 250 sites in 25 countries. Patients will be randomly assigned on a 1:1 basis to receive the recommended phase 3 dose of rinzimetostat at 400 mg once daily in combination with darolutamide, or physician's choice of an androgen receptor (AR) inhibitor or docetaxel (Taxotere). The primary end point is radiographic progression-free survival (rPFS), and the key secondary endpoint is overall survival. Additional secondary end points include prostate-specific antigen (PSA) response rate, objective response rate, and patient-reported outcomes.

Background and Dose Optimization Data

Rinzimetostat is an allosteric inhibitor of the polycomb repressive complex 2 (PRC2) that acts via the EED subunit, a mechanism distinct from AR-targeted therapy.

Dose optimization data were reported by the company at a cutoff date of March 2026. Rinzimetostat was evaluated in patients with post abiraterone mCRPC, with a median follow-up of 4.9 months.²

The combination was associated with landmark rPFS rates of 93%, 84%, and 84% at 3, 4, and 5 months, respectively, which the company characterized as consistent with a competitor PRC2 inhibitor currently in phase 3 development in the post abiraterone setting, and compared favorably with historical data from standard-of-care therapies in mCRPC, including enzalutamide (Xtandi), cabazitaxel, docetaxel, and lutetium Lu 177 vipivotide tetraxetan (Pluvicto), for which 5-month landmark rPFS ranges from approximately 60% to 75%, according to the company.

Among evaluable patients, 47% (n = 7/15) achieved a reduction in PSA of at least 50%, with 33% (n = 5/15) confirmed, and 71% (n = 10/14) achieved a greater than 50% reduction in circulating tumor DNA (ctDNA) across a range of AR mutations.

The vast majority of treatment-related adverse events (TRAEs) were grade 1 in severity and consistent with PRC2 and AR inhibition; a single grade 3 TRAE was observed, and no grade 4 or 5 adverse events were attributed to rinzimetostat or darolutamide. Dose modifications were rare, limited to 1 interruption and 1 discontinuation, with no dose reductions required.

The company also reported early data from a separate cohort of patients with mCRPC previously treated with an AR inhibitor. In this setting, rinzimetostat 400 mg once daily in combination with darolutamide demonstrated landmark rPFS rates of 93%, 85%, and 85% at 3, 4, and 5 months, respectively, at a median follow-up of 4.8 months. The company noted that the clinical benefit of AR pathway inhibitors in patients who had received prior AR inhibition is limited.

Preclinical data presented at the American Association for Cancer Research Annual Meeting further suggested that PRC2 inhibition reduces tumor adaptability and helps sustain the benefit derived from AR inhibition, with potential advantages of targeting the EED subunit over EZH2 inhibition, according to the company.³

REFERENCES

1. ORIC® Pharmaceuticals Announces Initiation of Himalayas-1 Phase 3 Trial in mCRPC Evaluating Rinzimetostat in Combination with NUBEQA® (Darolutamide), Supported by Clinical Collaboration with Bayer. News release. ORIC Pharmaceuticals. July 14, 2026. Accessed July 16, 2026. https://tinyurl.com/45bbrjrt

2. ORIC® Pharmaceuticals Reports First Quarter 2026 Financial Results and Operational Updates. News release. ORIC Pharmaceuticals. May 4, 2026. Accessed July 16, 2026. https://tinyurl.com/4yd3mssa

3.Daemen A, Pankov A, Yuen N, et al. ORIC-944, a PRC2 inhibitor with best-in-class properties, restores luminal features and restricts adaptation in prostate cancer models, conferring synergy with AR pathway inhibitors. Cancer Res. 2025;85(suppl 8):452. doi:10.1158/1538-7445.AM2025-452