Pivotal phase 3 trial launches of rinzimetostat plus darolutamide in mCRPC

ORIC Pharmaceuticals, in collaboration with Bayer, has initiated the pivotal phase 3 Himalayas-1 trial evaluating rinzimetostat plus darolutamide (Nubeqa) in patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease has progressed following treatment with abiraterone (Zytiga).¹

The study will compare the combination regimen with physician's choice of an androgen receptor pathway inhibitor (ARPI) or docetaxel and is designed to support potential regulatory approval if positive.

Rinzimetostat is an investigational allosteric inhibitor of the polycomb repressive complex 2 (PRC2). The agent demonstrated encouraging anti-tumor activity with favorable tolerability in combination with ARPIs in a phase 1b trial that reported results in March 2026.²

Related: ORIC-944 shows promise in combination with ARPIs for mCRPC

“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 toward establishing rinzimetostat as a potentially practice-changing therapy for patients,” said Jacob M. Chacko, MD, president and CEO of ORIC, in a news release.¹ “This collaboration with Bayer strengthens our global operational readiness by securing access to darolutamide for Himalayas-1 and underscores our shared interest in evaluating this regimen for patients with prostate cancer.”

How is the Himalayas-1 trial designed?

The Himalayas-1 trial is expected to enroll approximately 600 patients across more than 250 sites in 25 countries. Participants will be randomly assigned 1:1 to receive rinzimetostat at the recommended phase 3 dose of 400 mg once daily (with or without food) in combination with darolutamide or to physician's choice of an ARPI or docetaxel.

The primary end point is radiographic progression-free survival (rPFS), with overall survival serving as the key secondary end point. Additional secondary end points include prostate-specific antigen (PSA) response rate, objective response rate, and patient-reported outcomes.

What were the previously reported data on rinzimetostat?

The Himalayas-1 study follows dose optimization data from an ongoing phase 1b program in which ORIC selected the 400-mg once-daily dose as the recommended phase 3 regimen after discussions with the FDA and other global regulatory authorities. Preliminary findings from the study showed that PSA responses and ctDNA reductions were observed across all dose levels assessed (400 mg, 600 mg, 800 mg, and 1200 mg). These responses were comparable across patients who received rinzimetostat in combination with apalutamide or with darolutamide, according to ORIC.³

In the 400-mg cohort, rPFS rates were 93% at 3 months, 84% at 4 months, and 85% at 5 months. A PSA reduction of at least 50% (PSA50) was achieved in 47% of patients (7 of 15), with a confirmed PSA50 response rate of 33% (5 of 15). Further, 71% of patients (10 of 14) achieved a greater than 50% reduction in ctDNA.²

According to the company, safety data showed that rinzimetostat was tolerable at the 400-mg dose in combination with darolutamide. In the study, treatment-related adverse events (TRAEs) were generally grade 1 in severity and were consistent with the known adverse effects of PRC2 and AR inhibition. The most common TRAEs were fatigue (39%; 17% grade 1 and 22% grade 2), diarrhea (22%; 17% grade 1 and 6% grade 2) and nausea (22%; all grade 1). One patient experienced a grade 3 TRAE, and no grade 4 or 5 TRAEs were reported.

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 15, 2026. https://investors.oricpharma.com/news-releases/news-release-details/oricr-pharmaceuticals-announces-initiation-himalayas-1-phase-3

2. ORIC® Pharmaceuticals reports selection of rinzimetostat RP3D in combination with darolutamide for Himalayas-1 phase 3 global study with dose optimization data supporting its potential best-in-disease profile. News release. ORIC Pharmaceuticals. March 31, 2026. Accessed July 15, 2026. https://investors.oricpharma.com/news-releases/news-release-details/oricr-pharmaceuticals-reports-selection-rinzimetostat-rp3d

3. ORIC Pharmaceuticals announces completion of dose exploration portion of ORIC-944 phase 1b clinical trial and continues to demonstrate potential best-in-class efficacy and safety. News release. ORIC Pharmaceuticals. November 13, 2025. Accessed July 15, 2026. https://www.globenewswire.com/news-release/2025/11/13/3187843/0/en/ORIC-Pharmaceuticals-Announces-Completion-of-Dose-Exploration-Portion-of-ORIC-944-Phase-1b-Clinical-Trial-and-Continues-to-Demonstrate-Potential-Best-in-Class-Efficacy-and-Safety.html