Phase 3 rinzimetostat (ORIC-944) EED/PRC2 inhibitor + darolutamide AR antagonist in post-abiraterone mCRPC

ORIC Pharmaceuticals’ Himalayas-1 (NCT07723248) is a randomized, open-label Phase 3 study in metastatic castration-resistant prostate cancer (mCRPC) that has progressed after abiraterone acetate, testing whether adding rinzimetostat to darolutamide improves outcomes versus physician’s choice control. Rinzimetostat is an allosteric EED (PRC2) inhibitor intended to suppress PRC2-driven transcriptional programs that can support androgen-receptor signaling and treatment resistance; darolutamide (Bayer/Orion’s Nubeqa) and enzalutamide (Astellas/Pfizer) are androgen-receptor pathway inhibitors, while docetaxel is a microtubule-stabilizing taxane chemotherapy. The primary endpoint is superiority in radiographic progression-free survival (rPFS), with additional endpoints typically including overall survival, response rates, and safety. The key angle is the registrational-scale test of an epigenetic resistance-targeting add-on (PRC2/EED inhibition) layered onto AR blockade in a common “post-abiraterone” mCRPC sequence. Today’s care after abiraterone progression is typically a switch to another ARPI (with modest benefit due to cross-resistance) or taxane chemotherapy such as docetaxel (and, depending on prior therapies/biomarkers, options like cabazitaxel, PARP inhibitors for HRR-altered disease, radioligand therapy, and bone-targeted agents).