Phase 1/2 Trial: Valemetostat Plus Darolutamide in mCRPC

A phase 1/2 clinical trial investigating valemetostat (DS-3201b), a dual EZH1/2 inhibitor, combined with darolutamide in metastatic castration-resistant prostate cancer (mCRPC) is going to start to recruit participants. This study aims to evaluate the safety, tolerability, and preliminary efficacy of the combination in men whose disease has progressed despite prior androgen receptor pathway inhibitors (ARPIs). With enrollment targeting 60 patients across two cohorts, the trial emphasizes precision oncology through mandatory tumor biopsies and biomarker analysis.​

The interventional study requires ongoing androgen deprivation therapy (ADT) and divides participants into treatment arms based on genetic markers. Primary endpoints focus on dose-limiting toxicities, maximum tolerated dose, and recommended phase 2 dose (RP2D) during the phase 1 portion, transitioning to efficacy measures like radiographic progression-free survival in phase 2. Secondary endpoints include overall response rate, duration of response, and prostate-specific antigen (PSA) decline, assessed per PCWG3 criteria. Patients receive oral valemetostat (dose-escalation from 50-200 mg daily) alongside darolutamide, administered as film-coated tablets in the fasted state. The design incorporates fresh pre-treatment biopsies unless contraindicated, enabling pharmacodynamic assessment of H3K27me3 reduction and biomarker-driven cohort assignment.​

The trial operates at multiple international sites, with contacts available through ClinicalTrials.gov and collaborating registries.​

Valemetostat targets the Polycomb repressive complex 2 (PRC2) by inhibiting both EZH1 and EZH2, reducing repressive H3K27me3 marks that silence tumor suppressors like CDKN2A. In prostate cancer, EZH2 overexpression drives ARPI resistance by suppressing PSA transcription, promoting lineage plasticity toward neuroendocrine phenotypes, and enabling non-canonical pro-tumorigenic functions independent of PRC2. Dual inhibition prevents EZH1 compensation seen with EZH2-only blockers, achieving superior tumor regression in preclinical models. Darolutamide, a potent AR antagonist, complements this by blocking overexpressed or variant AR forms prevalent in mCRPC. AR inhibition itself disrupts EZH2-PRC2 assembly, potentially exacerbating pathologic EZH2 activity, making dual pathway blockade synergistic for overcoming resistance, reducing epithelial-to-mesenchymal transition, and delaying neuroendocrine differentiation.​

With mCRPC patients facing limited options post-ARPI and chemotherapy failure, this combination addresses epigenetic drivers of resistance that affect nearly all advanced cases. Valemetostat’s established safety in hematologic malignancies—primarily manageable thrombocytopenia and anemia, with no overlapping toxicities to darolutamide—supports feasibility. Early solid tumor data, including antitumor activity in INI1-negative tumors, bolster expansion into prostate cancer. As recruiting sites activate worldwide, this trial could redefine second-line strategies in mCRPC, leveraging valemetostat’s Japan approvals in lymphoma to accelerate development. Updates on dosing and initial safety data are anticipated as cohorts fill.​

Clinical trial.