MEVROMETOSTAT (PF-06821497) IN COMBINATION WITH ENZALUTAMIDE IN PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER PREVIOUSLY TREATED WITH ABIRATERONE ACETATE: THE PHASE 3, RANDOMIZED MEVPRO-1 STUDY

Abstract

Introduction

Resistance to androgen receptor (AR) pathway inhibitors (ARPI; e.g., abiraterone, enzalutamide) in metastatic castration-resistant prostate cancer (mCRPC) may be driven by preservation of AR signaling through various mechanisms. Enhancer of zeste homolog 2 (EZH2) is implicated in the pathogenesis of prostate cancer and ARPI resistance. Combining ARPI with therapies that modulate alternative signaling pathways, including epigenetic modifiers such as EZH2, could be a promising treatment approach to overcome resistance. Mevrometostat (PF-06821497) is a potent and selective small molecule EZH2 inhibitor. Results from the dose-escalation period of a phase 1 study (NCT03460977) showed promising activity for mevrometostat combined with enzalutamide, with a manageable adverse-event profile in abiraterone-exposed patients with mCRPC (Schweizer MT, et al. J Clin Oncol. 2024;42(16_suppl):5061). The current trial aims to evaluate radiographic progression-free survival (rPFS), overall survival (OS), and safety of mevrometostat plus enzalutamide compared with standard of care in patients with mCRPC previously treated with abiraterone.

Methods

MEVPRO-1 (registry#) is a global, open-label, phase 3 trial in patients with mCRPC aged ≥18 years with progression on/after ≥12 weeks abiraterone, castration testosterone levels ≤50 ng/dL, ECOG performance status 0–2, and life expectancy ≥6 months. Approximately 600 patients will be randomized 1:1 to receive mevrometostat (875mg BD with food) with enzalutamide (160mg QD), or physician's choice of enzalutamide (160mg QD) or docetaxel (75mg/m² intravenously every 21d). Randomization will be stratified by previous docetaxel in metastatic castration-sensitive setting, physician's choice of comparator (enzalutamide/docetaxel), and presence of hepatic metastases.

The primary endpoint is BICR-assessed rPFS per RECIST 1.1 (soft tissue) and PCWG3 (bone) assessed by blinded central radiology review. Key secondary endpoint is OS. Secondary endpoints include anti-tumor activity, safety, pharmacokinetics, ctDNA, and patient-reported outcomes. Stratified log-rank P-values, HRs, and 95% CIs will be estimated using a stratified Cox proportional hazard model, and Kaplan–Meier analysis will summarize time-to-event endpoints.