TPS284 Background: Enhancer of zeste homolog 2 (EZH2) enzymatic activity plays a crucial role in prostate cancer progression. Mevrometostat, an oral potent and selective EZH2 inhibitor may synergize with androgen receptor pathway inhibitors (ARPIs) to delay ARPI resistance In a phase I study (NCT03460977), mevrometostat combined with enzalutamide showed promising antitumor activity versus enzalutamide alone in heavily pre-treated patients with metastatic castration-resistant prostate cancer (mCRPC) (median 95% CI radiographic progression-free survival rPFS, 14.3 7.5, not estimable vs 6.2 4.1, 13.9 months; HR 90% CI 0.51 0.28, 0.95), and a manageable safety profile. Addition of mevrometostat to an ARPI in patients with mCSPC is hypothesized to prevent or delay progression to CRPC and improve survival. The ongoing phase III studies MEVPRO-1 (NCT06551324) and MEVPRO-2 (NCT06629779) are evaluating mevrometostat plus enzalutamide in patients with mCRPC. MEVPRO-3 (NCT07028853) will evaluate mevrometostat plus enzalutamide, versus placebo plus enzalutamide, in ARPI-naïve patients with mCSPC. Methods: MEVPRO-3 is a double-blind, randomized, global, phase III study enrolling patients aged ≥18 years with mCSPC and Eastern Cooperative Oncology Group performance status 0–1. Prior systemic therapy use in the metastatic setting is not allowed except for ≤3 months of androgen deprivation therapy (with or without first-generation antiandrogens), with no evidence of disease progression prior to Day 1. Prior palliative radiotherapy or surgery is allowed, but radical prostatectomy or prostate radiotherapy or metastasis-directed therapy for mCSPC is not. Around 1000 patients will be randomized 1:1 to mevrometostat (875 mg BID with food) plus enzalutamide (160 mg, QD) or placebo plus enzalutamide. Randomization will be stratified by low vs high disease volume and de novo vs relapsed mCSPC. The primary endpoint is rPFS per RECIST 1.1 (soft tissue) and PCWG3 criteria (bone) assessed by blinded independent central review. Secondary endpoints include overall survival; objective response rate; duration of response; time to PSA progression, initiation of new antineoplastic therapy, first symptomatic skeletal event, and CRPC; and patient-reported outcomes. Alpha-protected efficacy analyses will include tests for rPFS and OS. HRs and 95% CIs will be estimated via Cox proportional hazard model. P - values will be provided by stratified log-rank test. Pharmacokinetics and safety will also be assessed. Enrollment is ongoing in North America and the Asia-Pacific, and planned in Europe and Latin America. Disclosure: Pfizer’s generative AI tool, MAIA, was used in developing this abstract; the authors take full responsibility for the content. Clinical trial information: NCT07028853 .
Agarwal et al. (Sun,) studied this question.