The MEVPRO-1 trial, a global, randomized, open-label, phase III study, is evaluating the efficacy and safety of mevrometostat (PF-06821497) in combination with enzalutamide for patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously been treated with abiraterone acetate. The trial's design and objectives were presented at the 2024 Society of Urologic Oncology (SUO) annual meeting.
Resistance to androgen receptor pathway inhibitors (ARPIs) like abiraterone and enzalutamide remains a significant challenge in mCRPC treatment. One mechanism driving this resistance involves the preservation of AR signaling. Enhancer of zeste homolog 2 (EZH2) is implicated in prostate cancer pathogenesis and ARPI resistance through silencing tumor suppressor genes, activating AR transcription factors, and promoting neuroendocrine transdifferentiation. Combining ARPIs with agents that modulate alternative signaling pathways, such as EZH2 inhibitors, represents a promising strategy to overcome this resistance.
Mevrometostat is a potent and selective small molecule EZH2 inhibitor. Enzalutamide is an ARPI approved for mCRPC, nonmetastatic CRPC, metastatic castration-sensitive prostate cancer (CSPC), and nonmetastatic CSPC with biochemical recurrence at high risk for metastasis. Currently, there are no established guidelines for sequencing treatments post first-line ARPI (e.g., abiraterone) in mCRPC. Clinical decisions are primarily based on prior treatments and patient characteristics. While switching from abiraterone to enzalutamide can offer benefits, cross-resistance may limit its effectiveness.
The MEVPRO-1 trial (NCT06551324) includes mCRPC patients previously treated with abiraterone for ≥12 weeks. Approximately 600 patients will be randomized 1:1 to receive either mevrometostat (875 mg twice daily with food) plus enzalutamide (160 mg once daily) or physician’s choice of enzalutamide (160 mg once daily) or docetaxel (75 mg/m2 intravenously every 21 days). The physician’s choice must be pre-specified prior to randomization. Randomization is stratified by previous docetaxel use in the mCSPC setting, physician’s choice of comparator (enzalutamide or docetaxel), and presence of hepatic metastases.
The primary efficacy endpoint is radiographic progression-free survival (rPFS), assessed by blinded central radiology review per RECIST 1.1 (soft tissue) and PCWG3 (bone) criteria. Key secondary endpoints include overall survival, overall response rate, duration of response, patient-reported outcomes, pharmacokinetics, and circulating tumor DNA burden. Safety is monitored through adverse event reporting, physical examinations, vital signs, and clinical laboratory tests.
The first patient was enrolled on October 21, 2024, and the study is expected to be completed in October 2028. Five countries are currently enrolling patients in MEVPRO-1.
