Sponsor: Pfizer (industry)
Phase: 3
Start date: Oct. 22, 2024
Planned enrollment: 900
Mervometostat (also spelled Mevrometostat; development code PF-06821497) is an oral, selective inhibitor of the histone methyltransferase EZH2 under clinical evaluation, most prominently in metastatic castration‑resistant prostate cancer (mCRPC), including randomized dose‑expansion data and an ongoing phase 3 trial in combination with enzalutamide. Preclinical chemistry and target engagement for PF‑06821497 have been published, and multiple ASCO meeting abstracts have reported early clinical efficacy and safety signals. (pubs.acs.org)
Note: The foundational phase 1/2 program (NCT03460977) also included follicular lymphoma and small‑cell lung cancer cohorts; public efficacy details to date are concentrated in the mCRPC combination setting. (ascopubs.org)
ClinicalTrials.gov identifier for the foundational study: NCT03460977. (pfizeroncologydevelopment.com)
Last updated: Oct 2025
Goal: To determine whether adding the EZH2 inhibitor PF-06821497 (mevrometostat) to enzalutamide improves outcomes versus enzalutamide alone in men with metastatic castration-resistant prostate cancer (mCRPC) who are naïve to AR pathway inhibitors and abiraterone.
Patients: Adult men with histologically or cytologically confirmed prostate adenocarcinoma without small cell features, metastatic to bone and/or soft tissue, with progression in the castrate setting, ECOG 0–1 and life expectancy ≥12 months. Patients must be treatment-naïve in the mCRPC setting, allowing prior ADT and first-generation antiandrogens; docetaxel for mCSPC is permitted if no progression occurred during or within 3 months of completion. Key exclusions include clinically significant cardiovascular disease, active inflammatory GI disease or prior major gastric surgery, brain metastases or significant seizure history, recent or active suicidal ideation/behavior, prior myelodysplastic syndrome/AML or most other malignancies, prior ARSi, abiraterone, PARP inhibitor monotherapy, radioligand therapy, or other systemic therapy for mCRPC, recent investigational agents, and inadequate organ function.
Design: Global, multicenter, randomized, double-blind, placebo-controlled Phase 3 trial. Approximately 900 participants will be randomized 1:1 to experimental combination versus placebo control, with treatment, safety follow-up, and long-term follow-up phases.
Treatments: Arm A: PF-06821497 875 mg orally twice daily plus enzalutamide 160 mg once daily. Arm B: matching placebo twice daily plus enzalutamide 160 mg once daily. PF-06821497 (mevrometostat) is a potent, selective inhibitor of EZH2, the catalytic subunit of PRC2, reducing H3K27 methylation and reactivating silenced genes implicated in tumor growth and lineage plasticity. In early-phase studies in mCRPC, mevrometostat demonstrated manageable safety and signals of activity as monotherapy and with enzalutamide, including a reported median rPFS of about 17 months and objective responses in measurable disease. The rationale is to enhance ARSI benefit by epigenetic modulation via EZH2 inhibition. Enzalutamide is a standard androgen receptor signaling inhibitor that blocks AR nuclear translocation and transcriptional activity in mCRPC.
Outcomes: Primary endpoint: radiographic progression-free survival by BICR using RECIST v1.1 for soft tissue and PCWG3 for bone, or death. Key secondary endpoints include overall survival; time to pain progression (alpha protected); duration of response in measurable soft tissue disease; time to PSA progression; PSA50 response rate; time to initiation of any antineoplastic therapy and to first cytotoxic chemotherapy; time to first symptomatic skeletal event; PFS on next-line therapy; safety and tolerability (CTCAE v5.0); pharmacokinetics of PF-06821497 with enzalutamide; exploratory biomarkers including ctDNA burden; and patient-reported outcomes (BPI-SF, FACT-P, EQ-5D-5L, PRO-CTCAE), including time to definitive HRQoL deterioration.
Burden on patient: Moderate. The regimen consists of oral medications, which is convenient, but the Phase 3 design entails regular clinic visits for safety assessments, labs, and imaging for rPFS (typically every 8–12 weeks), serial PSA testing, and patient-reported outcome questionnaires. There are scheduled PK blood draws through at least six cycles and ctDNA sampling, adding venipuncture burden. No protocol-mandated biopsies or infusions are specified, and travel frequency should be similar to standard mCRPC monitoring with added early-cycle PK visits, resulting in a moderate overall burden.
Last updated: Oct 2025
Inclusion Criteria:
* Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features.
* Metastatic disease in bone documented on bone scan, or in soft tissue documented on CT/MRI scan.
* Progressive disease in the setting of medical or surgical castration.
* ECOG performance status 0 or 1, with a life expectancy of ≥12 months as assessed by the investigator.
Exclusion Criteria:
* Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that make the participant inappropriate for the study.
* Known history of active inflammatory gastrointestinal disease, chronic diarrhea, or previous gastric resection or lap-band surgery.
* Clinically significant cardiovascular disease.
* Known or suspected brain metastasis or active leptomeningeal disease or clinically significant history of seizure.
* Any history of myelodysplastic syndrome, acute myeloid leukemia, or any other prior malignancy with a few exceptions.
* Participants must be treatment naïve at the mCRPC stage, eg, no cytotoxic chemotherapy, radio-ligand therapy (i.e. 177Lu- PSMA-617), CDK4/6 inhibitors, 5-alpha reductase inhibitors for prostate cancer in any setting, androgen receptor signaling inhibitors (ARSi) including enzalutamide, apalutamide, darolutamide, poly ADP-ribose polymerase (PARP) monotherapy or other systemic anti-cancer treatment with the following exceptions:
1. Treatment with first-generation antiandrogen (ADT) agents;
2. Docetaxel treatment is allowed for mCSPC, as long as no signs of failure, or disease progression occurred during treatment or within 3 months of treatment completion.
* Previous administration with an investigational product (drug or vaccine) within 30 days or 5 half-lives preceding the first dose of study intervention (whichever is longer).
* Inadequate organ function.
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Tacoma, Washington, 98405, United States
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Seattle, Washington, 98195, United States
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La Serena, Coquimbo Region, 1720430, Chile
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Shenyang, 110001, China
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Napoli, 80131, Italy
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San Diego, California, 92123, United States
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