This study will explore whether a combination of the investigational drug mevrometostat (PF-06821497) and enzalutamide will work better than taking enzalutamide alone in participants with mCSPC who are ARPI naïve and have not yet received chemotherapy in the mCSPC setting.

This is a global, multicenter, randomized, double-blind, placebo-controlled Phase 3 study evaluating mevrometostat in combination with enzalutamide versus placebo in combination with enzalutamide in participants with mCSPC who have not received systemic anticancer treatments with the exception of androgen-deprivation therapy (ADT) and first-generation antiandrogen agents. Prior therapy with up to 3 months of ADT (chemical or surgical) is allowed, with no radiographic evidence of disease progression or rising PSA levels prior to Day 1.

This study consists of a Screening Phase, Randomization, Treatment Phase, Safety Follow-up, and Long-Term Follow-up. Participants will be randomized on a 1:1 basis to receive (Arm A) mevrometostat (PF-06821497) in combination with enzalutamide, or (Arm B) placebo in combination with enzalutamide.

Inclusion Criteria

• Male participants aged ≥18 years (or the minimum age of consent in accordance with local regulations) at screening.
• Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features.
• Metastatic prostate cancer documented by positive bone scan (for bone disease) or metastatic lesion(s) on CT or MRI (for soft tissue/visceral disease).
• Resolution of acute effects of any prior therapy to either baseline severity or CTCAE Grade ≤1 (except for AEs which do not constitute a safety risk in the investigator's judgement).
• Participants must have ECOG PS 0 or 1.

Exclusion Criteria

• Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
• Clinically significant cardiovascular disease.
• Known or suspected brain metastasis or active leptomeningeal disease.
• Participants must be treatment naïve at the mCSPC stage, eg, participants cannot have received any cytotoxic chemotherapy with the following exceptions: Treatment with first-generation antiandrogen (ADT) agents is allowed for mCSPC.
• Previous administration with an investigational product (drug or vaccine) within 30 days.
• Use of 5-alpha reductase inhibitors is prohibited within 28 days of randomization.
• Prior surgery from which the participant has not fully recovered at least 28 days prior to randomization
• Current use or anticipated need for drugs that are known strong CYP3A4/5 inhibitors and inducers (with exception of enzalutamide as part of this study).
• Inadequate organ function.
• Known allergic or hypersensitivity reactions to mevrometostat or its excipients or to enzalutamide or its excipients.

Male participants aged ≥18 years (or the minimum age of consent in accordance with local regulations) at screening with a diagnosis of mCSPC.

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.

This is a double-blind study. Participants will receive mevrometostat or matching placebo in a blinded fashion. Participants, investigators and site staff, and sponsor staff will be aware that participants in both study arms are receiving enzalutamide. Enzalutamide will be provided in an open-label manner to participants in each treatment arm.

Participants and their caregivers will be blinded to their assigned study intervention.

Investigators and other site staff will be blinded to participants' assigned study intervention Sponsor staff will be blinded to participants' assigned study intervention, except for sponsor staff involved in the assignment or distribution of study intervention.