This study will explore whether a combination of the investigational drug PF-06821497 and enzalutamide will work better than taking enzalutamide alone in participants with mCRPC who are ARSi or abiraterone naïve.

This is a global, multicenter, randomized Phase 3 study evaluating PF-06821497 (mevrometostat) in combination with enzalutamide versus placebo in combination with enzalutamide in participants with mCRPC where no systemic anti-cancer treatments have been initiated after documentation of mCRPC with the exception of ADT (androgen deprivation therapy) and first-generation anti-androgen agents. Prior treatment with any of the ARSi's enzalutamide, darolutamide, apalutamide, or abiraterone acetate, is not permitted in any setting. Chemotherapy is permitted in the castrate sensitive setting.

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) PF-06821497 in combination with enzalutamide, or (Arm B) placebo in combination with enzalutamide.

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 in the past year or suicidal behavior in the past 5 years 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, estrogens, progestins, cyproterone acetate;
  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.

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 PF-06821497 or matching placebo in a blinded fashion, as indicated in Section 6.1. 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.