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.

Radiographic Progression Free Survival (rPFS)

Timeframe: Randomization up to approximately 4 years

rPFS is defined as the time from randomization until PD based on BICR assessment per RECIST v1.1 (soft tissue disease) and PCWG3 (bone disease), or death due to any cause, whichever occurs first.

Overall survival (OS)

Timeframe: Randomization up to approximately 9 years

OS defined as the time from the date of randomization until the date of death due to any cause.

Objective response in measurable soft tissue disease

Timeframe: Randomization up to approximately 4 years

The proportion of participants with measurable soft tissue disease at baseline who have a confirmed objective response of CR or PR per RECIST v1.1 will be summarized along with the 95% CI.

Duration of Response (DoR) in measurable soft tissue disease

Timeframe: Randomization up to approximately 4 years

The DoR is defined as the time from the first objective evidence of soft tissue response (CR or PR, whichever is earlier) to radiographic progression or death due to any cause whichever occurs first.

Prostate Specific Antigen Response

Timeframe: Randomization up to approximately 4 years

The proportion of participants with a 50% decline from baseline in PSA that is confirmed by a second consecutive value at least 21 days later in participants with detectable PSA values at baseline will be calculated for each treatment arm.

Time to prostate specific antigen (PSA) progression

Timeframe: Randomization up to approximately 4 years

Time from the date of randomization to the date of the first PSA progression.

Time to initiation of antineoplastic therapy

Timeframe: Randomization up to approximately 4 years

Time from randomization to first use of new antineoplastic therapy for prostate cancer.

Time to first symptomatic skeletal event

Timeframe: Randomization up to approximately 4 years

Time from randomization to first tumor-related symptomatic bone fracture, surgery or radiotherapy to the bone, and spinal cord compression, whichever occurs first.

Time from randomization to CRPC

Timeframe: Randomization up to approximately 4 years

Time from randomization to the first date of CRPC event.

Incidence of Adverse Events

Timeframe: Randomization up to approximately 5 years

Type, incidence, severity \[as graded by National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) v5.0\], seriousness and relationship to study medications of AEs.

To evaluate the PK of mevrometostat when dosed in combination with enzalutamide

Timeframe: Cycle 3 Day 1 to last PK draw at Cycle 5 Day 1 (cycle length is 28 days)

PK characterized by pre-dose trough and post-dose plasma concentrations of PF-06821497 at selected visits.

Change from baseline in patient reported pain symptoms per Brief Pain Inventory-Short Form (BPI-SF)

Timeframe: Randomization up to approximately 5 years

Analysis of Brief Pain Inventory-Short Form (BPI-SF) will be based on the pain severity score (mean of individual BPI-SF items 3, 4, 5 and 6), the pain interference score (mean of items 9A-9G), and the single BPI-SF Item 3.

Change from baseline in health-related quality of life (HRQoL) per Functional Assessment of Cancer Therapy - Prostate (FACT-P)

Timeframe: Randomization up to approximately 5 years

Change from baseline in HRQoL (FACT-P total score) will be presented. The FACT-P total score will be calculated based on the participant responses to the 39 items in the FACT-P questionnaire.

Time to definitive deterioration in patient-reported health related quality of life (HRQoL) per FACT-P

Timeframe: Randomization up to approximately 5 years

Defined as the time from randomization to onset of definitive deterioration in FACT-P total score, which is defined as \>10 point decrease from baseline and no subsequent observations with a \<10 point decrease from baseline FACT-P total score

Patient-reported outcomes in cancer specific symptoms - time to definitive deterioration

Timeframe: Randomization up to approximately 5 years

Change from baseline and time to definitive deterioration in participant-reported prostate cancer specific functioning, and symptoms per EORTC QLQ-PR25

Change from baseline and time to confirmed deterioration in participant-reported fatigue symptoms per BFI

Timeframe: Randomization up to approximately 5 years

Change from baseline and time to confirmed deterioration in participant-reported fatigue symptoms (fatigue severity and fatigue interference) as per BFI.

Change from baseline in participant-reported general health status per EQ-5D-5L

Timeframe: Randomization up to approximately 5 years

Participants will self-rate their current state of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression by choosing 1 of 5 possible responses that record the level of severity (no problems, slight problems, moderate problems, severe problems, or extreme problems) within each dimension.

To assess circulating tumor DNA (ctDNA) at baseline and on treatment to evaluate tumor burden

Timeframe: Baseline up to approximately 4 years

Evaluation of ctDNA burden at baseline and on study.

Prostate Specific Antigen Response, Undetectable PSA after Randomization

Timeframe: Randomization up to approximately 4 years

The proportion of participants with undetectable PSA values after randomization, in participants with detectable PSA values at baseline, will be calculated for each treatment arm.