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.

Overall survival (OS)

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

Time frame: Randomization up to approximately 9 years

Objective response in measurable soft tissue disease

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.

Time frame: Randomization up to approximately 4 years

Duration of Response (DoR) in measurable soft tissue disease

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.

Time frame: Randomization up to approximately 4 years

Prostate Specific Antigen Response

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 frame: Randomization up to approximately 4 years

Time to prostate specific antigen (PSA) progression

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

Time frame: Randomization up to approximately 4 years

Time to initiation of antineoplastic therapy

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

Time frame: Randomization up to approximately 4 years

Time to first symptomatic skeletal event

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

Time frame: Randomization up to approximately 4 years

Time from randomization to CRPC

Time from randomization to the first date of CRPC event.

Time frame: Randomization up to approximately 4 years

Incidence of Adverse Events

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.

Time frame: Randomization up to approximately 5 years

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

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

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

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

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.

Time frame: Randomization up to approximately 5 years

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

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 frame: Randomization up to approximately 5 years

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

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

Time frame: Randomization up to approximately 5 years

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

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

Time frame: Randomization up to approximately 5 years

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

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

Time frame: Randomization up to approximately 5 years

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

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.

Time frame: Randomization up to approximately 5 years

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

Evaluation of ctDNA burden at baseline and on study.

Time frame: Baseline up to approximately 4 years