Overall survival (OS)

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

Randomization up to approximately 5 years

To demonstrate that PF-06821497 in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging TTPP

TTPP (alpha protected): assessed using time to first ≥2-point increase from baseline score on BPI-SF Item 3 (Worst Pain) observed at 2 consecutive visits or the initiation of short- or long-acting opioid use for pain

Randomization up to approximately 3 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.

Randomization up to approximately 3 years.

Time to prostate specific antigen (PSA) progression.

Time from the date of randomization to the date of the first PSA progression. PSA progression is defined as a ≥25% increase in PSA with an absolute increase of ≥2 ng/mL above the nadir (or baseline for participants with no PSA decline), confirmed by a second consecutive PSA value at least 21 days later.

Randomization up to approximately 3 years

Prostate Specific Antigen Response

Proportion of participants with PSA response ≥50% in participants with detectable PSA values at baseline.

Randomization up to approximately 3 years.

Time to initiation of antineoplastic therapy.

Time from randomization to first use of new antineoplastic therapy.

Randomization up to approximately 3 years.

Time to initiation of cytotoxic chemotherapy.

Time from randomization to first use of new cytotoxic chemotherapy.

Randomization up to approximately 3 years

Time to first symptomatic skeletal event

Time from randomization to first symptomatic skeletal event (symptomatic bone fractures, spinal cord compression, surgery or radiation to the bone whichever is first).

Randomization up to approximately 3 years.

Progression free survival on next line of therapy

the time from the date of randomization to the first occurrence of investigator-determined disease progression (PSA progression, progression on imaging, or clinical progression) or death due to any cause, whichever occurs first, while the participant was receiving first subsequent therapy for prostate cancer.

Randomization up to approximately 3 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.

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.

Baseline up to approximately 3 years.

To evaluate the PK of PF-06821497 when dosed with enzalutamide

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

Cycle 1 Day 15 to last PK draw at Cycle 6 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 which asks the patient to rate pain at its worst in the last 24 hours.

Randomization up to approximately 5 years

Change from baseline in BPI-SF Item 3 (Worst Pain) at Cycle 7 Day 1 (Week 25)

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 which asks the patient to rate pain at its worst in the last 24 hours.

Randomization up to Week 25

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. Each item is rated on a 0 to 4 Likert-type scale and then combined to produce the FACT-P total score (0-156), with higher scores representing better health-related quality of life.

Randomization up to approximately 5 years

Change from baseline in patient reported health status per European Quality of Life 5-Dimension 5 Level (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. The questionnaire also includes a visual analog scale to self-rate general health state on a scale from "the worst health you can imagine" to "the best health you can imagine."

Randomization up to approximately 5 years

Symptomatic toxicity as measured by items from the Patient-Reported Outcome CTCAE (PRO-CTCAE)

Each selected PRO-CTCAE items will be assessed related to one or more attributes that include counts for the frequency, severity, and/or interference with usual or daily activities.

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 \

Randomization up to approximately 5 years