Phase 3 Randomized Study of Talazoparib with Enzalutamide in Men with DDR Gene Mutated mCSPC

INTERVENTION: Product Name: Talazoparib Product Code: PF‐06944076 Pharmaceutical Form: Capsule, hard INN or Proposed INN: Talazoparib Current Sponsor code: PF‐06944076 Other descriptive name: TALAZOPARIB TOSYLATE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 0.25‐ Pharmaceutical form of the placebo: Capsule, hard Route of administration of the placebo: Oral use Trade Name: Xtandi Product Name: Xtandi 40 mg soft capsules Pharmaceutical Form: Capsule, soft INN or Proposed INN: ENZALUTAMIDE CAS Number: 915087‐33‐1 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 40‐ Product Name: Talazoparib Product Code: PF‐06944076 Pharmaceutical Form: Capsule, hard INN or Proposed INN: Talazoparib Current Sponsor code: PF‐06944076 Other descriptive name: TALAZOPARIB TOSYLATE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 0.1‐ Pharmaceutical form of the placebo: Capsule, hard Route of administration of the placebo: Oral use Product Name: Talazoparib Product Code: PF‐06944076 Pharmaceutical Form: Capsule, hard INN or Proposed INN: Talazoparib Current Sponsor code: PF‐06944076 Other descriptive name: TALAZOPARIB TOSYLATE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 1‐ Pharmaceutical form of the placebo: Capsule, hard Route of administration of the placebo: Oral use CONDITION: Metastatic Castration‐sensitive Prostate Cancer ; MedDRA version: 21.1 Level: PT Classification code 10036909 Term: Prostate cancer metastatic System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) Therapeutic area: Diseases [C] ‐ Cancer [C04] PRIMARY OUTCOME: Main Objective: •To demonstrate that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging investigator‐assessed rPFS, in participants with mCSPC harboring DDR deficiencies. Primary end point(s): •Investigator‐assessed rPFS per RECIST 1.1 (soft tissue disease) and PCWG3 (bone disease) in participants with mCSPC harboring DDR deficiencies. Secondary Objective: Key Secondary Objective ; •To demonstrate that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging OS in participants with mCSPC harboring DDR deficiencies.; Other Secondary Objectives; •To evaluate antitumor activity in participants with mCSPC harboring DDR deficiencies with respect to the following:; •Objective response in measurable soft tissue disease;; •Duration of response in measurable soft tissue disease;; •PSA response;; •Time to PSA progression;; •Time to initiation of antineoplastic therapy;; •Time to first symptomatic skeletal event;; •Opiate use for prostate cancer pain.; •To evaluate safety of talazoparib and enzalutamide administered in combination. ; •To evaluate the PK of talazoparib and enzalutamide (and its N desmethyl metabolite) when dosed in combination.; •Further secondary objectives are detailed in the protocol ; ; Timepoint(s) of evaluation of this end point: Radiographic imaging is every 8 weeks through Week 57, (9, 17, 25, 33, 41, 49, 57) then every 12 weeks thereafter until study intervention is discontinued for radiographic progression. SECONDARY OUTCOME: Secondary end point(s): •OS in participants with mCSPC harboring DDR deficiencies (alpha protected). ; •Proportion of participants with measurable soft tissue disease at baseline with an objective response per RECIST 1.1. ; •Duration of soft tissue response per RECIST 1.1. ; •Proportion of participants with PSA response 50% in participants with detectable PSA values at baseline..; •Time to PSA progression. ; •Time to initiation of antineoplastic therapy.; •Time to first symptomatic skeletal event.; •Time to opiate use for prostate cancer pain.; •Incidence of AEs characterized by type, severity (graded by NCI CTCAE version 4.03), timing, seriousness and relationship to study intervention.; •Predose trough plasma concentrations of talazoparib, enzalutamide and its N‐desmethyl metabolite; •Change from baseline in participant‐reported pain symptoms per BPI‐SF;; •Change from baseline in participant‐reported general health status per EQ‐5D‐5L;; •Change from baseline in participant‐reported cancer specific global health status/QoL, functioning, and symptoms per EORTC QLQ‐C30;; •Time to deterioration in participant‐reported pain symptoms per BPI‐SF;; •Time to definitive deterioration in participant‐reported global health status/QoL per EORTC QLQ‐C30;; •Time to definitive deterioration in participant‐reported disease specific urinary symptoms per EORTC QLQ‐PR25.; •Change from baseline in PGI‐S.; •ctDNA burden at baseline and on study, as assessed using FoundationOne liquid or another suitable validated assay.; Timepoint(s) of evaluation of this end point: As per protocol , through the treatment period and long term follow up. INCLUSION CRITERIA: Participants are eligible to be included in the study only if all of the following criteria apply: Age and Sex: 1.Male participants at least 18 years of age at screening. Refer to Appendix 4 of the protocol for reproductive criteria for male participants. Type of Participant and Disease Characteristics: 2.Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell or signet cell features. If the participant does not have a prior histological diagnosis, a baseline de novo biopsy must be used to confirm the diagnosis and may also be used to support biomarker analysis. 3.Confirmation of DDR gene mutation status by prospective or historical analysis (with sponsor pre‐approval) of blood (liquid biopsy) and/or de novo or archival tumor tissue using FoundationOne Liquid CDx or FoundationOne CDx. 4.Willing to provide tumor tissue when available (de novo or archived) for retrospective molecular profiling analysis, if n