Study of Talazoparib With Enzalutamide in Men With DDR Gene Mutated mCSPC

Inclusion Criteria:

1. Male participants at least 18 years of age at screening (20 years for Japan, 19years for Republic of Korea).

2. Histologically or cytologically confirmed adenocarcinoma of the prostate withoutneuroendocrine differentiation, small cell or signet cell features. If theparticipant does not have a prior histological diagnosis, a baseline de novo biopsymust be used to confirm the diagnosis and may also be used to support biomarkeranalysis.

3. Confirmation of DDR gene mutation status by prospective or historical analysis (withsponsor pre-approval) of blood (liquid biopsy) and/or de novo or archival tumortissue using FoundationOne Liquid CDx or FoundationOne CDx.

4. Willing to provide tumor tissue when available (de novo or archived) forretrospective molecular profiling analysis, if not already provided as part ofinclusion criterion 3.

5. Unless prohibited by local regulations or ethics committee decision, consent to asaliva sample collection for retrospective sequencing of the same DDR genes testedon tumor tissue and blood (liquid biopsy), or a subset thereof, and to serve as agermline control in identifying tumor mutations.

6. Ongoing ADT with a GnRH agonist or antagonist for participants who have notundergone bilateral orchiectomy must be initiated before randomization and mustcontinue throughout the study.

7. Metastatic prostate cancer documented by positive bone scan (for bone disease) ormetastatic lesions on CT or MRI scan (for soft tissue). Participants whose diseasespread is limited to regional pelvic lymph nodes are not eligible. Note: a findingof superscan at baseline is exclusionary.

8. Prior treatment of mCSPC with docetaxel is not permitted.

9. Treatment with estrogens, cyproterone acetate, or first-generation anti-androgens isallowed until randomization.

10. Other prior therapy allowed for mCSPC; ≤3 months of ADT (chemical or surgical) withor without approved NHT in mCSPC (ie, abiraterone + prednisone, apalutamide, orenzalutamide), if required prior to randomization, with no radiographic evidence ofdisease progression or rising PSA levels prior to Day 1.

11. Participant may have received palliative radiation or surgery for symptomaticcontrol secondary to prostate cancer, which should have been completed at least 2weeks prior to randomization. NOTE: Radical prostatectomy or definitive radiotherapyto the primary tumor for metastatic castration-sensitive prostate cancer withcurative intent is not permitted.

12. ECOG performance status 0 or 1.

13. Adequate organ function within 28 days before the first study treatment on Day 1,defined by the following:

• ANC ≥1500/µL, platelets ≥100,000/µL, or hemoglobin ≥9 g/dL (may not havereceived growth factors or blood transfusions within 14 days before obtainingthe hematology laboratory tests at screening).

• Total serum bilirubin <1.5 × ULN (<3 × ULN for participants with documentedGilbert syndrome or for whom indirect bilirubin concentrations suggest anextrahepatic source of elevation).

• AST or ALT <2.5 × ULN (<5 × ULN if liver function abnormalities are due tohepatic metastasis).

• Albumin >2.8 g/dL.

• eGFR ≥30 mL/min/1.73 m2 by the MDRD equation.

14. Sexually active participants that in the opinion of the investigator are capable ofejaculating, must agree to use a condom when having sex with a partner (female ormale) from the time of the first dose of study treatment through 4 months after lastdose of study treatment (or, if talazoparib/placebo has been stopped more than amonth earlier than enzalutamide, through 3 months after last dose of enzalutamide).Must also agree for female partner of childbearing potential to use an additionalhighly effective form of contraception from the time of the first dose of studytreatment through 4 months after last dose of study treatment (or, if talazoparib /placebo has been stopped more than a month earlier than enzalutamide, through 3months after last dose of enzalutamide) when having sex.

15. Must agree not to donate sperm from the first dose of study treatment to 4 monthsafter the last dose of study treatment (or, if talazoparib/placebo has been stoppedmore than a month earlier than enzalutamide, through 3 months after last dose ofenzalutamide).

16. Participants who are willing and able to comply with all scheduled visits, treatmentplan, laboratory tests, lifestyle considerations, and other study procedures,including being able to manage electronic diaries. The PRO assessments are notrequired to be completed if a patient does not understand the language(s) availablefor a specific questionnaire and/or cannot complete the specific questionnaireindependently.

17. Capable of giving signed informed consent.

18. For France only: Participants affiliated with the social security system orbeneficiaries of an equivalent system.

Exclusion Criteria:

1. Other acute or chronic medical (concurrent disease, infection, including chronicstable HIV, HBV, or HCV infection, or co-morbidity) or psychiatric conditionincluding recent (within the past year) or active suicidal ideation/behavior orlaboratory abnormality that interferes with a participant's ability to participatein the study, may increase the risk of associated with study participation or studytreatment administration, or may interfere with the interpretation of study results,and, in the investigator's judgment, make the participant inappropriate for entryinto the study. HIV/HBV/HCV testing is not required unless mandated by local healthauthority.

2. History of seizure or any condition (as assessed by investigator) that maypredispose to seizure (eg, prior cortical stroke, significant brain trauma),including any history of loss of consciousness or transient ischemic attack within 12 months of randomization.

3. Major surgery (as defined by the investigator) within 4 weeks before randomization.

4. Known or suspected brain metastasis or active leptomeningeal disease.

5. Symptomatic or impending spinal cord compression or cauda equina syndrome.

6. Any history of MDS, AML, or prior malignancy except for the following:

• Carcinoma in situ or non-melanoma skin cancer.

• A cancer diagnosed and treated ≥3 years before randomization with no subsequentevidence of recurrence.

• American Joint Committee on Cancer Stage 0 or Stage 1 cancer <3 years beforerandomization that has a remote probability of recurrence in the opinion of theinvestigator and the sponsor.

7. In the opinion of the investigator, any clinically significant gastrointestinaldisorder affecting absorption.

8. Clinically significant cardiovascular disease, including any of the following:

• Myocardial infarction or symptomatic cardiac ischemia within 6 months beforerandomization.

• Congestive heart failure New York Heart Association class III or IV.

• History of clinically significant ventricular arrhythmias (eg, sustainedventricular tachycardia, ventricular fibrillation, torsade de pointes) within 1year before screening.

• History of Mobitz II second degree or third-degree heart block unless apermanent pacemaker is in place.

• Hypotension as indicated by systolic blood pressure <86 mm Hg at screening.

• Bradycardia as indicated by a heart rate of <45 beats per minute on thescreening electrocardiogram.

• Uncontrolled hypertension as indicated by systolic blood pressure >170 mm Hg ordiastolic blood pressure >105 mm Hg at screening. However, participants can berescreened after adequate control of blood pressure is achieved.

9. Active COVID-19 infection detected by viral test or based on clinical diagnosis (asassessed by investigator). Asymptomatic participants with no active COVID-19infection detected but positive antibody tests, indicating past infection areallowed.

10. Prior ADT in the adjuvant/neoadjuvant setting, where the completion of ADT was lessthan 12 months prior to randomization and the total duration of ADT exceeded 36months.

11. Participant received treatment with systemic glucocorticoids greater than theequivalent of 10 mg per day of prednisone within 4 weeks prior to randomization,intended for the treatment of prostate cancer.

12. Any previous treatment with DNA-damaging cytotoxic chemotherapy (ie, platinum basedtherapy) within 5 years prior to randomization, except for indications other thanprostate cancer.

13. Prior treatment with a PARPi, or known or possible hypersensitivity to enzalutamide,any of enzalutamide capsule excipients or to any talazoparib/placebo capsuleexcipients.

14. Prior treatment in any setting with NHT, except as described in Inclusion Criterion

#10.

15. Current use of potent P-gp inhibitors within 7 days prior to randomization.

16. Treatment with any investigational study intervention within 4 weeks beforerandomization. Exception: COVID-19 vaccines authorized under an emergency useauthorization (or equivalent) can be administered without a washout period.

17. Baseline 12-lead ECG that demonstrates clinically relevant abnormalities that mayaffect participant safety or interpretation of study results (eg, QTcF interval >470msec, complete LBBB, signs of an acute or indeterminate age myocardial infarction,ST-T interval changes suggestive of myocardial ischemia, second or third degree AVblock, or serious bradyarrhythmias or tachyarrhythmias). If the baseline uncorrectedQT interval is >470 msec, this interval should be rate-corrected using theFridericia method and the resulting QTcF should be used for decision making andreporting. If QTc exceeds 470 msec, or QRS exceeds 120 msec, the ECG should berepeated 2 more times and the average of the 3 QTc or QRS values should be used todetermine the participant's eligibility. Computer-interpreted ECGs should beoverread by a physician experienced in reading ECGs before excluding participants.

18. Investigator site staff or Sponsor employees directly involved in the conduct of thestudy, site staff otherwise supervised by the investigator, and their respectivefamily members.

19. For France only: Persons deprived of their liberty by a judicial or administrativedecision, persons undergoing psychiatric care, as well as adults subject to a legalprotection measure (guardianship, curatorship, and safeguard of justice) covered byArticles 1121-6 to 1121-8 of the Public Health Code.