Talazoparib Plus Enzalutamide After Progression to Abiraterone in Metastatic Prostate Cancer: (TEAM PC)

Inclusion Criteria:

1. Male age 18 or older.

2. Histological diagnosis of prostate adenocarcinoma without neuroendocrinedifferentiation or small cell features.

3. Willing and able to provide written informed consent to participate in the study.Written consent must be given before registration, according to InternationalCouncil for Harmonisation of Technical Requirements for Pharmaceuticals for HumanUse (ICH) / Good clinical practice (GCP), and national/local regulations.

4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

5. Willing to provide tumor biopsies during the study. Note: At study entry, thepre-treatment fresh tumor biopsy could be replaced by an archived tumor biopsy uponagreement from the study chief investigator if such biopsy has been taken afterprogression to metastatic castration resistance and has both archived fresh-frozenmaterial and a Formalin-fixed and paraffin-embedded (FFPE) block with a minimumtumor content more less than30 percent. Still the patient must be amenable andwilling to undergo a new mandatory post-treatment biopsy.

6. Willing to provide blood samples for biomarker analysis.

7. Willing to give consent to sequencing of DNA damage repair (DDR) genes for analysisof the prevalence of somatic and germline aberrations in DNA damage repair genes.

8. Metastatic (M1) prostate cancer documented by bone scan, or soft tissue diseasedocumented by computed tomography (CT), or magnetic resonance imaging (MRI).

9. Asymptomatic or minimally symptomatic prostate cancer at screening.

10. Estimated life expectancy of greater than or equal to 6 months from screening.

11. Ongoing androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone (GnRH) agonist or antagonist for participants who have not undergone bilateralorchiectomy must be in place before screening and must continue throughout thestudy.

12 .Disease progression after at least 12 weeks of treatment with abiraterone for metastatic hormone-sensitive prostate cancer. Progression is defined as:

a. PSA rise of greater than or equal to 25 percent and an absolute increase of greater than or equal to 2 ng/mL above nadir (or baseline for participants with no PSA decline), confirmed by a second PSA value at least 3 weeks later.

and / or b. Limited radiographic progression: maximum of 2 new bone metastases, no new soft tissue metastasis and less than50percentincrease in the size of measurable soft tissue lesions.

13. Participants who have received prior docetaxel must meet the following criteria:

a. Received a maximum of 6 cycles of docetaxel for mHSPC. b. Received the last dose of docetaxel higher than 6 months prior to randomization.

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

15. Haemoglobin greater than or equal to 10 g/dL, no blood transfusions within 14 daysbefore obtaining the haematology laboratory tests at screening,

16. Platelets greater than or equal to 100,000/μL no platelets transfusions within 14days before obtaining the haematology laboratory tests at screening,

17. Neutrophils greater than or equal to 1500/μL, no growth factors given within 14 daysbefore obtaining the haematology laboratory tests at screening,

18. Serum creatinine less than1.5X ULN or calculated creatinine clearance greater thanor equal to 50 mL/min

19. Albumin greater than 3 g/dL,

20. AST or ALT less than 2.5 × ULN (less than 5 × ULN if liver function abnormalitiesare due to hepatic metastasis).

21. Total serum bilirubin less than 1.5 × ULN (less than 3 × ULN for participants withdocumented Gilbert syndrome or for whom indirect bilirubin concentrations suggest anextrahepatic source of elevation).

22. Ability to swallow study medication tablets and comply with study requirements.

23. Agrees to use a condom and another effective method of birth control if he ishaving sex with a woman of childbearing potential or agrees to use a condom ifhe is having sex with a woman who is pregnant, starting contraception atscreening and continue throughout the study period and for 3 months after thefinal treatment administration, unless the patient is unable to maintainintercourse due to the androgen deprivation.

24. Subjects must not donate sperm starting at screening and throughout the studyperiod and for 3 months after the final abiraterone acetate administration.

25. Subject agrees not to participate in another interventional study while ontreatment.

26. Willing and able to comply with all scheduled visits, treatment plan,laboratory tests and other study procedures.

Exclusion Criteria:

1. Prior abiraterone treatment for less than 12 weeks or disease progression (eitherPSA or radiographic progression) within 6 months of starting abiraterone.

2. Disease progression less than 6 months after the last administration of docetaxelfor mHSPC.

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

4. A finding of superscan in a bone scan at screening. Superscan is defined as a bonescan which demonstrates markedly increased skeletal radioisotope uptake relative tosoft tissues in association with absent or faint renal activity (absent kidneysign).

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

6. Use of opiate analgesia for pain from prostate cancer with average Brief paininventory (BPI) questionnaire score higher than 6 and/or uncontrolled prostatecancer-related pain requiring increasing doses of opiates within 4 weeks prior torandomization

7. Prior treatment with an AR-targeted therapy (enzalutamide, apalutamide,darolutamide, ketoconazole) other than abiraterone for mHSPC; chemotherapy otherthan 6 cycles of docetaxel for mHSPC, immunotherapy or radiopharmaceuticals.

8. Therapeutic radiation therapy within, 14 days (7 days for limited-field palliativeradiotherapy) prior to study enrolment, or participants who have not recovered fromradiotherapy-related toxicities to grade less than or equal to 1 according toNCI-CTCAE v.5.0.

9. Major surgery within 4 weeks prior to randomization or participants who have notrecovered from the side effects of any major surgery.

10. Administration of an investigational therapeutic or invasive surgical procedure (notincluding surgical castration) within 30 days of Cycle 1 Day 1 or currently enrolledin an investigational study.

11. History of seizure or any condition that may predispose to seizure (i.e., priorsignificant brain trauma, brain vascular malformation, etc) or subjects that havehad an unexplained loss of consciousness or transient ischemic attacks within 1 yearprevious to scheduled day 1 of treatment.

12. Congenital long QT syndrome or ECG at screening with QT interval corrected usingFridericia's formula (QTcF) greater than 500 milliseconds.

13. articipants with clinically significant cardiovascular disease including but notlimited to any of the following:

14. Stroke, transient ischemic attack, unstable angina pectoris or documentedmyocardial infarction within 12 months prior to study entry.

15. Symptomatic pericarditis or clinically significant pericardial effusion ormyocarditis

16. Documented congestive heart failure (New York Heart Association Class, NYHAfunctional classification III-IV)

17. Uncontrolled, persistent hypertension defined as systolic blood pressure lessthan 170mmHg or diastolic blood pressure less than100mmHg. Subjects with ahistory of hypertension are allowed provided blood pressure is controlled byanti-hypertensive treatment

18. Participants with any of the following cardiac conduction abnormalities: Ventriculararrhythmias except for benign premature ventricular contractions

19. Supraventricular and nodal arrhythmias requiring a pacemaker or not controlledwith medication.

20. Conduction abnormality requiring a pacemaker.

21. Other cardiac arrhythmia not controlled with medication.

22. Any clinically significant gastrointestinal disorder affecting absorption (i.e.,extensive small bowel resection, active inflammatory bowel disease).

23. Active or symptomatic viral hepatitis or chronic liver disease.

24. Known/possible hypersensitivity, allergies to enzalutamide, talazoparib or any ofcapsule excipients.

25. Other malignancy except:

26. Carcinoma in situ or non-melanoma skin cancer.

27. A cancer diagnosed and treated greater than or equal to 5 years beforerandomization with no subsequent evidence of recurrence.

28. Any condition or situation which, in the opinion of the investigator, would put thesubject at risk, may confound study results, or interfere with the subject'sparticipation in this study.