Talazoparib Plus Enzalutamide After Progression to Prior ARPi in Metastatic Prostate Cancer

Inclusion Criteria: 1. Male age 18 or older. 2. Histological diagnosis of prostate adenocarcinoma without neuroendocrine differentiation 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 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (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, the pre-treatment new tumor biopsy (fresh-frozen and Formalin-fixed and paraffin-embedded (FFPE) material) could be replaced by an archived tumor biopsy upon agreement from the study chief investigator if such biopsy has been taken after progression to metastatic castration resistance and has both archived fresh-frozen material and a FFPE block with a minimum tumor content over 30 percent. Still the patient must be amenable and willing 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 analysis of the prevalence of somatic and germline aberrations in DNA damage repair genes. 8. Metastatic (M1) prostate cancer documented by bone scan, or soft tissue disease documented 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 bilateral orchiectomy must be in place before screening and must continue throughout the study. 12 .Disease progression after at least 12 weeks of treatment with a prior androgen-receptor signalling inhibitor (ARPi), including abiraterone acetate or a direct AR inhibitor, such as enzalutamide, apalutamide, or darolutamide, for metastatic hormone-sensitive prostate cancer. Note: Patients who previously received Enzalutamide can be recruited but up to a maximum of 6. Those patients will be included directly into the experimental arm. 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 than 50 percent increase 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 and b. Received the last dose of docetaxel equal or higher than 6 months prior to randomization. 14\. Participants who have received prior Lu177-PSMA must meet the following criteria: a. Received a maximum of 6 cycles of docetaxel for mHSPC. b. Received the last dose of Lu177-PSMA equal or higher than 6 months prior to randomization 15. Adequate organ function within 28 days before the first study treatment on Day 1, defined by the following: 1. Haemoglobin greater than or equal to 10 g/dL, no blood transfusions within 14 days before obtaining the haematology laboratory tests at screening, 2. Platelets greater than or equal to 100,000/μL no platelets transfusions within 14 days before obtaining the haematology laboratory tests at screening, 3. Neutrophils greater than or equal to 1500/μL, no growth factors given within 14 days before obtaining the haematology laboratory tests at screening, 4. Serum creatinine less than1.5X ULN or calculated creatinine clearance greater than or equal to 50 mL/min 5. Albumin greater than 3 g/dL, 6. AST or ALT less than 2.5 × ULN (less than 5 × ULN if liver function abnormalities are due to hepatic metastasis). 7. Total serum bilirubin less than 1.5 × ULN (less than 3 × ULN for participants with documented Gilbert syndrome or for whom indirect bilirubin concentrations suggest an extrahepatic source of elevation). 16. Ability to swallow study medication tablets and comply with study requirements. 17\. Agrees to use a condom and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is having sex with a woman who is pregnant, starting contraception at screening and continue throughout the study period and for 3 months after the final treatment administration, (during the treatment period and for at least 90 days after last dose of enzalutamide or at least 120 days after las dose of talazoparib, whichever occurs later) unless the patient is unable to maintain intercourse due to the androgen deprivation. 18\. Subjects must not donate sperm starting at screening and throughout the study period and for 3 months after the final abiraterone acetate administration. 19\. Subject agrees not to participate in another interventional study while with experimental medical products or anticancer drugs not approved in this setting on treatment in this study. Exceptions could be allowed for protocols investigating the survival or quality of life impact of common routine or conventional drugs (i.e. acetylsalicylic acid, statins, oral antidiabetic drugs) as long as they do not intefere with the study treatment and the evaluation of the main study arms. 20\. Willing and able to comply with all scheduled visits, treatment plan, laboratory tests and other study procedures. Exclusion Criteria: 1. Prior ARPi treatment for less than 12 weeks or disease progression (either PSA or radiographic progression) within 6 months of starting abiraterone or ARi. 2. Known or suspected brain metastasis