Genomic Biomarker-Selected Umbrella Neoadjuvant Study for High Risk Localized Prostate Cancer

Inclusion Criteria: i. Males ≥ 18 years of age. ii. Histologically confirmed adenocarcinoma of the prostate without pathologic evidence of small cell differentiation at the time of initial diagnosis. Screening biopsy must be performed within 4 months of the screening visit. iii. High-risk localized prostate cancer as defined by at least one of the following: * Any combination of Gleason Score 4+3=7 and Gleason Score 8 (4+4 or 5+3) in ≥6 systematic cores (with ≥1 core Gleason Score 8 \[4+4 or 5+3\] included); * Any combination of Gleason Score 4+3 and Gleason Score 8 (4+4 or 5+3) in ≥3 systematic cores and PSA ≥20 ng/mL (with at least 1 core Gleason Score 8 \[4+4 or 5+3\] included); * Gleason Score ≥9 in at least 1 systematic or targeted core; * At least 2 systematic or targeted cores with Gleason Score ≥8, each with at least 80% involvement"; or * Gleason Score 4+3=7 in at least 6 systematic or targeted cores and PSA ≥20 ng/mL iv. Participants must provide consent blood collection and evaluation of diagnostic prostate tissue for genetic testing at registration and prior to assignment by a central reference laboratory. v. No prior systemic or localized treatment for prostate cancer (exception: up to 12 weeks of luteinizing hormone-releasing hormone agonist or antagonist (LHRHa) and bicalutamide is allowable prior to registration). vi. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix II) and a life expectancy of ≥ 3 years in the opinion of the treating oncologist. vii. Laboratory Requirements: Participants must have adequate end-organ function and all laboratory tests must be performed within 8 weeks prior to registration into master protocol (Table 1). viii. Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to registration in the trial to document their willingness to participate. ix. Archival tissue must be available for genetic analysis. Exclusion Criteria: Participants will be excluded if ANY of the following criteria are met: i. Received more than 12 weeks of LHRHa prior to registration. ii. Stage T4 prostate cancer by clinical examination or radiologic evaluation. iii. Hypogonadism or severe androgen deficiency as determined by the treating physician, or screening serum testosterone less than 50 ng/dL (1.7 nmol/L) iv. Participants with serious illnesses or medical conditions which could cause unacceptable safety risks or would not permit the participant to be managed according to the protocol. This includes but is not limited to: * Active infection or chronic liver disease requiring systemic therapy; * Active or known human immunodeficiency virus (HIV) with detectable viral load; * Participants with uncontrolled hypertension or diabetes. * Uncontrolled or recent clinically significant cardiac disease, including history of any of the following within 12 months prior to screening: * Severe or unstable angina, symptomatic pericarditis, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), clinically significant ventricular arrhythmias or New York Heart Association Class II to IV heart disease, coronary artery bypass grafting, coronary angioplasty, stenting, or myocardial infarction; uncomplicated deep vein thrombosis is not considered exclusionary). * History of any cardiac arrhythmias that preclude prostatectomy or treatment with study drugs, e.g. ventricular, supraventricular, nodal arrhythmias, or conduction abnormality. v. Participants who are unable to swallow oral medication and/or have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). vi. Participants with a history of hypersensitivity to any of the study drugs or any excipient. vii. Participants with a history of non-compliance to medical regimens. viii. Severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the participant inappropriate for registration or prostatectomy. ix. Prior androgen deprivation, chemotherapy, surgery, or radiation for prostate cancer. x. Receiving concurrent androgens, estrogens, or progestational agents, or received any of these agents within the 6 months prior to registration. xi. M1 by conventional imaging (CT, bone scan) or PSMA-PET. Participants with oligometastatic (\<3) metastases by PSMA imaging only who are deemed candidates for radical prostatectomy are eligible.