RE-sensitizing With Supraphysiologic Testosterone to Overcome REsistance (The RESTORE Study)

Inclusion Criteria: * Performance status ≤2 * Age ≥18 years * Histologically-confirmed adenocarcinoma of the prostate * Progressing on continuous androgen ablative therapy (either surgical castration or LHRH agonist). * Documented castrate level of serum testosterone (\<50 ng/dl). * For Cohorts A and B, patients must have progressed on prior treatment with enzalutamide or abiraterone acetate + prednisone (by PSA criteria or radiographically). * For castration-only Cohort C, patients must have developed castrate resistant prostate cancer after progressing on first line hormone therapy with either surgical castration or LHRH agonist or LHRH agonist plus an anti-androgen. * For Cohort D patients must have inactivating somatic or germline mutations in ≥2 of the genes TP53, PTEN, RB1 * Patients progressing on LHRH agonist plus an anti-androgen as first line therapy must be off anti-androgen for 4 weeks prior to first treatment with testosterone. * Patients with rising PSA on two successive measurements at least two weeks apart. * For Cohort A (enzalutamide) and Cohort B (abiraterone acetate): * Prior treatment with up to 2 additional second line hormone therapies, including ketoconazole is allowed. * Patients who have progressed on both enzalutamide and abiraterone acetate are eligible and post-BAT will be retreated with the last second line agent they had received (e.g. patient receiving abiraterone then enzalutamide would receive retreatment with enzalutamide post-BAT). * Patients must be withdrawn from enzalutamide or abiraterone acetate for ≥ 4 weeks and have documented PSA increase after the withdrawal period. * Patients receiving prednisone in conjunction with abiraterone acetate must be weaned off prednisone prior to starting BAT. * For Cohort C (castration-only): * Patients must continue on castrating therapy throughout BAT treatment. * No prior second line hormone treatment with flutamide, bicalutamide, nilutamide, enzalutamide, abiraterone, ketoconazole, ARN-509 or other investigational androgen ablative therapies is permitted for Cohort C. * For Cohort D (mutation cohort): * Patients must continue on castrating therapy throughout BAT treatment. * Treatment with first-generation hormonal therapy (i.e. flutamide, bicalutamide, nilutamide), is allowed * Patient must have received at least one and not more than two second generation hormone therapies (i.e. enzalutamide, abiraterone, apalutamide). * For Cohorts A-D, prior docetaxel for hormone-sensitive prostate cancer is permitted if ≤ 6 doses were given in conjunction with first-line androgen deprivation therapy and \>12 months since last dose of docetaxel * For Cohort D, one line of prior chemotherapy with docetaxel or cabazitaxel for metastatic castrate resistant prostate cancer is allowed * Acceptable liver function: * Bilirubin \< 2.5 times institutional upper limit of normal (ULN) * AST (SGOT) and ALT (SGPT) \< 2.5 times ULN * Acceptable renal function: \-- Serum creatinine \< 2.5 times ULN, OR * Acceptable hematologic status: * Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 (1.5 ×109/L) * Platelet count ≥ 100,000 platelet/mm3 (100 ×109/L) * Hemoglobin ≥ 9 g/dL. * At least 4 weeks since prior surgery with full recovery (no persistent toxicity ≥ Grade 1). * Ability to understand and willingness to sign a written informed consent document. Exclusion Criteria: * Pain due to metastatic prostate cancer requiring opioid analgesics. * \>5 sites of visceral disease in lung or liver (nonspecific lung nodules ≤1 cm in diameter are permitted). * Prior treatment with docetaxel or cabazitaxel for metastatic castration-resistant prostate cancer is prohibited. * Prior treatment with one line of chemotherapy for metastatic castration-resistant prostate cancer is allowed for Cohort D * Requires urinary catheterization for voiding due to obstruction secondary to prostatic enlargement thought to be due to prostate cancer or benign prostatic hyperplasia * Evidence of disease in sites or extent that, in the opinion of the investigator, would put the patient at risk from therapy with testosterone (e.g. femoral metastases with concern over fracture risk, spinal metastases with concern over spinal cord compression, lymph node disease with concern for ureteral obstruction). * Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition (including laboratory abnormalities) that could interfere with patient safety or provision of informed consent to participate in this study. * Active uncontrolled infection, including known history of AIDS or hepatitis B or C. * Any psychological, familial, sociological, or geographical condition that could potentially interfere with compliance with the study protocol and follow-up schedule. * Prior history of a thromboembolic event within the last two years and not currently on systemic anticoagulation. * Hematocrit \>50%, untreated severe obstructive sleep apnea, uncontrolled or poorly controlled heart failure \[per Endocrine Society Clinical Practice Guidelines (67)\].