Clinical Research Directory

Inclusion Criteria: * Patient must be ≥ 18 years of age * Patient must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 * Patient must have documented histologically confirmed adenocarcinoma of the prostate * Patient must have evidence of metastatic castration resistant prostate cancer (mCRPC) defined by Prostate Cancer Working Group 3 criteria as follows: * Prostate-specific antigen (PSA) progression defined as PSA ≥ 2 ng/mL and rising on two successive measurements at least 14 days apart (most recent PSA value must be within 28 days prior to randomization) AND * Castrate serum testosterone level ≤ 50 ng/dL * Patient must not be on systemic immunosuppressive medication, including steroids (if doses exceed the equivalent of prednisone 10 mg daily). Short courses of steroids, e.g., "burst", which are discontinued prior to randomization are acceptable. Patients on inhaled, intranasal, intra-articular and/or topical steroids are eligible * Patients must have progressed on prior androgen receptor pathway inhibitors (ARPI) including, but not limited to, abiraterone, enzalutamide, apalutamide, or darolutamide. There must be at least a 2-week washout period after stopping ARPI prior to randomization * NOTE: Prior bicalutamide is allowed and does not count as an ARPI * Patient must not have prior chemotherapy for the treatment of mCRPC. Patient may have received docetaxel for the treatment of hormone-sensitive prostate cancer * NOTE: This includes high dose testosterone therapy for prostate cancer * Patient must have at least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by CT, MRI and/or bone scan and is suitable for repeated assessment. Baseline imaging must be obtained within 28 days prior to randomization * Patient must not have current cancer-related pain requiring the use of opiates at the time of randomization * Patient must not have received any systemic therapy or radiotherapy within 14 days prior to randomization * NOTE: Luteinizing hormone-releasing hormone (LHRH) agonist/antagonist treatment is allowed * Patient must not have evidence of disease that, in the opinion of the investigator, would put the patient at risk from testosterone therapy (i.e., femoral metastases with concern over fracture risk, spinal or epidural metastases with concern over spinal cord compression) * Patient must not have tumor causing urinary outlet obstruction that requires self-catheterization for voiding. Patients with indwelling catheter (e.g., foley or suprapubic catheter) for urinary obstruction are eligible. Patients that require catheterization to void secondary to benign strictures or other non-cancer causes are eligible * Patient must not have prior history of deep venous thrombosis or pulmonary embolism within 5 years prior to randomization unless they are receiving therapeutic anticoagulation * Patient must not expect to father children by using accepted and effective method(s) of contraception or by abstaining from heterosexual intercourse for the duration of their participation in this study treatment and for four months after the last dose of Arm A protocol treatment and for 3 months after the last dose of Arm B protocol treatment * Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible * Hemoglobin (Hgb) \> 7 g/dL and \< 17 g/dL (obtained ≤ 14 days prior to protocol randomization) * Leukocytes ≥ 3,000/mm\^3 (obtained ≤ 14 days prior to protocol randomization) * Absolute neutrophil count (ANC) ≥ 1,500/mm\^3 (obtained ≤ 14 days prior to protocol randomization) * Platelets ≥ 100,000/mm\^3 (obtained ≤ 14 days prior to protocol randomization) * Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (obtained ≤ 14 days prior to protocol randomization) * Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) ≤ 3.0 × institutional ULN (obtained ≤ 14 days prior to protocol randomization) * Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m\^2 (obtained ≤ 14 days prior to protocol randomization) * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load * Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression * Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial * Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2 or better * Patient must be English or Spanish speaking to be eligible for the QOL component of the study * NOTE: Sites cannot translate the associated QOL forms