A Study Comparing ARB With Radium-223 vs ARB Therapy With Placebo and the Effect Upon Survival for mCRPC Patients

Inclusion Criteria: 1. Able and willing to provide informed consent. 2. Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma. 3. Men ≥ 18 years. 4. ECOG performance status of 0 or 1 at screening. 5. Metastatic to bone with ≥ 2 bone metastases (area of increased uptake on 99mTc bone scan); equivocal lesions on the bone scan must be confirmed by standard X-ray, CT, or MRI. 6. Patients must have progressive metastatic castration-resistant prostate cancer (mCRPC) at screening and on androgen deprivation therapy (ADT) as evidenced by either: 1. For patients who manifest disease progression solely as a rising prostate-specific antigen (PSA) level - documentation of a sequence of two rising PSA values at a minimum of 1-week apart with the Screening value ≥1 ng/ml (see Appendix D); 2. For patients with disease progression manifested in the bone, irrespective of progression by rising PSA - defined by the appearance of 2 or more new skeletal lesions demonstrated by 99Tc bone imaging. Ambiguous results should be confirmed by other imaging modalities than bone scan and x-ray (e.g.: CT-scan or MRI). 3. For patients with disease progression manifested at nodal sites, irrespective of progression by rising PSA - progression defined per RECIST 1.1. 7. Ongoing ADT with luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or bilateral orchiectomy. 8. Use of bone health agents (denosumab or zoledronic acid or other bisphosphonates) starting any time prior to R1 unless contraindicated or considered not in the best interest of the patient. A waiver must be approved by the medical monitor if bone health agents cannot be used. Bone health agents should be continued throughout both RT1 and RT2 treatment periods. 9. Adequate bone marrow and organ function as defined by: 1. Hemoglobin ≥ 10.0 g/dL 2. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 3. Platelets ≥ 100 x 109/L 4. Serum creatinine ≤ 1.95 mg/dL 5. Estimated creatinine clearance \>/= 30 mL/min by Cockroft-Gault calculation 6. Alanine aminotransferase (ALT) ≤ 175 U/L 7. Aspartate aminotransferase (AST) ≤ 100 U/L 8. Total bilirubin ≤ 1.8 mg/dL (unless the patient a diagnosis of Gilbert's disease or a similar syndrome involving slow conjugation of bilirubin; in patients with Gilbert's, the total bilirubin should be less than 6 mg/dL if patient has Gilbert's and the elevation should be seen in the unconjugated or indirect bilirubin measurement) 9. LDH ≤ 224 U/L at screening. 10. Albumin ≥ 2.5 g/dL 10. Fertile male patients, defined as all males physiologically capable of conceiving offspring with female partners of child-bearing potential, must be willing to use condoms plus spermicidal agent during the study treatment period and for 6 months after the last dose of study drug, and not father a child or donate sperm during this period. 11. The treating site investigator deems RT1 (Enzalutamide or Darolutamide) treatment safe and feasible. Subjects must meet the remaining inclusion criteria in order to be qualified for the second randomization (R2). Only subjects that complete the initial 12 weeks of run-in RT1 should be evaluated. Prior inclusion criteria do not need to be re-evaluated: 12. Patients must have a documented ≥ 30% decline of PSA at any time during the 12 weeks of RT1. 13. Patients must have no evidence of visceral metastatic disease at the time of RT2 randomization 14. Ongoing treatment with RT1 and bone health agents at time of RT2 randomization. 15. The treating site investigator deems RT2 (Ra-223 dichloride) treatment safe and feasible. Exclusion Criteria: 1. Pathological finding consistent with small cell carcinoma of the prostate. 2. Prior chemotherapy for CRPC. Prior docetaxel for hormone-sensitive disease is permitted under the following conditions: started within 3 months of ADT initiation, given for a maximum of 6 cycles and progression occurred \> 6 months after the last dose of docetaxel. 3. Prior treatment for mCRPC or CRPC. However, the following therapies are permitted and not exclusionary: Sipuleucel-T, 5-alpha-reductase inhibitors, estrogens, or older antiandrogens (such as flutamide, bicalutamide, or nilutamide). 4. Prior treatment for more than 2 months with CYP17 inhibitors (e.g. abiraterone or orteronel). 5. Prior treatment for more than 2 months with agents inhibiting androgen receptor signaling (e.g. enzalutamide, apalutamide, or darolutamide). 6. Prior hemibody or whole-body external radiotherapy. Other types of prior external radiotherapy and brachytherapies are allowed. 7. Prior therapy with radionuclides (e.g., radium-223, strontium-89, samarium-153, rhenium-186, rhenium-188, actinium-225 and lutetium-177). 8. Current involvement in any drug or device trial involving investigational agent or medical device within the last 28 days prior to R1. 9. In general, any prior investigational agent for nmCRPC/mCRPC; however, may be reviewed by medical monitor/PIs for waiver consideration, on a case-by-case basis. 10. Hypersensitivity to compounds related to enzalutamide, darolutamide, or Ra-223. 11. A blood transfusion ≤ 28 days prior to R1. 12. Major surgical procedures ≤ 28 days or minor surgical procedures ≤7 days prior to R1. No waiting period is required following port-a-cath placement. 13. Patients with visceral metastases, clinical evidence of central nervous system metastases, or leptomeningeal tumor spread as demonstrated via CT/MRI of chest, abdomen, pelvis, and CNS (if needed). CT/MRI of the CNS only performed if suspicion of CNS metastases or leptomeningeal tumor spread. Nodules \< 1 cm alone will not be considered visceral metastases. Renal masses \< 3 cm will not be considered exclusionary. 14. Serious active infection at the time of screening or another serious underlying medical condition that would impair the ability of the patient to receive protocol treatment. 15. Presence of other active cancers, or history of treatment for invasive cancer ≤2 years of R1. Patients with Stage I/II cancer who have received definitive local treatment and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e., non-invasive) and superficial bladder cancer are eligible, as are patients with history of non-melanoma skin cancer. 16. Any other serious or unstable illness, or medical, social, or psychological condition, that could jeopardize the safety of the subject and/or his/her compliance with study procedures, or may interfere with the subject's participation in the study or evaluation of the study results.