Clonal Emergence and Regression During Radium-223 Therapy for Metastatic Prostate Cancer

INCLUSION CRITERIA 1. Prostate adenocarcinoma by history or medical records. 2. Two or more bone metastases as demonstrated by imaging studies (technetium bone scan, fluoride PET scan, FDG PET scan, fluciclovine PET scan, CT scan, or MRI scan) or by biopsy. 3. Patients must be on ADT with a GnRH receptor agonist/antagonist or orchiectomy, with or without an anti-androgen or testosterone synthesis inhibitor. Patients must have a documented castrate level of testosterone (\<50ng/dL) and be willing to continue their GnRH agonist/antagonist during the course of radium-223 therapy. 4. Patients may have had localized external beam radiation to as much as 20% of the skeleton 5. Adequate hematopoietic, renal, and hepatic function. These parameters include: * Hemoglobin ≥ 10gm/dL * WBC ≥ 3.0K/mcL * ANC ≥ 1.5K/mcL * Platelet count ≥ 100K/mcL * Creatinine \< 1.5 ng/mL * Total bilirubin \<1.5 ng/mL. * Albumin \> 25 g/L 6. Patients should have an elevated, relevant tumor marker such as PSA, CEA, or LDH. 7. Age ≥18 years old 8. Life expectancy of at least 24 weeks 9. Subjects must be able to understand and be willing to sign the written informed consent form. A signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedures. Subjects must be willing and able to comply with the protocol, including follow-up visits and examinations. 10. Men of childbearing potential must agree to use adequate contraception beginning at the signing of the informed consent until at least 30 days after the last dose of radium-223 treatment or during the course of radium-223 treatment. 11. Subjects must have had a Guardant 360 ctDNA-based genomic profile performed up to four months prior to the first dose of radium-223, with no new therapy started in the interim. This assay must show at least one single nucleotide variant, either missense or synonymous, or one amplification. 12. Subjects should continue any previously-started bone-hardening agents (zoledronic acid or denosumab) during radium-223 therapy. 13. All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v 5.0 Grade 1 or less at the time of signing the Informed Consent Form (ICF). EXCLUSION CRITERIA 1. Initiation of any additional anti-tumor therapy within 2 months of starting radium-223 treatment 2. Presence of only lytic bone metastases 3. Prior cytotoxic chemotherapy for metastatic PCa 4. Prior systemic therapy with radionuclides (e.g., strontium-89, samarium-153, rhenium-186, or rhenium-188, or Radium Ra 223 dichloride) for the treatment of bony metastases 5. Other malignancy requiring systemic therapy within the last 3 years (except non melanoma skin cancer or low-grade superficial bladder cancer) 6. Visceral (i.e. liver, lung, brain, adrenal, brain, but not lymph node) metastases as assessed by chest, abdominal, or pelvic computed tomography, or other imaging modality) 7. Lymphadenopathy exceeding 6 cm in short-axis diameter, or any size pelvic lymphadenopathy if it is thought to be a contributor to concurrent hydronephrosis 8. Imminent spinal cord compression based on clinical findings and/or MRI. Treatment should be completed for spinal cord compression. 9. Any infection ≥ Grade 2 per NCI-CTCAE version 5.0 10. Cardiac failure NYHA III or IV 11. Crohn's disease or ulcerative colitis 12. Bone marrow dysplasia, myelodysplasia 13. Fecal incontinence 14. Inability to comply with the protocol and/or not willing or not available for follow-up assessments. 15. Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation. 16. Concurrent use of abiraterone or enzalutamide. A 28-day washout period is required for both agents.