Bipolar Androgen Therapy (BAT) and Radium-223 (RAD) in Metastatic Castration-resistant Prostate Cancer (mCRPC)

Inclusion Criteria:

• Histologically documented adenocarcinoma of the prostate confirmed by pathologyreport from prostate biopsy or a radical prostatectomy specimen. If prostatic tumoris of mixed histology, > 50% of the tumor must be adenocarcinoma.

• Bone metastases as manifested by one or more lesions on a Technetium 99m bone scanperformed within 2 months of screening

• Castrate-resistant prostate cancer, in the setting of castrate levels oftestosterone (≤ 50 ng/dL), defined as current or historical evidence of diseaseprogression concomitant with surgical castration or androgen deprivation therapy (ADT), as demonstrated by two consecutive rises in PSA OR new lesions on bone scan:

• PSA progression will be defined as 2 rising PSA values compared to a referencevalue, measured at least 7 days apart and the second value is ≥ 2 ng/mL. Appearanceof one or more new areas of abnormal uptake on bone scan when compared to imagingstudies acquired during castration therapy or against the precastration studies ifthere was no response. Increased uptake of pre-existing lesions on bone scan doesnot constitute progression. It must be documented within 8 weeks of screeningDocumented bone lesions by the appearance of ≥ 2 new lesions by bone scintigraphy ordimensionally measurable soft tissue metastatic lesion assessed by CT or MRI.

• Serum PSA ≥ 2.0 ng/mL

• Patients must be on bone health agents, either zoledronic acid or denosumab, for atleast 4 weeks before enrollment. These treatments must then be continued during thestudy.

• Screening Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

• Asymptomatic or minimally symptomatic disease (no opioids)

• Prior treatment with no more than one novel AR targeted drug (abiraterone,enzalutamide, darolutamide or apalutamide) is permitted, but not required. Priorfirst-generation AR targeted therapies such as bicalutamide or nilutamide arepermitted as previous therapy and does not count as novel AR targeted therapy.

• Prior chemotherapy for hormone-sensitive prostate cancer (given ≥ 12 months prior tostudy entry) is allowed, but not necessary.

• Adequate bone marrow, renal and liver function (Absolute Neutrophil count > 1,000,Platelets >100,000, Hemoglobin ≥ 9g/dL aspartate aminotransferase/ alanine aminotransferase (AST)/(ALT) within normal limits (WNL); Total Bilirubin WNL.

• No evidence (within 5 years) of prior malignancies (except successfully treatedbasal cell or squamous cell carcinoma of the skin).

• All patients must have tissue for genomic analysis. A biopsy of a metastatic sitemay be done during the screening; however, archive tissue will be allowed. Prostatetissue from prostate biopsy will be allowed.

Exclusion Criteria:

• The presence of known visceral metastasis, including lung, liver and brainmetastases.

• Spinal cord compression, imminent long bone fracture, or any other condition that,in the opinion of the investigator, is likely to require radiation therapy and/orsteroids for pain control during the active phase.

• Previous treatment with chemotherapy for mCRPC, or chemotherapy for any reasonwithin 12 months prior to registration. (Chemotherapy in the adjuvant setting or forhormone-sensitive prostate cancer is permitted, as long as it was completed morethan 6 months before registration).

• History of radiation therapy, either via external beam or brachytherapy within 28days prior to registration.

• Systemic therapy with strontium-89, samarium-153, rhenium-186 or rhenium-188 for thetreatment of bony metastases within previous 24 weeks

• Use of opioid analgesics for cancer-related pain such as oxycodone, morphine ormethadone. Weak opioid analgesics such as codeine or tramadol are permitted.

• Use of experimental drug within 4 weeks of treatment.

• Patients with an intact prostate AND urinary obstructive symptoms are excluded (which includes patients with urinary symptoms from benign prostatic hyperplasia (BPH).

• Patients receiving anticoagulation therapy with warfarin are not eligible for study.Patients on other anticoagulants such as rivaroxaban, dabigatran, apixaban arepermitted.

• Symptomatic nodal disease, i.e. scrotal, penile or leg edema.

• Poor medical risk due to a serious, uncontrolled medical disorder, non-malignantsystemic disease, or active, uncontrolled infection or a disease that may compromisesafety. Examples include, but are not limited to, diabetes, heart failure, chronicobstructive pulmonary disease (COPD), ulcerative colitis, or Crohn's disease,Paget's disease, ventricular arrhythmia, recent (within 12 months) myocardialinfarction, thromboembolic events or any psychiatric disorder that prohibitsobtaining informed consent. Any medical intervention, any other condition, or anyother circumstance which, in the opinion of the investigator, could compromiseadherence with study requirements or otherwise compromise the study's objectives.

• 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. femoralmetastases with concern over fracture risk, severe and extensive spinal metastaseswith concern over spinal cord compression, etc). Patients with low volume visceralmetastasis are permitted at the discretion of the investigator, however bone diseasemust be predominant.