Enzalutamide with or without Radium Ra 223 Dichloride in Patients with Metastatic, Castration-Resistant Prostate Cancer

Inclusion Criteria

• Men with metastatic, castration resistant prostate cancer involving the bone, which is symptomatic or asymptomatic
• Castration resistance will be defined as the development of disease progression, defined as one of the following AND despite ongoing luteinizing hormone-releasing hormone (LHRH) therapy OR testosterone level < 50: * Rising PSA x 2 values >= 2 weeks apart; minimum absolute PSA value 2 ng/mL * Radiographic progression, with at least 1 new site of metastasis * Symptomatic progression (ex: increase in pain despite stable imaging)
• Men must have osseous metastases, but the presence of visceral metastases will not exclude patients from participation * Prior external beam radiation therapy (> 4 weeks prior to enrollment) for palliation of osseous metastatic disease is allowed, provided there is at least one osseous metastasis which has not been irradiated and which can be biopsied * Note: Patients must start treatment with a bone protecting agent (at doses used to reduce the incidence of skeletal related events) ideally before or at the time of randomization, if patient is not already on one. A minimum of two doses is recommended before the first administration of Ra223 in the experimental arm. The first administration of Ra223 should be scheduled at least 6 weeks after the first administration of bone protecting agent
• No prior docetaxel or cabazitaxel chemotherapy for metastatic castration-resistant prostate cancer (mCRPC) (men treated with prior docetaxel administered as up-front therapy with androgen deprivation therapy [ADT] > 6 months ago will be eligible); prior abiraterone is allowed
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Hemoglobin >= 9.5 g/dL
• Absolute neutrophil count >= 1,500
• Platelets >= 100,000
• Total bilirubin within normal institutional limits
• Creatinine clearance (calculated or measured) > 30 mL/min
• At least one risk factor predicting higher likelihood of bone marrow sample yield: elevated alkaline phosphatase, low hemoglobin, or elevated lactate dehydrogenase (LDH). If a patient has a NEW bone metastasis which can be biopsied, they do not need to meet one of these criteria
• Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria

• Prior treatment with docetaxel or cabazitaxel for mCRPC (up-front docetaxel, as in CHAARTED type therapy, is allowed)
• Prior treatment with ARN-509 or enzalutamide (there is a grace period for men who wish to enroll and who have recently started enzalutamide for the first time but have taken less than 15 days of therapy) * Concurrent use of androgen deprivation therapy aside from LHRH agonist or antagonist (i.e. bicalutamide, flutamide, nilutamide, abiraterone, ketoconazole, estrogen); there will be a 2 week wash-out period from the last dose of any of these agents until the first dose of enzalutamide on study; patients who have just started enzalutamide for fewer than 5 doses prior to enrollment in the trial are still considered eligible and not subject to wash-out
• Concurrent oral corticosteroid use aside from adrenal replacement, or use of other immunosuppressive agents (ex: infliximab); topical or inhaled steroids will be allowed
• Received 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
• History of seizures except for remote with specific etiology which has resolved (ex: alcohol induced seizure); transient ischemic attack (TIA) or cerebrovascular accident (CVA) within last 6 months
• Known untreated central nervous system (CNS) metastases; leptomeningeal disease will be an absolute exclusion criterion due to limited life expectancy
• Chronic diarrhea > grade 1, or a diagnosis of Crohn’s or ulcerative colitis
• Known hepatitis (hep) B or C, or known cirrhosis (screening for viral hepatitis is not required)
• Uncontrolled intercurrent illness such as infection, symptomatic congestive heart failure, unstable angina pectoris, osteonecrosis of the jaw or psychiatric illness which would limit compliance with study requirements
• Imminent spinal cord compression based on clinical findings and/or magnetic resonance imaging (MRI); treatment should be completed for spinal cord compression