Investigation of Radium-223 Dichloride (Xofigo), a Treatment That Gives Off Radiation That Helps Kill Cancer Cells, Compared to a Treatment That Inactivates Hormones (New Antihormonal Therapy, NAH) in Patients With Prostate Cancer That Has Spread to the Bone Getting Worse on or After Earlier NAH

Inclusion Criteria:

• Participants who have histologically confirmed adenocarcinoma of the prostate.

• Participants with mCRPC progressing on/after one line of an approved NAH (eg.abiraterone, enzalutamide, apalutamide, or darolutamide, after being treated for atleast 3 months) in an authorized prostate cancer indication.

• One prior taxane treatment regimen (at least 2 cycles) for metastatic prostatecancer (mHSPC and mCRPC) or refusal or ineligibility of such a regimen.

• Prostate cancer progression documented by PSA according to the Prostate CancerWorking Group 3 (PCWG3) criteria or radiological progression according to RECIST,version 1.1.

• At least 2 bone metastases on bone scan within 4 weeks prior to randomization withno current or history of lung, liver, other visceral, and / or brain metastasis.

• Symptomatic prostate cancer. A worst pain score (WPS) of at least 1 on the BriefPain Inventory-Short Form (BPI-SF) Question #3 (worst pain in last 24 hours). Thisis to be assessed once during the Screening period.

• Maintenance of medical castration or surgical castration with testosterone less than 50 ng/dL (1.7 nmol/L). If the participant is being treated with luteinizing hormonereleasing hormone (LHRH) agonists or antagonists (participant who has not undergoneorchiectomy), this therapy must have been initiated at least 4 weeks prior torandomization and must be continued throughout the study.

• Participants must be on a BHA treatment, such as bisphosphonates or denosumabtreatment unless such treatment is contraindicated or not recommended perinvestigator's judgement and inclusion is agreed to by the medical monitor.

• Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.

• Life expectancy ≥ 6 months.

• Able to swallow abiraterone and prednisone/prednisolone or enzalutamide as wholetablets/capsules.

• Laboratory requirements:

• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L

• Platelet count ≥ 100 x 10^9/L

• Hemoglobin (Hb) ≥ 9.0 g/dL (90 g/L; 5.6 mmol/L)

• Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN) (exceptfor participants with documented Gilbert's disease)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN

• Creatinine ≤ 1.5 x ULN or estimated glomerular filtration rate (eGFR) ≥ 30mL/min/1.73 m^2 as calculated using the Cockcroft-Gault equation

• International normalized ratio (INR) of prothrombin time (PT; PT-INR) andpartial thromboplastin time (PTT) ≤ 1.5 times the ULN. Participants treatedwith warfarin or heparin will be allowed to participate in the study if nounderlying abnormality in coagulation parameters exists per prior history;weekly evaluation of PT-INR / PTT will be required until stability is achieved (as defined by local standard of care and based on pre-study PT-INR / PTTvalues)

• Serum albumin > 30 g/L

• Serum potassium ≥ 3.5 mmol/L

• Capable of giving signed informed consent

Exclusion Criteria:

• Active infection or other medical condition that would make prednisone /prednisolone (corticosteroid) use contraindicated.

• Any chronic medical condition requiring a higher dose of corticosteroid than 10 mgprednisone / prednisolone equivalent daily for more than 2 months.

• Pathological finding consistent with tumors with predominant neuroendocrine featuresor small cell carcinoma of the prostate.

• History of osteoporotic fracture

• History of visceral metastasis, or presence of visceral metastasis detected byscreening imaging examinations.

• History of or known brain metastasis.

• Malignant lymphadenopathy exceeding 3 cm in short-axis diameter.

• Other malignancy treated within the last 3 years (except non-melanoma skin cancer orlow-grade superficial bladder cancer)

• Imminent spinal cord compression based on clinical findings and / or magneticresonance imaging (MRI). Participants with history of spinal cord compression shouldhave completely recovered.

• Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic bloodpressure ≥ 95 mmHg). Participants with a history of hypertension are allowedprovided blood pressure is controlled by anti-hypertensive treatment.

• Active or symptomatic viral hepatitis

• History of pituitary or adrenal dysfunction

• Any other serious illness or medical condition such as, but not limited to:

• Any infection ≥ National Cancer Institute Common Terminology Criteria forAdverse Events (NCI-CTCAE) version 5.0 Grade 2

• Clinically significant heart disease as evidenced by myocardial infarction, orarterial thrombotic events in the past 6 months, severe or unstable angina, orNew York Heart Association (NYHA) Class II to IV heart disease or cardiacejection fraction measurement of <50% at baseline

• Current clinical evidence of any uncontrolled cardiac arrhythmia

• Crohn's disease or ulcerative colitis

• Bone marrow dysplasia

• Moderate and severe hepatic impairment (Child-Pugh Classes B and C)

• Unmanageable fecal incontinence.

• Any condition, which in the opinion of the investigator would preclude participationin this trial (eg, history of seizure).

• Hypersensitivity to the active substances or to any excipients of radium-223dichloride, or abiraterone acetate or enzalutamide.

• Prior therapeutic systemic radiation with any radiopharmaceutical medication for thetreatment of prostate cancer, including but not limited to lutetium-177,strontium-89, samarium-153, iodine-131, rhenium-186, rhenium-188, or radium-223.Radiopharmaceutical compounds used for diagnosis purposes only are allowed.

• Prior hemibody external radiotherapy is excluded. Participants who received othertypes of prior external radiotherapy are allowed provided that the bone marrowfunction is assessed and meets the protocol requirements for Hb, ANC, and plateletcount.

• Blood transfusion or erythropoietin stimulating agents 4 weeks prior to Screeningand during the whole Screening period before randomization.

• Excessive intake of biotin above the recommended daily dose of 30 μg. Biotin isfound in multivitamins, including prenatal multivitamins, biotin supplements, anddietary supplements for hair, skin, and nail growth at levels that may interferewith laboratory tests.

• Prior administration of an investigational therapeutic for CRPC.

• Previous (within the last 4 weeks of randomization) or concurrent participation inany interventional clinical study with investigational study drug administration.