- Participants who have histologically confirmed adenocarcinoma of the prostate.
- Participants with metastatic castrate resistant prostate cancer (mCRPC) progressing
on/after one line of novel anti-hormonal therapy (NAH) (after being treated for at
least 3 months) for metastatic prostate cancer (mHSPC and mCRPC).
- One prior taxane treatment regimen (at least 2 cycles) for metastatic prostate cancer
(mHSPC and mCRPC) or refusal or ineligibility of such a regimen.
- Prostate cancer progression documented by PSA according to the Prostate Cancer Working
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 with no
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 Brief Pain
Inventory-Short Form (BPI-SF) Question #3 (worst pain in last 24 hours). This is 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 hormone
releasing hormone (LHRH) agonists or antagonists (participant who has not undergone
orchiectomy), this therapy must have been initiated at least 4 weeks prior to
randomization and must be continued throughout the study.
- Participants must be on a BHA treatment, such as bisphosphonates or denosumab
treatment unless such treatment is contraindicated or not recommended per
investigator'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 whole
- 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) (except
for 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) ≥ 30
mL/min/1.73 m^2 as calculated using the Cockcroft-Gault equation
- International normalized ratio (INR) of prothrombin time (PT; PT-INR) and partial
thromboplastin time (PTT) ≤ 1.5 times the ULN. Participants treated with warfarin
or heparin will be allowed to participate in the study if no underlying
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 / PTT values)
- Serum albumin > 30 g/L
- Serum potassium ≥ 3.5 mmol/L
- Capable of giving signed informed consent
- 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 5 mg
prednisone / prednisolone twice daily.
- Pathological finding consistent with tumors with neuroendocrine features or small cell
carcinoma of the prostate.
- History of osteoporotic fracture
- History of visceral metastasis, or presence of visceral metastasis detected by
screening 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 or
low-grade superficial bladder cancer)
- Imminent spinal cord compression based on clinical findings and / or magnetic
resonance imaging (MRI). Participants with history of spinal cord compression should
have completely recovered.
- Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood
pressure ≥ 95 mmHg). Participants with a history of hypertension are allowed provided
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 for Adverse
Events (NCI-CTCAE) version 5.0 Grade 2
- Clinically significant heart disease as evidenced by myocardial infarction, or
arterial thrombotic events in the past 6 months, severe or unstable angina, or
New York Heart Association (NYHA) Class II to IV heart disease or cardiac
ejection fraction measurement of <50% at baseline
- Atrial fibrillation, or other cardiac arrhythmia requiring therapy
- 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 participation
in this trial (eg, history of seizure).
- Hypersensitivity to the active substances or to any excipients of radium-223
dichloride, or abiraterone acetate or enzalutamide.
- Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186, rhenium-188,
- Prior hemibody external radiotherapy is excluded. Participants who received other
types of prior external radiotherapy are allowed provided that the bone marrow
function is assessed and meets the protocol requirements for Hb, ANC, and platelet
- Blood transfusion or erythropoietin stimulating agents 4 weeks prior to Screening and
during the whole Screening period before randomization.
- Excessive intake of biotin above the recommended daily dose of 30 μg. Biotin is found
in multivitamins, including prenatal multivitamins, biotin supplements, and dietary
supplements for hair, skin, and nail growth at levels that may interfere with
- Prior administration of an investigational therapeutic for CRPC.
- Previous (within the last 4 weeks of randomization) or concurrent participation in any
interventional clinical study with investigational study drug administration.