A Randomized Phase IIa Efficacy and Safety Study of Radium-223 Dichloride With Abiraterone Acetate or Enzalutamide in Metastatic Castration-resistant Prostate Cancer (CRPC)

The primary objective in this study is to evaluate bone scan response at Week 24 based on the quantified technetium-99 bone scan lesion area (BSLA). The safety of radium-223 dichloride in combination with abiraterone acetate or enzalutamide will be investigated. The study will evaluate radiological progression free survival, overall survival, and skeletal events. This study will also explore the clinical utility of different imaging modalities (whole body quantified technetium-99 bone scan, DW-MRI \[diffusion-weighted magnetic resonance imaging\] and NaF \[sodium fluoride\] PET-CT \[positron emission tomography-computed tomography\] scan) and will have a separate central radiological review for applicable secondary and exploratory imaging endpoints. All subjects will be randomized as assigned randomly by the IXRS (interactive voice / web response system) system in a 1:1:1 ratio into one of the treatment arms: radium-223 dichloride alone, 50 kBq/kg (55 kBq/kg after implementation of NIST \[National Institute of Standards and Technology\] update) every 4 weeks for up to 6 doses; radium-223 dichloride, 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks up to 6 doses together with abiraterone acetate 1,000 mg daily and prednisone 5 mg bid (twice daily); radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks up to 6 doses together with enzalutamide 160 mg daily. The study will consist of screening, treatment and follow-up periods. Study will continue until disease progression as determined by investigator, or when patient meets criteria for withdrawal from study. Subjects in treatment arms with abiraterone/prednisone or enzalutamide will have the option to continue taking oral study therapy until the end of the study (2 years from the last dose of radium-223 dichloride) if the investigator deems the subject may benefit and there is no clinical or radiological progression. Subjects who discontinue all study treatment prior to 2 years from last radium-223 dichloride treatment will enter active follow-up. During the active follow-up period, the subject will have a safety visit at the clinic every 12 weeks from the EOT (end of treatment) for up to 2 years from the last dose of radium-223 dichloride. Beyond 2 years from last radium-223 dichloride treatment,subjects will enter long-term follow-up and will be followed via phone contact at intervals to assess for safety (hematological toxicity and new primary malignancies) and overall survival. A separate long-term safety follow-up study protocol is planned. Once implemented, the study subjects surviving after the end of the active follow-up will be transitioned to this separate long-term safety follow-up protocol.


Eligibility Criteria:
Inclusion Criteria:

* Histologically or cytologically confirmed adenocarcinoma of the prostate
* Known castration-resistant disease
* Serum PSA ≥2 ng/mL (μg/L)
* Multiple skeletal metastases (≥2 hot spots) on bone scan
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2.
* Life expectancy ≥6 months
* Adequate hematologic, hepatic, and renal function

Exclusion Criteria:

* History of visceral metastasis, or visceral metastases
* Malignant lymphadenopathy with lymph nodes exceeding 3 cm in short axis diameter
* Medical condition that would make prednisone (corticosteroid) use contraindicated
* Any chronic medical condition requiring a higher dose of corticosteroid than 5 mg prednisone bid
* Treatment with more than one chemotherapy agent for prostate cancer
* Prior systemic radiotherapy and hemibody external radiotherapy
* History of pituitary or adrenal dysfunction
* Chronic conditions associated with non-malignant abnormal bone growth (e.g., confirmed Paget's disease of bone)
* Atrial fibrillation, or other cardiac arrhythmia requiring medical therapy
* History of seizures (taking/not taking anticonvulsants), arteriovenous malformation in the brain, head trauma with loss of consciousness
* Central nervous system (CNS) metastases