Combination radium-223 therapies in patients with bone metastases from castration-resistant prostate cancer: A review

•In bone mCRPC, each treatment has an effect on PCa cells and bone microenvironment.•Clinical trials have been performed to evaluate radium 223-based combination therapies.•Pretreated and un-pretreated patients have different morbidity and clinical outcomes.•Different bone metabolic status could justify the different clinical outcomes.•Associating bone protecting agents reduce treatment-related morbidity. Chemotherapeutic agents (docetaxel, cabazitaxel), hormonal therapies (abiraterone, enzalutamide) and radium-223 improve survival in patients with bone metastatic castration-resistant prostate cancer (mCRPC). Combinations of radium-223 with these agents or novel drugs have been investigated in order to improve survival and decrease bone-related morbidity. In mCRPC, clinical and preclinical data indicate that radium-223, abiraterone and enzalutamide have a direct effect on prostate cancer cells and bone microenvironment when administered as single agents. Initial results from studies of radium-223 and abiraterone, enzalutamide or docetaxel demonstrated efficacy without any safety concern in pre-treated mCRPC; however, this safety profile changed when radium-based combination therapies were administered in un-pretreated mCRPC. This review underline the biological rationale for combining radium strategies, investigating their effects on bone in terms of control of skeletal-related events and bone disease progression. The aim is to understand the possible reasons why different radium-based combination treatments can led to different clinical outcomes.