Figure 1 gives an overview of the procedures that patients will undergo during the study. In both study groups, all active metastases will be treated with stereotactic body radiation therapy or intensity-modulated radiation therapy for local control. All patients will then receive six 120-mg doses of subcutaneously injected denosumab every four weeks as the best standard of care (BSoC) for CRPC patients with bone metastasis. The control group will receive BSoC only, while the radium-223 group will also receive a maximum of six doses of the study's research drug, radium-223; Xofigo® (Bayer Inc.), intravenously at 55 kBa/kg every four weeks, starting within two weeks after the completion of radiotherapy for active metastases. No placebo will be used in this study.

Design of the MEDAL trial

If an adverse reaction occurs due to radium-223 administration, the degree of the adverse reaction should be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and the dose should be withdrawn or reduced. In case of grade 3 or higher neutropenia, anemia, or thrombocytopenia, administration should be postponed until recovery to grade 2 or lower, and then resumed after confirmation of recovery. If the grade of neutropenia or thrombocytopenia does not recover to grade 2 or below within 6 weeks of the last dose, administration should be discontinued. For grade 3 or higher diarrhea, nausea, vomiting, or constipation, postpone administration until recovery to grade 2 or lower, and resume administration after confirming recovery. If grade 4 events persist for more than 7 days, administration should be discontinued.
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