BackgroundSix radium-223 injections at 4-week intervals is indicated for patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases. However, patients usually develop disease progression after initial treatment. This prospective phase I/II study assessed re-treatment safety and efficacy of up to six additional radium-223 injections.Patients and methodsPatients had CRPC and bone metastases and six initial radium-223 injections with no on-treatment bone progression; all had subsequent radiologic or clinical progression. Concomitant agents were allowed at investigator discretion, excluding chemotherapy and initiation of new abiraterone or enzalutamide. The primary endpoint was safety; additional exploratory endpoints included time to radiographic bone progression, time to total alkaline phosphatase (tALP) and prostate-specific antigen (PSA) progression, radiographic progression-free survival (rPFS), overall survival, time to first symptomatic skeletal event (SSE), SSE-free survival (SSE-FS), and time to pain progression.ResultsAmong 44 patients, 29 (66%) received all six re-treatment injections. Median time from end of initial radium-223 treatment was 6 months. Forty-one (93%) reported ≥1 treatment-emergent adverse event (TEAE). No grade 4-5 hematologic TEAEs occurred. Only one (2%) patient had radiographic bone progression; eight (18%) had radiographic soft tissue tumor progression (three lymph node, five visceral metastases). Median times to tALP and PSA progression were not reached and 2.2 months, respectively. Median rPFS was 9.9 months (12.8-mo maximum follow-up). Five (11%) patients died and eight (18%) experienced first SSEs. Median overall survival, time to first SSE, and SSE-FS were not reached. Five (14%) of 36 evaluable patients (baseline worst pain score ≤7) had pain progression. After 2 years of follow-up, 28 (64%) patients died, and the median overall survival was 24.4 months.ConclusionsRe-treatment with a second course of six radium-223 injections after disease progression is well tolerated, with minimal hematologic toxicity and low radiographic bone progression rates in this small study with limited follow-up. Favorable safety, and early effects on disease progression indicate that radium-223 re-treatment is feasible and warrants further evaluation in larger prospective trials.