Overall Survival in Men With Bone Metastases From Castration-Resistant Prostate Cancer Treated With Bone-Targeting Radioisotopes A Meta-analysis of Individual Patient Data From Randomized Clinical Trials

Importance Both alpha-emitting and beta-emitting bone-targeted radioisotopes (RIs) have been developed to treat men with metastatic castration-resistant prostate cancer (CRPC). Only 1 phase 3 randomized clinical trial has demonstrated an overall survival (OS) benefit from an alpha-emitting RI, radium 223 (Ra-223), vs standard of care. Yet no head-to-head comparison has been done between alpha-emitting and beta-emitting RIs. Objective To assess OS in men with bone metastases from CRPC treated with bone-targeted RIs and to compare the effects of alpha-emitting RIs with beta-emitting RIs. Data Sources PubMed, Cochrane Library, ClinicalTrials.gov, and meeting proceedings between January 1993 and June 2013 were reviewed. Key terms included randomized trials, radioisotopes, radiopharmaceuticals, and prostate cancer. Data were collected, checked, and analyzed from February 2017 to October 2018. Study Selection Selected trials included patients with prostate cancer, recruited more than 50 patients from January 1993 to June 2013, compared RI use with no RI use (placebo, external radiotherapy, or chemotherapy), and were randomized. Patients were diagnosed with histologically proven prostate cancer and disease progression after both surgical or chemical castration and have evidence of bone metastasis. Nine randomized clinical trials were identified as eligible, but 3 were excluded for insufficient data. Data Extraction and Synthesis Individual patient data were requested for each eligible trial, and all data were checked with a standard procedure. The log-rank test stratified by trial was used to estimate hazard ratios (HRs), and a similar fixed-effects (FE) model was used to estimate odds ratios (ORs). The between-trial heterogeneity of treatment effects was evaluated by Cochran test and I-2 and was accounted by a random-effects (RE) model. Main Outcomes and Measures Overall survival; secondary outcomes were symptomatic skeletal event (SSE)-free survival and adverse events. Results Based on 6 randomized clinical trials including 2081 patients, RI use was significantly associated with OS compared with no RI use (HR, 0.86; 95% CI, 0.77-0.95; P = .004) with high heterogeneity (chi(2)(5) = 24.46; P < .001; I-2 = 80%), but this association disappeared when using an RE model (HR, 0.80; 95% CI, 0.61-1.06; P = .12; tau(2) = 0.08). The heterogeneity is explained both by the type of RI and by the inclusion of 2 outlier trials that included 275 patients; the OS benefit was significantly higher with the alpha-emitting RI Ra-223 (HR, 0.70; 95% CI, 0.58-0.83) but not significant with the beta-emitting RI strontium-89 (HR, 0.96; 95% CI, 0.84-1.10) (P for interaction = .004). Excluding the outlier trials led to an overall HR of 0.82 (95% CI, 0.73-0.92; P < .001) (between-trial heterogeneity: chi(2)(3) = 6.51; P = .09; I-2 = 54%) using an FE model and an HR of 0.80 (95% CI, 0.65-0.99; P = .04; tau(2) = 0.02) using an RE model. The HR for SSE-free survival was 0.81 (95% CI, 0.69-0.93; P = .004) (between-trial heterogeneity: chi(2)(3) = 6.71; P = .08; I-2 = 55%) when using an FE model and was 0.76 (95% CI, 0.58-1.01; P = .06; tau(2) = 0.04) when using an RE model. There were more hematological toxic effects with RI use compared with no RI use (OR, 1.48; 95% CI, 1.17-1.88; P = .001). Conclusions and Relevance In metastatic CRPC, a significant improvement of OS and SSE-free survival was obtained with bone-targeted alpha-emitting but not beta-emitting RIs. Caution is necessary for generalizability of these results, given the between-trial heterogeneity. This meta-analysis of randomized clinical trials assesses overall survival in men with bone metastases from castration-resistant prostate cancer treated with bone-targeted radioisotopes and compares the effects of alpha-emitting with beta-emitting radioisotopes. Question What is the benefit of bone-targeted radioisotope (RI) use in metastatic castration-resistant prostate cancer, and is there any difference between alpha-emitting and beta-emitting RIs? Finding This meta-analysis of individual patient data was based on 6 randomized clinical trials including 2081 patients that compared RI use with no RI use study arms with no overall significant difference. While an alpha-emitting RI (radium 223) was significantly associated with higher overall survival and higher symptomatic skeletal event-free survival, a beta-emitting RI (strontium-89) was not associated with these outcomes. Meaning This meta-analysis suggests a benefit of alpha-emitting RIs but not of beta-emitting RIs for overall survival and symptomatic skeletal event-free survival, although caution is necessary for generalizability of these results, given the between-trial heterogeneity.