Overall Survival in Men With Bone Metastases From Castration-Resistant Prostate Cancer Treated With Bone-Targeting Radioisotopes

Importance

Both α-emitting and β-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 α-emitting RI, radium 223 (²²³Ra), vs standard of care. Yet no head-to-head comparison has been done between α-emitting and β-emitting RIs.

Objective

To assess OS in men with bone metastases from CRPC treated with bone-targeted RIs and to compare the effects of α-emitting RIs with β-emitting RIs.

Data Sources

PubMed, Cochrane Library, ClinicalTrials.gov, and meeting proceedings between January 1993 and June 2013 were reviewed. Key terms includedrandomized trials,radioisotopes,radiopharmaceuticals, andprostate 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 andI²and 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 (χ²₅ = 24.46;P < .001;I² = 80%), but this association disappeared when using an RE model (HR, 0.80; 95% CI, 0.61-1.06;P = .12; τ² = 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 α-emitting RI²²³Ra (HR, 0.70; 95% CI, 0.58-0.83) but not significant with the β-emitting RI strontium-89 (HR, 0.96; 95% CI, 0.84-1.10) (Pfor 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: χ²₃ = 6.51;P = .09;I² = 54%) using an FE model and an HR of 0.80 (95% CI, 0.65-0.99;P = .04; τ² = 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: χ²₃ = 6.71;P = .08;I² = 55%) when using an FE model and was 0.76 (95% CI, 0.58-1.01;P = .06; τ² = 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 α-emitting but not β-emitting RIs. Caution is necessary for generalizability of these results, given the between-trial heterogeneity.