Bone-Targeting Radioisotopes Tied to OS in Patients With Bone Metastases From CRPC

Findings from a meta-analysis of patients with bone metastases from castration-resistant prostate cancer (CRPC) treated with bone-targeted radioisotopes (RIs) suggest that there may be survival benefits with α-emitting versus β-emitting RIs (JAMA Oncol. 2019 Dec 12. Epub ahead of print).

“Both α-emitting and β-emitting bone-targeted radioisotopes (RIs) have been developed to treat men with metastatic castration-resistant prostate cancer (CRPC),” explained Safae Terrisse, MD, Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France, and colleagues.

“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,” they continued.

To fill this gap in literature, Dr Terrisse et al conducted a study evaluating OS in patients with bone metastases from CRPC treated with bone-targeted RIs, and to compare α-emitting RIs with β-emitting RIs. They did this using data from select randomized trials of patients with prostate cancer that compared RI use with no RI use.

Trial data spanning between January 1993 and June 2013 were collected via PubMed, Cochrane Library, ClinicalTrials.gov, and meeting proceedings before being reviewed and analyzed. Of 9 studies deemed eligible for inclusion, 3 were excluded for having insufficient data.

The main end point of the study was OS, and secondary end points included symptomatic skeletal event (SSE)-free survival and adverse events; data were analyzed between February 2017 and October 2018.

Hazard ratios (HRs) were estimated with the log-rank test stratified by trial, and a similar fixed-effects (FE) model was used to estimate odds ratios (ORs). The Cochran test was used to assess between-trial heterogeneity of treatment effects, and I2 and was accounted for via a random-effects (RE) model.

Ultimately, in 6 randomized studies comprising 2081 patients, RI use was significantly tied to 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%); however, this link was nonexistent when an RE model was used (HR, 0.80; 95% CI, 0.61-1.06; P = .12; τ2 = 0.08).

According to Dr Terrisse and co-investigators, the heterogeneity is explained by RI type and the fact that 2 outlier trials comprising 275 patients were included; with the α-emitting RI 223Ra, OS benefit was significantly higher (HR, 0.70; 95% CI, 0.58-0.83) but the same was not observed with the β-emitting RI strontium-89 (HR, 0.96; 95% CI, 0.84-1.10; P for interaction = .004).

When outlier trials were excluded, an FE model yielded an overall HR of 0.82 (95% CI, 0.73-0.92; P < .001; between-trial heterogeneity, χ23 = 6.51; P = .09; I2 = 54%) and an RE model showed an HR of 0.80 (95% CI, 0.65-0.99; P = .04; τ2 = 0.02). With the same 2 models, exclusion of outlier trials led to an HR for SSE-free survival of 0.81 (95% CI, 0.69-0.93; P = .004; between-trial heterogeneity, χ23 = 6.71; P = .08; I2 = 55%) and 0.76 (95% CI, 0.58-1.01; P = .06; τ2 = 0.04), respectively.

Notably, patients had more hematologic toxicities with versus without RI use (OR, 1.48; 95% CI, 1.17-1.88; P = .001).

“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,” Dr Terrisse and colleagues concluded.—Hina Porcelli