Addition of Radium-223 to Abiraterone Acetate and Prednisone or Prednisolone in Metastatic Castration-Resistant Prostate Cancer
In the phase III ERA 223 trial reported in The Lancet Oncology, Smith et al found that the addition of radium-223 to abiraterone acetate and prednisone or prednisolone did not improve symptomatic skeletal event-free survival and was associated with increased risk of fracture in patients with metastatic castration-resistant prostate cancer and bone metastases.
Study Details
In the double-blind trial, 806 patients from 165 sites in 19 countries were randomly assigned between March 2014 and August 2016 to receive radium-223 (n = 401) or placebo (n = 405) in addition to abiraterone acetate plus prednisone or prednisolone. Patients had to have progressive, chemotherapy-naive, and asymptomatic/mildly symptomatic disease. Patients were to receive up to six intravenous injections of radium-223 (55 kBq/kg) or matching placebo once every 4 weeks, with all patients receiving abiraterone acetate 1,000 mg once daily plus oral prednisone or prednisolone 5 mg twice daily during and after radium-223 or placebo treatment.
The primary endpoint was symptomatic skeletal event-free survival assessed in the intention-to-treat population.
Symptomatic Skeletal Event-Free Survival
The study was unblinded prematurely in November 2017, after an ad hoc analysis showed more fractures and deaths in the radium-223 group. At that time, all patients had completed radium-223 or placebo treatment.
Median follow-up was 21.2 months. Median symptomatic skeletal event-free survival was 22.3 months in the radium-223 group vs 26.0 months in the placebo group (hazard ratio [HR] = 1.122, P = .2636). Use of external beam radiotherapy was the most common first symptomatic skeletal event, occurring in 37% of the radium-223 group and 42% of the placebo group. Median overall survival was 30.7 months vs 33.3 months (HR = 1.195, P = .1280). Median radiologic progression-free survival was 11.2 months vs 12.4 months (HR = 1.152, 95% confidence interval = 0.960–1.383).
Fractures and Other Adverse Events
Fractures of any grade occurred in 29% of the radium-223 group and 11% of the placebo group. The most common grade 3 or 4 adverse events for the radium-223 vs placebo groups were hypertension (11% vs 13%), fractures (9% vs 3%), and increased alanine aminotransferase (9% vs 7%). Serious adverse events occurred in 41% vs 39% of patients. Treatment-related death occurred in two patients in the radium-223 group (due to acute myocardial infarction and interstitial lung disease) and one patient in the placebo group (arrhythmia).
The investigators concluded, “The addition of radium-223 to abiraterone acetate plus prednisone or prednisolone did not improve symptomatic skeletal event-free survival in patients with castration-resistant prostate cancer and bone metastases, and was associated with an increased frequency of bone fractures compared with placebo. Thus, we do not recommend use of this combination.”
Matthew Smith, MD, of Massachusetts General Hospital Cancer Center, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Bayer. The study authors' full disclosures can be found at thelancet.com.
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