Radium-223 Improves Overall Survival in Prostate Cancer

In men with castration-resistant prostate cancer and bone metastases, the use of the targeted alpha emitter radium-223 dichloride (radium-223) showed enough improvement in overall survival to warrant the trial’s early discontinuation, allowing those taking placebo to cross over and receive the study treatment, according to results of a recent study [N Engl J Med. 2013;369(3):213-223].

ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer Patients) was a phase 3, randomized, double-blind, multinational study that compared the efficacy and safety of radium-223 versus placebo in patients with castration-resistant prostate cancer and at least ≥2 bone metastases. Additionally, patients were required to have symptomatic disease necessitating the regular use of analgesic medication or external-beam radiation therapy for cancer-related bone pain, and a baseline PSA level of 5 ng/mL that was progressively increasing. Patients were ineligible if they had received chemotherapy within the past 4 weeks or had not recovered from adverse events related to chemotherapy.

Conducted between June 2008 and February 2011, the trial consisted of 921 patients who were stratified according to their previous use of docetaxel, baseline alkaline phosphatase level (<220 U/L vs ≥220 U/L), and current use or nonuse of a bisphosphonate. They were then randomly assigned to receive either 6 IV injections of radium-223 (dose of
50 kBq/kg of body weight) (n=614) or matching placebo (n=307). Injections were to be administered every 4 weeks.

No chemotherapy, hemibody external radiotherapy, or other systemic radionuclides were permitted during the study period. Planned follow-up was 3 years.

The primary end point was overall survival, and secondary end points were an increase in the total alkaline phosphatase level, total alkaline phosphatase response, time to first symptomatic skeletal event, normalization of the total alkaline phosphatase level, and time to an increase in the PSA level. The researchers used the Lan-DeMets alpha spending function approach with O’Brien-Fleming stopping boundaries to evaluate the difference in overall survival between the 2 groups and the stratified log-rank test as the primary analysis for survival.

Results of the interim analysis, which was done after there had been 314 deaths, showed the median overall survival to be 14 months in the radium-223 group compared with 11.2 months in the placebo group. At that point, the trial was discontinued and patients receiving placebo were crossed over to receive radium-223. Compared with placebo, radium-223 was associated with a 30% reduction in the risk of death (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.55-0.88; 2-sided, P=.002). The effect of radium-223 on overall survival was shown to be consistent across all subgroups.

The updated analysis, conducted after there had been 528 deaths and before cross-over treatment was done, showed median overall survival to be 14.9 months for the radium-223 group and 11.3 months for the placebo group, and the 30% reduction in risk of death was confirmed (HR, 0.70; 95% CI, 0.58-0.83; P<0.001). Among 614 patients in the radium-223 group, 333 had died (54%), and of 307 patients taking placebo, 195 (64%) had died.

The use of radium-223 also showed benefit with regard to secondary end points. Compared with placebo, radium-223 was associated with a significant increase in the time to the first symptomatic skeletal event (median, 15.6 months vs 9.8 months; HR, 0.66; 95% CI, 0.52-0.83; P<.001); the time to an increase in the total alkaline phosphatase level (HR, 0.17; 95% CI, 0.13-0.22; P<.001); and the time to an increase in the PSA level (HR, 0.64; 95% CI, 0.54-0.77; P<.001).

Fewer adverse events occurred among patients taking radium-223 compared with the placebo group (558 of 600 [93%] vs 290 of 301 [96%] for all adverse events). The incidence of grade 3/4 events was 56% for the radium-223 group versus 62% for the placebo group; serious events, 47% versus 60%, and discontinuation because of adverse events, 16% versus 21%. Patients taking radium-223 also reported meaningful improvement in quality of life according to the FACT-P total score compared with the placebo group (25% vs 16%; P=.02).