ERA 223

ERA 223 is the clearest example in prostate cancer of a combination that was harmful, and of a harm that was preventable. It randomised 806 men with chemotherapy-naive, bone-metastatic castration-resistant prostate cancer to abiraterone with prednisone or prednisolone plus either radium-223 or placebo.

The study was unblinded prematurely on 17 November 2017 after an unplanned ad hoc analysis found more fractures and more deaths in the radium-223 group, although by then every man had finished radium-223 or placebo.

At the primary analysis (data cutoff 15 February 2018, median follow-up 21.2 months) the primary endpoint had not been met: 196 of 401 men (49 percent) on radium-223 and 190 of 405 (47 percent) on placebo had a symptomatic skeletal event or died, median symptomatic skeletal event-free survival 22.3 months (95 percent confidence interval 20.4 to 24.8) against 26.0 months (21.8 to 28.3), hazard ratio 1.122 (0.917 to 1.374, p=0.2636).

The fracture figures are the reason the trial is remembered. Fractures of any grade occurred in 112 of 392 men (29 percent) on radium-223 and 45 of 394 (11 percent) on placebo; grade 3 to 4 fractures in 36 (9 percent) against 12 (3 percent). Bone-protecting agents were not mandatory.

PEACE-3 later tested the same concept with enzalutamide and with bone-protecting agents mandatory for everyone, and found an overall survival benefit with a hazard ratio of 0.76. The difference between the two trials is the single most useful practical fact about radium-223 combinations: give the bone-protecting agent.