ERA-223
The safety trial that changed how radium-223 is combined, fractures with abiraterone
Quick Answer
ERA-223 (Smith et al., Lancet Oncology 2019) was the phase 3 randomized trial that tested adding ²²³Ra to abiraterone acetate plus prednisone/prednisolone in chemotherapy-naïve mCRPC with bone metastases. The combination did not improve symptomatic-skeletal-event-free survival and caused more fractures (and a numerically higher death rate), leading to a label restriction. It is the landmark safety trial of the radium story: it established that Ra-223 should not be combined with abiraterone + steroid, and that a bone-health agent (denosumab or a bisphosphonate) should accompany Ra-223.
The trial
Design: phase 3, double-blind, placebo-controlled, 806 patients with asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC and bone metastases. Randomized to ²²³Ra plus abiraterone + prednisone/prednisolone versus placebo plus abiraterone + prednisone/prednisolone. Primary endpoint: symptomatic skeletal event–free survival.
Key result
The combination did not prolong symptomatic skeletal event–free survival and produced more fractures (~29% vs ~11%), with a numerically higher rate of death. Importantly, fracture risk was far lower in patients taking a bone-health agent at baseline, implicating loss of bone-protective co-therapy in the excess fractures. The trial was unblinded early on the recommendation of the data-monitoring committee.
Why it mattered
ERA-223 changed practice and labeling: Ra-223 is not combined with abiraterone + prednisone/prednisolone, and Ra-223 should be given with a bone-health agent and generally as monotherapy for bone-dominant disease. It is the counterpoint to ALSYMPCA — the trial that defined the safe boundaries of radium-223 use, and a standing caution about combining bone-targeted radionuclide therapy with agents that reduce bone density.
Context & caveats
The mechanism of excess fractures is attributed to the combination lowering bone integrity without protective co-therapy, rather than to Ra-223 alone (which in ALSYMPCA had a favorable skeletal profile). The later PEACE-3 trial re-examined Ra-223 combinations (with enzalutamide) under mandatory bone-protective therapy, reinforcing the bone-health-agent lesson.
Self-Check
Q1. What did ERA-223 test and find?
Answer: Ra-223 + abiraterone + prednisone vs placebo + abiraterone + prednisone in chemo-naïve mCRPC — the combination did not improve outcomes and caused more fractures.
Q2. What is the practical rule that came from it?
Answer: Do not combine Ra-223 with abiraterone + prednisone/prednisolone; give Ra-223 with a bone-health agent (denosumab/bisphosphonate).
Q3. What factor mitigated the fracture risk?
Answer: Baseline use of a bone-health agent — fracture rates were much lower in those patients.
Q4. How does ERA-223 relate to ALSYMPCA?
Answer: ALSYMPCA established Ra-223's survival benefit as monotherapy; ERA-223 defined its safety boundaries — the combination with abiraterone is avoided.
Key References
- Smith M, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019;20:408–419. doi:10.1016/S1470-2045(18)30860-X
Evidence & sources
https://nuc.med/era-223-trial/ Report an issue