Prednisone to Blame for ERA 223 Trial Failure?

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An new editorial offers an explanation why radium-223 used in combination with prednisone and abiraterone did not lower the risk of symptomatic skeletal events in men with mCRPC.
An new editorial offers an explanation why radium-223 used in combination with prednisone and abiraterone did not lower the risk of symptomatic skeletal events in men with mCRPC.

The ERA 223 trial, however, was unblinded early after investigators observed more fractures and deaths among patients in the radium-223 group. The median time to SSEs in the radium-223 arm was 22.3 months vs 26.0 months in the placebo arm, and the median OS was 30.7 months vs 33.3 months in the placebo arm. Results showed that 29% of men who received radium-223 experienced fractures compared with 11% of the placebo arm. Use of bisphosphonates or denosumab was associated with lower fracture rates in both treatment groups.

Based on the study findings, the investigators said they do not recommend radium-223 in combination with abiraterone plus prednisone.

“The results of the ERA trial suggest that the concomitant administration of glucocorticoids is detrimental and should be in principle avoided,” Dr Berruti said. “However, if deemed necessary by the clinicians, concomitant administration of bone resorption inhibitors (denosumab and bisphosphonates) are needed to counteract the increased risk of fragility skeletal fractures.”

The randomized phase 3 ALSYMPCA trial showed that administration of radium-223 was associated with a significant delay in time to first SSE and significant improvement in OS compared with placebo, regardless of previous docetaxel use.3

Michael J. Morris, MD, clinical director of the Genitourinary Medical Oncology Service and head of the Prostate Cancer Section at Memorial Sloan Kettering Cancer Center in New York, said clinicians have feel their way when deciding how much prednisone to use. “Prednisone mitigates important side effects of abiraterone, such as hypertension, hypokalemia, and edema,” Dr Morris said. “Most practitioners try to find the right balance of steroid use with each patient, and the right dose for a given patient is frequently individualized.”

The editorial raises good points, he said, but more research is warranted to better understand the mechanisms involved when combining abiraterone and prednisone with radium-223. “It could be the combination of these drugs has biological effects that occur in the bone that we don't know about. Everyone is struggling to come up with an explanation, and this is just one hypothesis,” he said.

Howard Sandler, MD, a professor and chair of radiation oncology at Cedars-Sinai Medical Center in Los Angeles, noted that the ongoing Phase III Radium-223 mCRPC-PEACE III (PEACE III) trial (NCT02194842) could provide additional insight into the use of radium-223. The randomized open-label trial is assessing whether upfront use of a combination of enzalutamide plus radium-223 improves radiographic PFS compared with enzalutamide alone in men with asymptomatic or mildly symptomatic CRPC patients with bone metastases.4

“More studies are always helpful, and some are underway,” Dr Sandler said. “I'm not involved in any guideline panels for prostate cancer metastatic to bone, but I'm sure guidelines panels would suggest caution using radium-223 and abiraterone/prednisone at the present time.”  He noted, however, that the original study showing a benefit with the use of radiation in the form of radium-223 as a single agent still stands as a positive trial with a survival benefit and very little in the way of side effects.

References

1.    1. Dalla Volta A, Formenti A, Berruti A. Higher risk of fragility fractures in prostate cancer patients treated with combined radium-223 and abiraterone: Prednisone may be the culprit. Eur Urol. 2019; published online ahead of print.

2.    2. Smith MR, Parker CC, Saad F, et al. ERA 223: v ERA 223: a phase 3 trial of radium-223 (Ra-223) in combination with abiraterone acetate and prednisone/prednisolone for the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients with mCRPC. Presented at the 2018 congress of the European Society of Medical Oncology.

3. Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014; 15:738-746.

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