Bone loss resulting from excessive use of prednisone with abiraterone and radium-223 may explain the higher risk of fragility fractures among men in the ERA clinical trial, according to an editorial published in European Urology.1

“This editorial was written in order to provide potential explanations on why the association of radium-223 with abiraterone plus prednisone unexpectedly failed to meet its primary endpoint, the prevention of skeletal-related events,” corresponding author Alfredo Berruti, MD, professor of medical oncology at the University of Brescia in Italy, told Renal & Urology News.

Glucocorticoid-induced inhibition of bone formation involves multiple pathways, resulting in strong suppression of osteoblast differentiation, maturation, and activity, Dr Berruti and his colleagues wrote. He and his colleagues say they believe the trial findings, which were presented at the 2018 congress of the European Society for Medical Oncology, were primarily due to a negative interaction between radium-223 and prednisone leading to a synergistic inhibition on osteoblast activity and the consequent bone coupling derangement favoring the prevalence of osteoclast activity. “Prednisone supplementation needs to be administered to patients during abiraterone therapy in order to inhibit ACTH [adrenocorticotropic hormone] increase and the consequent mineral corticoid excess; however, the prednisone dose administered in the ERA223 trial (10 mg daily) is excessive,” Dr. Berruti said. “We felt it important to share our point of view in the scientific community since the consequence of this trial is a sort of pessimism linked to radium-223 administration, and we strongly believe the drug still remains an important therapeutic option in the management of castration resistant prostate cancer patients.”

The ERA 223 trial2 was a randomized phase 3 study that enrolled 806 men with asymptomatic or mildly symptomatic men with chemotherapy-naïve castration-resistant prostate cancer (CRPC) and bone metastases (more than 2 bone metastatic lesions). Patients received a combination of standard-dose abiraterone (1000 mg daily) combined with 5 mg of prednisone (twice daily) and radium-223 or placebo.

Previous studies have shown that abiraterone and prednisone/prednisolone improves progression-free survival (PFS) and overall survival (OS) in men with metastatic CRPC (mCRPC). In addition, data have shown that use of radium-223 is associated with increased OS and a decreased risk of symptomatic skeletal events (SSEs) in men with mCRPC and bone metastases.

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. 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. 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.