ASCO 2019: Decreased Fracture Rate by Mandating Bone-protecting Agents in the EORTC 1333/PEACE III Trial

Chicago, IL ( Skeletal fractures, pathological or not, are a frequent and underestimated side-effect of systemic treatment of metastatic castration-resistant prostate cancer (mCRPC). The ERA223 trial randomized 806 patients with chemotherapy-naïve, mCRPC with bone metastasis to radium-223 or placebo, in addition to abiraterone acetate.1 Symptomatic skeletal event-free survival was the primary outcome. The trial was unblinded prematurely as more fractures and deaths were identified in the radium-223 arm than among patients receiving placebo.

Median skeletal event-free survival was 22.3 months (interquartile range 17.0 to 25.8 months) among patients receiving radium-223 and abiraterone acetate and 26.0 months (interquartile range 21.8 months to 28.3 months) in patients receiving placebo and abiraterone acetate (HR 1.12, 95% CI 0.92-1.37). Fractures were more common among patients receiving radium-223 and abiraterone acetate (29%) than those receiving placebo and abiraterone acetate (11%). Subsequently, the FDA and EMA advised against this combination. The question of whether mandated use of bone protecting agents, zoledronic acid or denosumab, would have mitigated the fracture risk and whether this risk also exists in the enzalutamide-radium-223 combination is presently unknown. At the ASCO 2019 prostate cancer session, Bertrand F. Tombal, MD, PhD, presented results of mandating bone protective agents for patients in the EORTC-1333-GUCG/PEACE III trial.

Dr. Tombal notes that 40% of the excess fractures in the abiraterone-radium 223 study occurred in the first six months. Furthermore, unfortunately, only 40% of patients in this trial received bone protective agents. In a post-hoc analysis of this data, bone protective agents significantly impacted the rate of fracture in both arms: 37% vs 15% in the abiraterone-radium 223 arm with and without bone protective agents, respectively. Dr. Tombal highlighted that after the abiraterone-radium 223 study was prematurely halted, an urgent safety letter was released by the EORTC-1333-GUCG/PEACE III trial IMDC on March 14, 2018, mandating bone protecting agents among both arms of the EORTC-1333-GUCG/PEACE III trial on April 19, 2018.

The phase III EORTC-1333-GUCG/PEACE III trial is comparing enzalutamide to a combination of radium-223 and enzalutamide in asymptomatic or mildly symptomatic mCRPC patients. After the mandate, bone protective agent use increased dramatically from 42.6% to 86.7%. Among 146 patients treated as of January 1, 2019 addition of bone protective agents has reduced the rates of fractures in this trial:

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Dr. Tombal highlights that this confirms what is already rigorously mentioned in all advanced prostate cancer guidelines: that patients with advanced prostate cancer need bone protective agents.

Dr. Tombal concluded with several take-home messages from his presentation:
  • Pathological and non-pathological fractures are well-recognized complications in advanced prostate cancer.
  • There is a 13% risk of fracture with enzalutamide in asymptomatic mCRPC, in line with previous reports.
  • This risk is significantly increased to 33% when radium-223 is added to enzalutamide.
  • The risk is almost abolished by mandatory continuous administration of bone protective agents starting at least 6 weeks before the first injection of radium-223, thus emphasizing the importance of treating mCRPC patients with bone protective agents.
  • The IMDC will continue to closely monitor the study at regular intervals.
Clinical trial information: NCT02194842

Presented by: Bertrand F. Tombal, MD, PhD, Professor, Chairman, Service d'Urologie, Université Catholique de Louvain, Brussels, Belgium

Co-authors: Yohann Loriot, Fred Saad, Raymond S. McDermott, Tony Elliott, Alejo Rodriguez-Vida, Franco Nole, Beatrice Fournier, Laurence Collette, Silke Gillessen; Institut de Cancérologie Gustave Roussy, Villejuif, France; Centre Hospitalier de l’Université de Montréal/CRCHUM, Montréal, QC, Canada; Adelaide and Meath Hospital and University College Dublin, Dublin, Ireland; Christie Hospital NHS Foundation Trust, Manchester, United Kingdom; Hospital del Mar, Barcelona, Spain; Medical Oncology Division of Urogenital and Head and Neck Tumors, European Institute of Oncology, Milan, Italy; EORTC, Brussels, Belgium; European Organisation for Research and Treatment of Cancer, Brussels, Belgium; University of Manchester, and The Christie Manchester, Manchester, United Kingdom

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md, at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

  1. Smith M, Parker C, Saad F, 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 randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019 Mar;20(3):408-419.
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Watch: Decreased Fracture Rate When Adding Bone Protecting Agents to Radium-223: PEACE III - Bertrand Tombal