It is well appreciated that men with bone metastases are at risk for fracture and symptomatic skeletal-related events (SREs), and that men on long-term potent hormonal therapies are at risk for fragility fractures due to ongoing bone loss. However, the utilization of denosumab and zoledronic acid, despite the widespread guideline recommendations for their consideration, remains low internationally. This was recently highlighted at ASCO 2021 with the PEACE3 clinical trial, where the mandated use of bone antiresorptive therapy in this bone mCRPC protocol of enzalutamide +/- radium-223 led to an improvement in the use of these agents in this population from 55% to 97%, and reduced the observed fracture rate at 18 months with enzalutamide alone from 22% to 2.6%, a major reduction in risk.1
In this context, McGregor and colleagues from the Dana Farber Cancer Institute report their single-center experience of men with bone mCRPC treated with abiraterone or enzalutamide in the first-line setting and estimated fracture risk based on the number of bone metastases and the use of bone antiresorptive therapy.2 In 249 men, they identified a 42% reduced risk of a skeletal-related event, even in men with 4 or more bone metastases (HR 0.58 95% CI 0.36-0.95, p=0.03) but no such protective effect was observed in men with 1-3 bone metastases (HR 1.24 95% CI 0.75-2.02, p=0.4). Men with de novo bone metastases and those with prior SREs were at the highest risk for future SREs, giving some guidance to the personalized use of these bone antiresorptive therapies based on underlying patient risk. In practice, decisions on the use of these agents for SRE prevention or osteopenia/osteoporosis treatment/prevention should be dictated based on risk of fracture, osteonecrosis of the jaw (ONJ), thus emphasizing the importance of bone density monitoring over time and considerations based on the number and location of bone metastases as well as the risks of disease progression over time.
Guidance for the use of these therapies based on fracture risk is provided by the NCCN: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf (see PROS-G and H).
Written by: Andrew Armstrong, MD, Professor of Medicine, Associate Professor in Pharmacology and Cancer Biology, Professor in Surgery, Duke Cancer Institute
1. Gilleson S., Choudhury A., Alejo Rodriguez-Vida A., et al. Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACEIII trial combining Ra223 with enzalutamide versus enzalutamide alone: An updated safety analysis. ASCO 2021 abstract 5002 10.1200/JCO.2021.39.15_suppl.5002 Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021) 5002-5002.
2. McGregor et al PCAN 2021
Read the Full-Text Article: Bone Targeted Therapy and Skeletal Related Events in the Era of Enzalutamide and Abiraterone Acetate for Castration-Resistant Prostate Cancer With Bone Metastases
ASCO 2021: Decreased Fracture Rate by Mandating Bone Protecting Agents in the EORTC 1333/PEACEIII Trial Combining Ra223 with Enzalutamide Versus Enzalutamide Alone: An Updated Safety Analysis
The Importance of Bone-Protecting Agents When Treating mCRPC with Bone Metastatic Disease The PEACE III Trial – Silke Gillessen