Treatment with bone-protecting agents (BPAs) zoledronic acid or denosumab entirely eliminated the risk of fracture as seen in a study of men with metastatic castration-resistant prostate cancer (CRPC) treated with enzalutamide alone or in combination with radium-223 (Ra223).
“If you follow these patients long enough, fractures are very common,” said Bertrand F. Tombal, MD, PhD, of the Catholic University Louvain in Belgium. He said that previous studies have shown the benefit of BPAs in prostate cancer, but the management of complications in these patients is sometimes somewhat forgotten. Tombal presented results of the new analysis (abstract 5007) at the American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago.
A previous study, the ERA223 trial, was recently unblinded following a report of increased fracture risk when abiraterone was combined with Ra223. The new PEACE III trial amended its protocols following the ERA223 unblinding to mandate the use of BPAs; Tombal reported the fracture results in a total safety population of 160 patients enrolled in the PEACE III trial.
All patients included had bone-predominant metastatic CRPC (at least 2 bone metastases), were asymptomatic or mildly symptomatic, and had a WHO performance status of 0 or 1. Patients could not have received prior treatment with cyp17 inhibitors, enzalutamide, Ra223 or other radionucleotides, or other hemibody radiotherapy.
A total of 115 patients were randomized before an urgent safety letter regarding the use of BPAs was sent; 62 of those patients (53.9%) did not receive BPAs at any point. Among the other 45 patients who were randomized after the letter, 8.9% never received BPAs. In those randomized before the letter, 15.7% had BPA use at trial registration and continued it, 1.7% had use at registration but discontinued use, and 27.0% had no use at registration but started BPAs during the study protocol. Most of those randomized after the letter (73.3%) received BPAs beginning at trial registration and then continued. In total, 55.0% of the full cohort received some bone protection during treatment.
In the patients who did not have exposure to BPAs, the 1-year risk of bone fracture was 12.4% in those treated with enzalutamide alone; this rose to 37.4% when Ra223 was added to the therapy. At 18 months, those rates were 16.6% and 43.6%, respectively. In the patients who did have exposure to BPAs, there were no fractures at all in either treatment group, for a cumulative incidence of 0%.
“These results strongly suggest that the risk of fractures is very well controlled in both arms when patients receive bone-protecting agents,” Tombal said. “The analysis actually confirms the importance of complying with international recommendations and guidelines when treating metastatic CRPC patients.”
Michael A. Carducci, MD, of Johns Hopkins University, who was the discussant for the abstract, noted that, “Men are on these drugs longer, men are living longer,” adding that this will increase the likelihood of fractures. “If I’m using radium, I’m going to start a bone-targeted agent. Any time a patient has a skeletal-related event, I’m going to start a bone-targeted agent,” he said.
He noted there are still some questions about BPA duration and schedule. “Can we use some of the oral bisphosphonates earlier for osteopenia so we can get to a point where patients don’t have to have the more complicated approach, and increase the number of medicines they are on?” he wondered.