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The use of bone-protecting agents (BPAs) substantially reduced the risk of fracture in men with castration-resistant prostate cancer (CRPC) and bone metastases who were being treated with enzalutamide with and without radium-223, according to an updated safety analysis of the EORTC 1333/PEACE III trial.

Among patients who did not receive zoledronic acid or denosumab, cumulative incidence of fracture was 37.1% in the combination arm and 15.6% in the enzalutamide-alone arm at 1 year, compared with just 2.7% and 2.6%, respectively, of patients who took BPAs, reported Silke Gillessen, MD, of the Oncology Institute of Southern Switzerland.

"This safety analysis confirms the importance of giving a bone-protecting agent when treating patients with CRPC and bone metastases," Gillessen said during a presentation at the virtual American Society of Clinical Oncology (ASCO) .

"Skeletal complications are common in patients with advanced prostate cancer," she added. "And they have an impact on the quality of life of our patients."

These complications result from osteoporotic fractures and skeletal-related events, including pathologic bone fracture, spinal cord compression, orthopedic surgery, and palliative radiation, which occur due to bone metastases, she noted.

To prevent skeletal complications, many guidelines recommend the use of BPAs such as zoledronic acid and denosumab in patients with CRPC and bone metastases.

The ongoing phase III has a history that was complicated by results from the , which compared radium-223 plus abiraterone acetate versus abiraterone acetate alone in patients with chemotherapy-naive CRPC with bone metastases. The primary outcome of the trial was symptomatic skeletal event-free survival.

ERA 223 was in 2017 following the report of a significant increase in fracture rates and deaths in the combination group. Sixty percent of patients had not received a BPA when entering the trial, and a post-hoc analysis showed that BPAs significantly decreased the rate of fractures in both study arms.

Based on these results, the independent data monitoring committee of the EORTC 1333/PEACE III trial -- which has a primary endpoint of radiographic progression-free survival in patients with asymptomatic or mildly symptomatic metastatic CRPC -- mandated the use of BPAs in study participants.

The trial as amended requires the use of a BPA at least 6 weeks before the injection of radium-223. Before this requirement was mandatory, however, 45% of patients randomized into the trial had not received a BPA. After the mandate, this proportion of patients fell to 2.9%.

At 21 months, patients who did not take a BPA in the combination arm and the enzalutamide-alone arm had a cumulative incidence of fracture of 52.0% and 21.9% compared with just 4.3% and 2.6%, respectively, for patients using BPAs.

"Our updated safety analysis confirms that the risk is well controlled in both arms when patients receive a bone-protecting agent," Gillessen noted.

"It was good to see that the fracture rate in the radium-223 arm did in fact improve," observed ASCO discussant Lisa Horvath, PhD, MBBS, of Sydney Cancer Center in Australia. "But what I found most impressive was the efficacy of bone-protecting agents in the standard-of-care enzalutamide arm."

The study showed how independent data safety monitoring committees can improve outcomes, she said, given that incidence of fractures across both arms of the study fell with the implementation of the BPA requirement.

Horvath pointed out that the analysis was not a randomized comparison, contained small numbers, and has yet to report on toxicity and quality of life. "But it does address one of the great fears of medical oncologists -- the fear of osteonecrosis of the jaw," she said, adding that this concern "should be balanced against the 1-year fracture rate from 15.6% down to 2.6%, which I think proves the point we should be using these agents more frequently."

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