For the prevention of skeletal-related events (SREs) in breast cancer patients with bone metastasis, denosumab proved superior to zoledronic acid (ZA) in a head-to-head randomized comparison conducted in 2048 women.
"Denosumab prevented more events, was better tolerated, and, as a subcutaneous [SC] injection, was more convenient for patients in this randomized double- blind trial against what has been the standard of care for treating bone metastasis," said Alison Stopeck, MD, of the University of Arizona Cancer Center, Tucson, who described the study at a press briefing.
She told reporters that should denosumab become US Food and Drug Administration (FDA)-approved, she will incorporate the drug "quickly" into her care of patients with bone metastases, "because subcutaneous administration is easy, you don't need to monitor creatinine, and it is less toxic, assuming the price is not exorbitant."
Denosumab works by inhibiting RANK ligand, which regulates osteoclast activity and function. It is not yet FDA-approved for use in metastatic breast cancer.
Patients with bone metastases not previously treated with intravenous (IV) bisphosphonates were randomized to treatment with SC denosumab 120 mg every 4 weeks and IV placebo, or SC placebo and IV ZA 4 mg every 4 weeks. Patients also received supplemental calcium and vitamin D.
During the 34-month study, 36.5% of patients treated with ZA developed SREs compared with 30.7% receiving denosumab, for a 6% absolute reduction in risk and a 16% relative risk reduction, Stopek announced.
The study's primary end point, time to first on-study SRE (pathologic fracture, radiation or surgery to bone, or spinal cord compression), was significantly shorter with ZA, at a median of 26.5 months, whereas half the denosumab-treated group has not yet experienced an SRE (ie, the end point has not been reached), Stopek reported.
"We also assessed whether staying on denosumab was beneficial, since patients who have an SRE are at risk for a second one," she said. Again, the benefit of denosumab was clear, as time to first-andsubsequent on-study SRE was reduced by 23%, over ZA. At 30 months, 608 events occurred with ZA compared with just 474 events with denosumab, a highly significant difference.
"Another encouraging observation was that the curves continue to separate," she added. "We expect the data to continue to strengthen as patients are on the drug longer."
Denosumab was also more protective against hypercalcemia of malignancy, and was superior in an analysis of skeletal morbidity rate.
"Most importantly for patients," she said, denosumab was associated with a delay in the onset of moderate-to-severe pain, from 64 days with ZA to 88 days. "What makes bone metastases so brutal is the pain, and patients on denosumab took longer to develop moderate-tosevere pain," she reported.
Adverse events were similar, although ZA was associated with higher incidence of acute-phase reactions (27.3% vs 10.4%). There was more renal toxicity with ZA but more hypercalcemia with denosumab. The occurrence of osteo necrosis of the jaw (ONJ) was rare and was not significantly different between the groups, occurring in 14 patients (1.4%) with ZA and 20 (2.0%) with denosumab. Importantly, 80% of subjects developing ONJ had risk factors for the condition, including dental extraction, poor dental hygiene, or dental appliances.
Theresa Guise, MD, professor of medicine and Jerry W. and Peg S. Throg martin professor of oncology at Indiana University School of Medicine, commented as moderator of the press briefing: "This study is very important. It shows that by inhibiting bone resorption in different ways we can get improved effects on preventing SREs."