SAN ANTONIO—Denosumab was superior to zoledronic acid(Drug information on zoledronic acid) (Zometa) for the prevention of skeletal-related events in breast cancer patients with bone metastasis, according to a head-to-head randomized comparison conducted in 2,048 women.
“Denosumab prevented more events, was better tolerated, and 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, from the University of Arizona Cancer Center in Tucson.
Denosumab works by inhibiting RANK ligand, which regulates osteoclast activity and function. Patients with bone metastases not previously treated with IV bisphosphonates were randomized to treatment with SC denosumab (120 mg every four weeks) and IV placebo, or SC placebo and IV zoledronic acid (4 mg every four weeks). Patients also received supplemental calcium and vitamin D (abstract 22).
Time to first on-study skeletal-related event (pathologic fracture, radiation or surgery to bone, or spinal cord compression), the primary endpoint, was reduced by 18% with denosumab. The median time to first skeletal-related event was 26.5 months in the zoledronic acid arm, but median time has not been reached with denosumab treatment. The statistical significance for non-inferiority was P < .0001 and for superiority was P = .01.
“We also assessed whether staying on denosumab was beneficial, since patients who have a skeletal-related event are at risk for a second one,” Dr. Stopek said. Again, the benefit of denosumab was clearly shown, because time to first and subsequent on-study skeletal-related event was reduced by 23%. At 30 months, 608 events occurred with zoledronic acid compared with just 474 events with denosumab (P = .001). “Another encouraging thing is that we see the curves continuing to separate,” she added.
Most important for patients, denosumab was associated with a delay in onset of moderate or severe pain (88 days vs 64; P = .009), she said. “What makes bone metastases so brutal is the pain, and patients on denosumab took longer to develop moderate to severe pain.”
Adverse events were reported by almost all patients in both arms, approximately 45% of which were serious. The main difference between the arms was the higher incidence of acute phase reactions with zoledronic acid (27.3% vs 10.4%). There was also more renal toxicity with zoledronic acid (8.5% vs 4.9%). Osteonecrosis of the jaw (ONJ) was rare, and its incidence was not significantly different between the groups, occurring in 14 patients with zoledronic acid and in 20 with denosumab. Eighty percent of patients in whom ONJ developed had risk factors for the conditions, including dental extraction, poor dental hygiene, or dental appliances, Dr. Stopek said.
Dr. Stopek said that should denosumab gain FDA approval, she would 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.”
SABCS press conference moderator Theresa Guise, MD, deemed the study very important. “It shows that by inhibiting bone resorption in different ways we can get improved effects on skeletal-related events in patients with bone metastases,” said Dr. Guise, who is professor of medicine and Jerry W. and Peggy S. Throgmartin Professor of Oncology at Indiana University School of Medicine in Indianapolis.