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, an associate professor of medicine at Tucson's University of Arizona and director of the clinical breast cancer program at the Arizona Cancer Center.
©SABCS/Todd Buchanan 2009
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 subcutaneous 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 (SABCS 2009 abstract 22).
©SABCS/Todd Buchanan 2009
Time to first on–study skeletal–related event (SRE) (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 SRE was 25.5 months in the zoledronic acid arm, but median time has not been reached with denosumab treatment. The statistical significance for noninferiority was P < .0001 and for superiority was P = .01.
"We also assessed whether staying on denosumab was beneficial, since patients who have an SRE are at risk for a second one," Dr. Stopeck said. Again, the benefit of denosumab was clearly shown, because time to first and subsequent on–study SREs 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. Stopeck said.
Dr. Stopeck 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."
Care of bone mets in breast cancer makes progress
The results of this study are exciting, because the study brings good news on several fronts, said Dr. Van Poznak. "Certainly, denosumab's statistically significant improved control of time to first on–study SREs, the improved control on the risk of first and subsequent SREs, and the data on hypercalcemia of malignancy (HCM), are all welcome news to those affected by bone metastases from breast cancer."
Dr. Van Poznak is an assistant professor in the department of internal medicine at the University of Michigan in Ann Arbor.
While the adverse–event profiles, particularly the acute phase reaction and the renal profile, were expected, the lack of statistical significance in the frequency of ONJ was noteworthy, she said. "Perhaps ONJ is related to osteoclast inhibition regardless of the pathway used to induce this inhibition. Or perhaps other factors—such as other systemic medications, oral health, trauma, infection, or other etiologies—are the major driving force behind the pathogenesis of ONJ." The etiology of ONJ remains unknown and the trial demonstrated the incidence to be 1% to 2% in this patient population, she added.
"One of the facts from this study that I find most encouraging is that the median time to first on–study SRE or HCM was 25.5 months for zoledronic acid; the median time had not been reached for the denosumab arm at the time of reporting," Dr. Van Poznak stated. "In the past, without osteoclast inhibition, three or four SREs would have occurred annually. The report of the median time to SRE being two years or more suggests to me that the care of patients with bone metastases is making definite progress."