SAN ANTONIO—Denosumab was superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) in 2046 women with advanced breast cancer and bone metastases, according to new trial results. Denosumab, a monoclonal antibody acting via a novel mechanism, targets the receptor activator of nuclear factor kappa-B (RANK) ligand, important for the survival of osteoclasts, and thereby inhibits bone resorption.
In this phase 3 trial, participants were randomized to receive every 4 weeks subcutaneously (SC) plus intravenous (IV) placebo or ZA 4 mg (adjusted for renal function) IV plus placebo SC. All patients received supplemental calcium and vitamin D.
Lead investigator Alison Stopeck, MD, associate professor of medicine and director of the Clinical Breast Cancer Program at the Arizona Cancer Center of the University of Arizona in Tucson, reported that denosumab treatment resulted in a median 5-month longer time to a first on-study SRE compared with ZA during 33 months of observation (32.4 vs 27.4 months, respectively; hazard ratio [HR], 0.82; P = .0096). The median time to a first on-study SRE or hypercalcemia was 7 months longer with denosumab (32.4 vs 25.1 months; HR, 0.82; P = .0076). An SRE was defined as a fracture, radiation or surgery to bone, or spinal cord compression. A multiple event analysis indicated a 22% delay in the time to first and subsequent SREs with denosumab versus ZA (P = .0008).
Stopeck said average life expectancy with metastatic breast cancer is about 2.5 years “So if you can prolong the time without a skeletal-related event by 5 months, you are substantially benefiting the patient.” Overall survival and disease progression were similar for the two groups.
Almost all patients (>96%) in each group experienced adverse effects (AEs). Serious AEs affected about half of the patients in each group. More AEs related to renal toxicity (9.4% vs 5.4% with denosumab) and more acute-phase reactions (28.2% vs 10.7% with denosumab) occurred with ZA. The incidence of osteonecrosis of the jaw was low and not significantly different between the arms (1.8% with ZA, 2.5% with denosumab; P = .286). More hypocalcemia, mostly grade 1 or 2, occurred with denosumab (6.1% vs 3.7% with ZA).
Stopeck noted that SC administration makes denosumab more convenient than the IV dosing of ZA and that renal monitoring and dose adjustments are not required. She speculated that these study results will change practice for women with breast cancer and bone metastases.
In the AZURE trial, also presented at the symposium, ZA did not prolong overall or disease-free survival in women with stage II/III breast cancer. William Gradishar, MD, professor of medicine and director of breast medical oncology at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, who was not associated with either study, said preclinical data suggest RANK ligand may have an effect in tumor cells. “There’s reason to think that interrupting that pathway is going to have some effect,” he said, “but we just don’t have clinical data to support it at this point.”
A phase 3 trial (D-CARE; NCT0107 - 7154) is currently recruiting patients to study the effect of adjuvant denosumab on disease recurrence in bone or elsewhere in the body for women with earlystage breast cancer who are at high risk of disease recurrence