A Comparison of Denosumab Versus Zoledronic Acid for the Prevention of Skeletal-Related Events in Breast Cancer Patients with Bone Metastases.
Authors: Stopeck A. , de Boer R. , Fujiwara Y. , Lichinitser M. , Tonkin K. , Yardley D. , Fan M. , Jiang Q. , Jun S. , Dansey R. , Braun A. 
Published: December 2010

Abstract
Background: Up to 75% of advanced breast cancer patients develop bone metastases (BM) that induce increased osteoclast activity resulting in local bone destruction. The ensuing skeletal complications, including fractures, may have serious consequences. Denosumab, a fully human monoclonal antibody, inhibits RANKL, a key mediator of osteoclast activity. Denosumab has been shown to increase bone mineral density and reduce fractures in postmenopausal women with low bone mass. Primary results from a recently completed randomized pivotal study demonstrated that denosumab was superior to zoledronic acid (ZA) in delaying and preventing skeletal-related events (SREs) in breast cancer patients with bone metastases. Here, we describe results of other endpoints from the study.Methods: Patients with breast cancer and BM (N=2046) who had not been treated with intravenous (IV) bisphosphonates were randomized 1:1 to receive either subcutaneous (SC) denosumab 120 mg and IV placebo, or SC placebo and IV ZA 4 mg every 4 weeks. All patients were encouraged to take daily supplemental calcium (≥500 mg) and vitamin D (≥400 IU). The primary endpoint was time to first on-study SRE (predefined as pathologic fracture, radiation to bone, surgery to bone, or spinal cord compression). Other endpoints included time to first radiation of bone; time to first on-study SRE or hypercalcemia of malignancy (HCM); skeletal morbidity rate (SMR; the number of SREs per year); and the proportion of patients with at least 1 on-study SRE. SMR was defined as the ratio of the number of SREs, allowing for one event every 21 days, divided by the patient's time at risk.Results: As previously reported, denosumab was superior to ZA in significantly delaying the time to first on-study SRE (hazard ratio [HR] 0.82; 95% CI: 0.71, 0.95; P&lt;0.0001 noninferiority; P=0.01 superiority) and the time to first and subsequent on-study SRE (rate ratio 0.77; 95%CI: 0.66, 0.89; P=0.001). Denosumab also significantly delayed the time to first radiation to bone (HR 0.74; 95% CI: 0.59, 0.94; P=0.01) and the time to first on-study SRE or HCM (HR 0.82; 95% CI: 0.70, 0.95; P=0.007) compared with ZA. Denosumab reduced the mean SMR compared with ZA (0.45 vs 0.58, respectively; P=0.004). The total number of SREs was 491 events for denosumab and 623 events for ZA. At the primary data analysis cut-off date (study duration: 34 months), the proportion of patients (95% CI) experiencing at least 1 on-study SRE was lower in the denosumab arm (30.7% [27.9%, 33.5%]) than the ZA arm (36.5% [33.5%, 39.4%]). Overall, the incidence of adverse events (AEs) and serious AEs was consistent with what has been previously reported for these two agents. AEs potentially associated with acute phase reactions during the first 3 days of study were reported in 10% of the denosumab arm and 27% of the ZA arm.Conclusion: Denosumab was more efficacious than ZA in delaying time to first radiation to bone and first on-study SRE or HCM and in reducing skeletal morbidity (SMR) and the proportion of patients with an SRE.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 22.