The evidence supporting this protocol is provided by a phase 3 multicentre, international, randomised, double-blind, double-dummy trial involving 2,049 patients comparing denosumab and placebo with zoledronic acid and placebo in patients with cytologically confirmed breast adenocarcinoma with radiographic evidence of at least one bone metastasis.r
Between April 2006 and December 2007, 1,026 patients were randomised to receive subcutaneous injection of denosumab 120 mg and an intravenous infusion of placebo every 4 weeks, and 1,026 patients were randomised to receive an intravenous infusion (lasting no less than 15 minutes) of zoledronic acid 4 mg and a subcutaneous injection of placebo every 4 weeks.r
The primary end point was time to first on-study Skeletal Related Event (SRE) (noninferiority analysis), defined as pathologic fracture (excluding major trauma), radiation therapy to bone, surgery to bone, or spinal cord compression. Secondary end points were time to first on-study SRE (superiority analysis) and time to first and subsequent on-study SREs (multiple event analysis). Subsequent events must have occurred at least 21 days apart from the most recent event to ensure that linked events (e.g. surgery to repair a fracture or multiple doses of radiation during a course of treatment) were not counted as separate SREs.r
Safety end points included incidence of treatment-emergent adverse events (AEs), changes in laboratory values, and incidence of anti-denosumab antibodies.r
Efficacy
After a median time on study of 17 months, the median time to first on-study SRE was 26.4 months for the zoledronic acid group and has not yet been reached for the denosumab group. (Denosumab significantly delayed time to first on-study SRE by 18% compared with zoledronic acid (HR, 0.82; 95% CI, 0.71 to 0.95; P < .001 noninferiority; P =.01 superiority).r
Kaplan-Meier estimates of (A) time to first SRE and (B) time to first and subsequent SREsr
© Journal of Clinical Oncology 2010
Kaplan-Meier estimates of (A) overall survival and (B) time to disease progressionr
© Journal of Clinical Oncology 2010
Quality of life (QOL) data was not collected in the key evidence.
Toxicity
Note: 40% of patients were also receiving chemotherapy.r
© Journal of Clinical Oncology 2010