AOSOP6 Results from the 2-year open-label extension treatment phase of a pivotal phase 3 study of denosumab in patients with breast cancer and bone metastases previously treated with zoledronic acid or denosumab

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Background Denosumab was superior to zoledronic acid (ZA) in reducing the risk of a first on-study skeletal-related event (SRE; HR, 0.82; 95% confidence interval (CI) 0.71, 0.95; p = 0.01) in patients with breast cancer and bone metastases (BMs; Stopeck et al., 2010). All patients who remained on treatment after the primary analysis were offered open-label (OL) denosumab for a pre-specified 2-year extension phase. Methods Women with BMs secondary to breast cancer ( N = 2046) were randomly assigned to subcutaneous denosumab 120 mg or IV ZA 4 mg (adjusted for renal function) Q4W. Patients who completed this double-blind, double-dummy treatment phase were offered OL denosumab Q4W. Patients who did not participate in the OL phase were followed up for survival every 12 weeks for up to 2 years after their last dose of investigational drug. Findings Of the 752 patients who completed the double-blind phase, 667 (89%) chose to receive OL denosumab: 325 initially randomly assigned to denosumab (DD) and 342 to ZA (ZD). Total median (Q1, Q3) cumulative denosumab exposure in DD patients was 19.3 months (9.2, 32.2) (range 0.9–59.8 months). Adverse events (AEs) were comparable between groups ( n = 283/318 [89%] for DD; n = 303/334 [91%] ZD) during the OL phase; 20 and 18 patients, respectively, reported osteonecrosis of the jaw; cumulative incidence was 4.7% in DD patients and 3.5% in ZD patients for the entire study duration of 5 years. Hypocalcaemia was comparable between groups ( n = 12 DD; n = 9 ZD). Serious AEs were reported in 126 (39.6%) DD patients and 133 (39.8%) ZD patients. Overall survival was similar between the groups for the entire study: median 34.4 months (95% CI 31.5, 39.3) and 34.2 months (95% CI 31.0, 37.6), respectively. Interpretation This OL extension treatment phase confirmed the safety profile of denosumab in patients with breast cancer with BMs receiving up to 5 years of monthly denosumab therapy or switching to denosumab after up to 3 years of ZA. Funding Funding was provided by Amgen Inc. A.T. Stopeck is a consultant for Amgen and Novartis; A. Lipton is a member of the speakers’ bureau, is a consultant, has received research support from Amgen and Novartis, and has provided expert testimony for Novartis; M. Martin is a consultant for Amgen; J-J. Body is a consultant for and has received lecture fees from both Amgen and Novartis; A. Paterson has received honoraria for speaking from Amgen, Roche, and Novartis; G.G. Steger has received travel grants and attended advisory boards for Amgen and Novartis; K. Tonkin has no disclosures; R.H. de Boer has no disclosures; Y. Fujiwara, Chugai Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma KK, Janssen Pharmaceutical KK, and Takeda Bio Development Center Limited; D. Yardley has no disclosures; J. Jassem has no disclosures; T. Takano is a medical consultant for Daiichi Sankyo; P. Solal-Celigny has no disclosures; and M. Fan and A. Braun are employed by Amgen and own stock.