[P6-14-01] Effect of Denosumab Versus Zoledronic Acid Treatment in Patients with Breast Cancer and Bone Metastases: Results from the Extended Blinded Treatment Phase.

Stopeck A, Martin M, Ritchie D, Body J-J, Paterson A, Viniegra M, Jassem J, Takano T, Van Poznak C, Bourgeois H, Fan M, Dansey R, Braun A. University of Arizona, Tucson; Hospital General Universitario Gregorio Maranon, Madrid, Spain; Beatson Oncology Centre, Glasgow, United Kingdom; CHU Brugmann, Université Libre de Bruxelles, Brussels, Belgium; Tom Baker Cancer Centre, Calgary, AB, Canada; Corporacion Medica de General San Martin, Buenos Aires, Argentina; Akademickie Centrum Kliniczne Szpital Akademii Medycznej w Gdansku, Gdansk, Poland; Toranomon Hospital, Tokyo, Japan; University of Michigan Comprehensive Cancer Center, Ann Arbor; Clinique Victor Hugo, Le Mans, France; Amgen Inc., Thousand Oaks, CA

Background: Denosumab is a fully human monoclonal antibody which inhibits RANKL, a key mediator of osteoclast activity. Results from the primary analysis of this pivotal phase 3 trial showed that denosumab was superior to zoledronic acid (ZA) in delaying the time to first on-study skeletal-related events (SRE) in patients with breast cancer and bone metastases. We now report results including an additional 4 months of blinded treatment.
Methods: Randomized patients received either subcutaneous (SC) denosumab (120 mg) and intravenous (IV) placebo or IV ZA (4 mg, adjusted for renal function) and SC placebo every 4 weeks. No dose adjustments were made for SC denosumab. All patients were advised to take daily calcium (≥ 500 mg) and vitamin D (≥ 400 IU) supplements. The primary endpoint was time to first on-study SRE (predefined as pathologic fracture, radiation or surgery to bone, or spinal cord compression). Time to first and subsequent SRE (multiple event analysis) and safety endpoints were also evaluated. Analyses for the extended treatment phase are considered exploratory.
Results: Overall, 2046 patients enrolled: 1026 were randomized to denosumab and 1020 were randomized to ZA. Denosumab was superior to ZA in delaying the time to first on-study SRE by 18%, and the time to first and subsequent on-study SRE by 22% (Table). The median time to first on-study SRE was 5 months longer for the denosumab group (32.4 months) than the ZA group (27.4 months). Overall survival and disease progression were similar for both treatment groups. Similar percentages of subjects reported adverse events (AEs; 96.2% denosumab, 97.4% ZA) and serious AEs (47.9% denosumab, 50.2% ZA). Positively adjudicated cases of osteonecrosis of the jaw were reported in 2.5% (n=26) of denosumab-treated patients and 1.8% (n=18) of ZA-treated patients (P=0.29). Hypocalcemia was reported by 62 (6.1%) patients in the denosumab group and 37 (3.7%) patients in the ZA group.

Table. Efficacy of Denosumab vs ZA Treatment on SREs
Study EndpointHazard Ratio (95% CI)Adjusted P-value†
Time to first on-study SRE0.82 (0.71, 0.95)< 0.01*
Time to first and subsequent on-study SRE**0.78 (0.68, 0.90)0.002
†P-values were adjusted for multiplicity according to a hierarchically testing strategy. *Superiority analysis; P < 0.0001 for noninferiority analysis. **This endpoint is reported as a rate ratio.

Conclusion: Among patients with breast cancer and bone metastases, denosumab was superior to ZA in delaying or preventing SREs, and continued treatment with denosumab resulted in a median time to first SRE that was 5 months longer than treatment with ZA. Denosumab, with its novel mode of action, may represent a potential treatment option for patients with breast cancer and bone metastases without the need for dose adjustment or renal monitoring.

Sunday, December 12, 2010 7:00 AM

Poster Session 6: Treatment - Therapeutic Strategies: New Drugs and Treatment Strategies (7:00 AM-8:30 AM)

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