Originally published as JCO Early Release 10.1200/JCO.2007.11.8604 on September 4 2007

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Randomized Active-Controlled Phase II Study of Denosumab Efficacy and Safety in Patients With Breast Cancer-Related Bone Metastases

Allan Lipton, Guenther G. Steger, Jazmin Figueroa, Cristina Alvarado, Philippe Solal-Celigny, Jean-Jacques Body, Richard de Boer, Rossana Berardi, Pere Gascon, Katia S. Tonkin, Robert Coleman, Alexander H.G. Paterson, Mark C. Peterson, Michelle Fan, Amy Kinsey, Susie Jun

From the Penn State Milton S. Hershey Medical Center, Hershey, PA; Universitätsklinik für Innere Medizin, Wien, Austria; Hospital General de Mexico; Hospital Juarez de Mexico, Mexico City, Mexico; Clinique Victor Hugo, LeMans, France; Institut Jules Bordet, Brussels, Belgium; Western Hospital, Footscray, Australia; Università Politecnica delle Marche, Ancona, Italy; Hospital Clínic de Barcelona, Barcelona, Spain; Cross Cancer Center, Edmonton; Tom Baker Cancer Centre, Calgary, Alberta, Canada; Weston Park Hospital, Sheffield, United Kingdom; and Amgen Inc, Thousand Oaks, CA

Address reprint requests to Allan Lipton, MD, Milton S. Hershey Medical Center Oncology, 500 University Dr, Hershey, PA 17033-0850; e-mail: alipton{at}psu.edu

Purpose Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-B ligand, suppresses bone resorption. In this study, we evaluated the efficacy and safety of five dosing regimens of denosumab in patients with breast cancer-related bone metastases not previously treated with intravenous bisphosphonates (IV BPs).

Patients and Methods Eligible women (n = 255) with breast cancer-related bone metastases were stratified by type of antineoplastic therapy received and randomly assigned to one of six cohorts (five denosumab cohorts [blinded to dose and frequency]; one open-label IV BP cohort). Denosumab was administered subcutaneously every 4 weeks (30, 120, or 180 mg) or every 12 weeks (60 or 180 mg). The primary end point was percentage of change in the bone turnover marker urine N-telopeptide corrected for urine creatinine (uNTx/Cr) from baseline to study week 13. The percentage of patients achieving more than 65% uNTx/Cr reduction, time to more than 65% uNTx/Cr reduction, patients experiencing one or more on-study skeletal-related events (SRE), and safety were also evaluated.

Results At study week 13, the median percent reduction in uNTx/Cr was 71% for the pooled denosumab groups and 79% for the IV BP group. Overall, 74% of denosumab-treated patients (157 of 211) achieved a more than 65% reduction in uNTx/Cr compared with 63% of bisphosphonate-treated patients (27 of 43). On-study SREs were experienced by 9% of denosumab-treated patients (20 of 211) versus 16% of bisphosphonate-treated patients (seven of 43). No serious or fatal adverse events related to denosumab occurred.

Conclusion Subcutaneous denosumab may be similar to IV BPs in suppressing bone turnover and reducing SRE risk. The safety profile was consistent with an advanced breast cancer population receiving systemic therapy.

published online ahead of print at www.jco.org on September 4, 2007.

Supported by Amgen Inc, Thousand Oaks, CA.

Presented in part at 42nd Annual Meeting of the American Society of Clinical Oncology Atlanta, GA, June 3-6, 2006; First International Symposium on Secondary Causes of Osteoporosis, Florence, Italy, July 7-8, 2006; 31st ESMO Congress, Istanbul, Turkey, September 29-October 2, 2006; Second Annual Oncology Congress, New York, NY, October 19-21, 2006; Chemotherapy Foundation Symposium XXIV, New York, NY, November 8- 11, 2006; and the Sixth International Meeting on Cancer Induced Bone Disease, San Antonio, TX, December 10-14, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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