Originally published as JCO Early Release 10.1200/JCO.2008.19.2146 on February 23 2009

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Randomized Phase II Trial of Denosumab in Patients With Bone Metastases From Prostate Cancer, Breast Cancer, or Other Neoplasms After Intravenous Bisphosphonates

From the Institut Gustave Roussy, Villejuif; Hôpital Bicêtre, Université Paris-Sud, Le Kremlin Bicêtre, France; Milton S. Hershey Medical Center, Hershey, PA; Seattle Cancer Care Alliance, Seattle, WA; Amgen Inc, Thousand Oaks, CA; Centre Hospitalier Universitaire Brugmann, Université Libre de Bruxelles, Brussels, Belgium; Toronto East General Hospital, Toronto, Ontario, Canada.

Corresponding author: Karim Fizazi, MD, PhD, Department of Medicine, Institut Gustave Roussy, University of Paris XI, 39 Rue Camille Desmoulins, 94800 Villejuif, France; e-mail: fizazi{at}igr.fr.

Purpose Patients with bone metastases and elevated urinary N-telopeptide (uNTx), representing excessive bone resorption, are at increased risk for skeletal-related events (SREs), cancer progression, and death. Osteoclast-mediated bone resorption is regulated by RANKL. We evaluated the effect of denosumab, a fully human monoclonal antibody against RANKL, in patients with bone metastases and elevated uNTx levels despite ongoing intravenous (IV) bisphosphonate (BP) therapy.

Patients and Methods Eligible patients had histologically confirmed malignancy, 1 bone metastases, and uNTx levels higher than 50 nmol/L bone collagen equivalents (BCE)/mM creatinine despite IV BPs. They were stratified by tumor type and screening uNTx levels (50 to 100 or > 100 nmol/L BCE/mM creatinine), and randomly assigned to continue IV BPs every 4 weeks or receive subcutaneous denosumab 180 mg every 4 weeks or every 12 weeks.

Results Among 111 patients accrued, the primary end point of uNTx levels lower than 50 nmol/L BCE/mM creatinine (uNTx < 50) at week 13 was achieved by 49 (71%) of 69 patients in the denosumab arms, compared with 10 (29%) of 35 patients in the IV BP arm (P < .001). The proportion of patients with uNTx lower than 50 was maintained at week 25 (64% denosumab arms; 37% IV BP arm; P = .01). The incidence of SREs was six (8%) of 73 and six (17%) of 35 in the denosumab group and IV BP group, respectively. Rates of adverse events were similar between treatment groups.

Conclusion Among patients with elevated uNTx despite ongoing IV BP therapy, denosumab normalized uNTx levels more frequently than the continuation of IV BP. Fewer patients receiving denosumab experienced on-study SREs than those receiving IV BPs.

Supported by Amgen Inc, Thousand Oaks, CA.

Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31 to June 3, 2008; at the 1st European Multidisciplinary Conference, Barcelona, Spain, November 2–4, 2007; at the ASCO Breast Cancer Symposium, San Francisco, CA, September 7–8, 2007; at the American Urological Association Annual Meeting, Anaheim, CA, May 19–24, 2007; at the ASCO Prostate Cancer Symposium, Orlando, FL, February 22–24, 2007; at the Prostate Cancer Update, Vail, CO, February 15–17, 2007; at the European Society for Medical Oncology Annual Meeting, Istanbul, Turkey, September 29 to October 3, 2006; and at the ASCO Annual Meeting, Atlanta, GA, June 2–6, 2006.

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

Clinical Trials repository link available on JCO.org.

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• A Step in the Journey of Denosumab From Bone-Targeted Therapy to Seed- and Soil-Targeted Therapy
  Stéphane Vignot and David Khayat
  JCO 2009 27: 1534-1536 [Full Text]

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