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J Clin Oncol. 2013 Oct 20;31(30):3800-6. doi: 10.1200/JCO.2012.44.6716. Epub 2013 Sep 16.

Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time.

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  • 1Matthew R. Smith, Massachusetts General Hospital Cancer Center, Boston, MA; Fred Saad, University of Montreal Hospital Center, Montreal, Quebec, Canada; Stephane Oudard, Georges Pompidou Hospital, Paris; Karim Fizazi, Institut Gustave Roussy, University of Paris Sud, Villejuif, France; Neal Shore, Carolina Urological Research Center, Myrtle Beach, SC; Paul Sieber, Urological Associates of Lancaster, Lancaster, PA; Bertrand Tombal, Université Catholique de Louvain Cliniques Universitaires Saint Luc, Bruxelles, Belgium; Ronaldo Damiao, Hospital Universitario Pedro Ernesto, Rio de Janeiro, Brazil; Gavin Marx, Sydney Haematology and Oncology Clinic, University of Sydney, Wahroonga, New South Wales, Australia; Kurt Miller, Charité Berlin, Berlin, Germany; Peter Van Veldhuizen, Kansas City Veterans Affairs Medical Center, Kansas City, MO; Juan Morote, Hospital Vall d'Hebron, Barcelona, Spain; and Zhishen Ye, Roger Dansey, and Carsten Goessl, Amgen, Thousand Oaks, CA.



Denosumab, an anti-RANK ligand monoclonal antibody, significantly increases bone metastasis-free survival (BMFS; hazard ratio [HR], 0.85; P = .028) and delays time to first bone metastasis in men with nonmetastatic castration-resistant prostate cancer (CRPC) and baseline prostate-specific antigen (PSA) ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤ 10.0 months. To identify men at greatest risk for bone metastasis or death, we evaluated relationships between PSA and PSADT with BMFS in the placebo group and the efficacy and safety of denosumab in men with PSADT ≤ 10, ≤ 6, and ≤ 4 months.


A total of 1,432 men with nonmetastatic CRPC were randomly assigned 1:1 to monthly subcutaneous denosumab 120 mg or placebo. Enrollment began February 2006; primary analysis cutoff was July 2010, when approximately 660 men were anticipated to have developed bone metastases or died.


In the placebo group, shorter BMFS was observed as PSADT decreased below 8 months. In analyses by shorter baseline PSADT, denosumab consistently increased BMFS by a median of 6.0, 7.2, and 7.5 months among men with PSADT ≤ 10 (HR, 0.84; P = .042), ≤ 6 (HR, 0.77; P = .006), and ≤ 4 months (HR, 0.71; P = .004), respectively. Denosumab also consistently increased time to bone metastasis by PSADT subset. No difference in survival was observed between treatment groups for the overall study population or PSADT subsets.


Patients with shorter PSADT are at greater risk for bone metastasis or death. Denosumab consistently improves BMFS in men with shorter PSADT and seems to have the greatest treatment effects in men at high risk for progression.

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