title: Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Matthew 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.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Smith
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.forename: Stephane
authors.initials: S
authors.lastname: Oudard
authors.forename: Neal
authors.initials: N
authors.lastname: Shore
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.forename: Paul
authors.initials: P
authors.lastname: Sieber
authors.forename: Bertrand
authors.initials: B
authors.lastname: Tombal
authors.forename: Ronaldo
authors.initials: R
authors.lastname: Damiao
authors.forename: Gavin
authors.initials: G
authors.lastname: Marx
authors.forename: Kurt
authors.initials: K
authors.lastname: Miller
authors.forename: Peter
authors.initials: P
authors.lastname: Van Veldhuizen
authors.forename: Juan
authors.initials: J
authors.lastname: Morote
authors.forename: Zhishen
authors.initials: Z
authors.lastname: Ye
authors.forename: Roger
authors.initials: R
authors.lastname: Dansey
authors.forename: Carsten
authors.initials: C
authors.lastname: Goessl
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D001859:Bone Neoplasms / Q000175:diagnosis* / Q000556:secondary; D002369:Castration / Q000379:methods; D000069448:Denosumab; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D016017:Odds Ratio; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D053245:RANK Ligand; D000069448:Denosumab; D017430:Prostate-Specific Antigen
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