title: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study.
abstract: BACKGROUND
  Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer.
  
  
  METHODS
  In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed.
  
  
  RESULTS
  1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9-18·5) for patients on denosumab and 11·2 months (IQR 5·6-17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8-24·9) with denosumab compared with 17·1 months (15·0-19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71-0·95; p = 0·0002 for non-inferiority; p = 0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22 [2%] vs 12 [1%]; p = 0·09).
  
  
  CONCLUSIONS
  Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer.
  
  
  BACKGROUND
  Amgen.
authors.affiliation: Institut Gustave Roussy, University of Paris Sud, Villejuif, France. fizazi@igr.fr
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.forename: Michael
authors.initials: M
authors.lastname: Carducci
authors.forename: Matthew
authors.initials: M
authors.lastname: Smith
authors.forename: Ronaldo
authors.initials: R
authors.lastname: Damião
authors.forename: Janet
authors.initials: J
authors.lastname: Brown
authors.forename: Lawrence
authors.initials: L
authors.lastname: Karsh
authors.forename: Piotr
authors.initials: P
authors.lastname: Milecki
authors.forename: Neal
authors.initials: N
authors.lastname: Shore
authors.forename: Michael
authors.initials: M
authors.lastname: Rader
authors.forename: Huei
authors.initials: H
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Jiang
authors.forename: Sylvia
authors.initials: S
authors.lastname: Tadros
authors.forename: Roger
authors.initials: R
authors.lastname: Dansey
authors.forename: Carsten
authors.initials: C
authors.lastname: Goessl
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D000069448:Denosumab; D004164:Diphosphonates / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000601:surgery; D053245:RANK Ligand / Q000009:adverse effects / Q000627:therapeutic use*; D000077211:Zoledronic Acid
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D053245:RANK Ligand; D000069448:Denosumab; D000077211:Zoledronic Acid