title: Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma.
abstract: OBJECTIVE
  This study compared denosumab, a fully human monoclonal anti-receptor activator of nuclear factor kappa-B ligand antibody, with zoledronic acid (ZA) for delaying or preventing skeletal-related events (SRE) in patients with advanced cancer and bone metastases (excluding breast and prostate) or myeloma.
  
  
  METHODS
  Eligible patients were randomly assigned in a double-blind, double-dummy design to receive monthly subcutaneous denosumab 120 mg (n = 886) or intravenous ZA 4 mg (dose adjusted for renal impairment; n = 890). Daily supplemental calcium and vitamin D were strongly recommended. The primary end point was time to first on-study SRE (pathologic fracture, radiation or surgery to bone, or spinal cord compression).
  
  
  RESULTS
  Denosumab was noninferior to ZA in delaying time to first on-study SRE (hazard ratio, 0.84; 95% CI, 0.71 to 0.98; P = .0007). Although directionally favorable, denosumab was not statistically superior to ZA in delaying time to first on-study SRE (P = .03 unadjusted; P = .06 adjusted for multiplicity) or time to first-and-subsequent (multiple) SRE (rate ratio, 0.90; 95% CI, 0.77 to 1.04; P = .14). Overall survival and disease progression were similar between groups. Hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred at similarly low rates in both groups. Acute-phase reactions after the first dose occurred more frequently with ZA, as did renal adverse events and elevations in serum creatinine based on National Cancer Institute Common Toxicity Criteria for Adverse Events grading.
  
  
  CONCLUSIONS
  Denosumab was noninferior (trending to superiority) to ZA in preventing or delaying first on-study SRE in patients with advanced cancer metastatic to bone or myeloma. Denosumab represents a potential novel treatment option with the convenience of subcutaneous administration and no requirement for renal monitoring or dose adjustment.
authors.affiliation: Joan Karnell Cancer Center, Philadelphia, PA 19106, USA. davidhenry@pennoncology.com
authors.forename: David H
authors.initials: DH
authors.lastname: Henry
authors.forename: Luis
authors.initials: L
authors.lastname: Costa
authors.forename: Francois
authors.initials: F
authors.lastname: Goldwasser
authors.forename: Vera
authors.initials: V
authors.lastname: Hirsh
authors.forename: Vania
authors.initials: V
authors.lastname: Hungria
authors.forename: Jana
authors.initials: J
authors.lastname: Prausova
authors.forename: Giorgio Vittorio
authors.initials: GV
authors.lastname: Scagliotti
authors.forename: Harm
authors.initials: H
authors.lastname: Sleeboom
authors.forename: Andrew
authors.initials: A
authors.lastname: Spencer
authors.forename: Saroj
authors.initials: S
authors.lastname: Vadhan-Raj
authors.forename: Roger
authors.initials: R
authors.lastname: von Moos
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Willenbacher
authors.forename: Penella J
authors.initials: PJ
authors.lastname: Woll
authors.forename: Jianming
authors.initials: J
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Jiang
authors.forename: Susie
authors.initials: S
authors.lastname: Jun
authors.forename: Roger
authors.initials: R
authors.lastname: Dansey
authors.forename: Howard
authors.initials: H
authors.lastname: Yeh
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D000069448:Denosumab; D004164:Diphosphonates / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007390:International Agencies; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053245:RANK Ligand / Q000627:therapeutic use*; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult; 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