title: Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials.
abstract: BACKGROUND
  Patients with bone metastases from advanced cancer often experience skeletal-related events (SRE), which cause substantial pain and morbidity. Denosumab, a fully human monoclonal antibody that inhibits RANK Ligand (RANKL), is a novel bone-targeted agent with a distinct mechanism of action relative to the bisphosphonate zoledronic acid, for prevention of SRE. This pre-planned analysis evaluates the efficacy and safety of denosumab versus zoledronic acid across three pivotal studies.
  
  
  METHODS
  Patient-level data from three identically designed, randomised, double-blind, active-controlled, phase 3 trials of patients with breast cancer, prostate cancer, other solid tumours or multiple myeloma were combined. End-points included time to first SRE, time to first and subsequent (multiple) SRE, adverse events, time to disease progression and overall survival.
  
  
  RESULTS
  Denosumab was superior to zoledronic acid in delaying time to first on-study SRE by a median 8.21months, reducing the risk of a first SRE by 17% (hazard ratio, 0.83 [95% confidence interval (CI): 0.76-0.90]; P<0.001). Efficacy was demonstrated for first and multiple events and across patient subgroups (prior SRE status; age). Disease progression and overall survival were similar between the treatments. In contrast to zoledronic acid, denosumab did not require monitoring or dose modification/withholding based on renal status, and was not associated with acute-phase reactions. Hypocalcaemia was more common for denosumab. Osteonecrosis of the jaw occurred at a similar rate (P=0.13).
  
  
  CONCLUSIONS
  Denosumab was superior to zoledronic acid in preventing SRE with favourable safety and convenience in patients with bone metastases from advanced cancer.
authors.affiliation: Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, PA 17033, USA. alipton@hmc.psu.edu
authors.forename: Allan
authors.initials: A
authors.lastname: Lipton
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.forename: Alison T
authors.initials: AT
authors.lastname: Stopeck
authors.forename: David H
authors.initials: DH
authors.lastname: Henry
authors.forename: Janet E
authors.initials: JE
authors.lastname: Brown
authors.forename: Denise A
authors.initials: DA
authors.lastname: Yardley
authors.forename: Gary E
authors.initials: GE
authors.lastname: Richardson
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.forename: Pablo
authors.initials: P
authors.lastname: Maroto
authors.forename: Michael
authors.initials: M
authors.lastname: Clemens
authors.forename: Boris
authors.initials: B
authors.lastname: Bilynskyy
authors.forename: Veena
authors.initials: V
authors.lastname: Charu
authors.forename: Philippe
authors.initials: P
authors.lastname: Beuzeboc
authors.forename: Michael
authors.initials: M
authors.lastname: Rader
authors.forename: Maria
authors.initials: M
authors.lastname: Viniegra
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.forename: Chunlei
authors.initials: C
authors.lastname: Ke
authors.forename: Ada
authors.initials: A
authors.lastname: Braun
authors.forename: Susie
authors.initials: S
authors.lastname: Jun
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000209:etiology; D050071:Bone Density Conservation Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary*; D017326:Clinical Trials, Phase III as Topic; D000069448:Denosumab; D004164:Diphosphonates / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D005260:Female; D006801:Humans; D006996:Hypocalcemia / Q000139:chemically induced; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012307:Risk Factors; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D000077211:Zoledronic Acid
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000069448:Denosumab; D000077211:Zoledronic Acid