title: Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors.
abstract: OBJECTIVE
  Bone complications of metastatic disease, including skeletal-related events (SREs), impair patients' functioning and quality of life. In a randomized, phase 3 trial of 1,776 patients with metastases from solid tumors (except breast or prostate) or multiple myeloma, denosumab was non-inferior to zoledronic acid (ZA) in delaying or preventing SREs. This ad hoc analysis reports outcomes in the subgroup of 1,597 patients with solid tumors, excluding patients with multiple myeloma.
  
  
  METHODS
  Patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg, adjusted for creatinine clearance, with calcium and vitamin D supplementation recommended. Endpoints included times to first on-study SRE, first-and-subsequent SREs, and pain worsening.
  
  
  RESULTS
  Denosumab significantly delayed time to first on-study SRE compared with ZA (HR, 0.81; 95 % CI, 0.68-0.96) and time to first-and-subsequent SREs (RR, 0.85; 95 % CI, 0.72-1.00). Denosumab also significantly delayed time to development of moderate or severe pain (HR, 0.81; 95 % CI, 0.66-1.00), pain worsening (HR, 0.83; 95 % CI, 0.71-0.97), and worsening pain interference in patients with no/mild baseline pain (HR, 0.77; 95 % CI, 0.61-0.96). Adverse event rates were 96 % in both groups. Grade 3 or 4 hypocalcemia, mostly without clinical sequelae, was more frequent in denosumab-treated patients (denosumab 4 %, ZA 2 %). Osteonecrosis of the jaw occurred infrequently (denosumab 0.8 %, ZA 1.1 %).
  
  
  CONCLUSIONS
  Denosumab was more effective in delaying or preventing SREs in patients with bone metastases from solid tumors and also prevented pain progression compared to ZA in this ad hoc analysis.
authors.affiliation: Joan Karnell Cancer Center, Pennsylvania Hospital, 230 W Washington Square, Philadelphia, PA, 19106, USA, davidhenry@pennoncology.com.
authors.forename: David
authors.initials: D
authors.lastname: Henry
authors.forename: Saroj
authors.initials: S
authors.lastname: Vadhan-Raj
authors.forename: Vera
authors.initials: V
authors.lastname: Hirsh
authors.forename: Roger
authors.initials: R
authors.lastname: von Moos
authors.forename: Vania
authors.initials: V
authors.lastname: Hungria
authors.forename: Luis
authors.initials: L
authors.lastname: Costa
authors.forename: Penella J
authors.initials: PJ
authors.lastname: Woll
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scagliotti
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Smith
authors.forename: Amy
authors.initials: A
authors.lastname: Feng
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; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000503:physiopathology / Q000556:secondary*; D001862:Bone Resorption / Q000188:drug therapy* / Q000517:prevention & control; D000069448:Denosumab; D004164:Diphosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000473:pathology; D009369:Neoplasms / Q000473:pathology* / Q000503:physiopathology; D010146:Pain / Q000188:drug therapy / Q000517:prevention & control; 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