title: Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases.
abstract: OBJECTIVE
  Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-kappaB ligand, suppresses bone resorption. In this study, we evaluated the efficacy and safety of five dosing regimens of denosumab in patients with breast cancer-related bone metastases not previously treated with intravenous bisphosphonates (IV BPs).
  
  
  METHODS
  Eligible women (n = 255) with breast cancer-related bone metastases were stratified by type of antineoplastic therapy received and randomly assigned to one of six cohorts (five denosumab cohorts [blinded to dose and frequency]; one open-label IV BP cohort). Denosumab was administered subcutaneously every 4 weeks (30, 120, or 180 mg) or every 12 weeks (60 or 180 mg). The primary end point was percentage of change in the bone turnover marker urine N-telopeptide corrected for urine creatinine (uNTx/Cr) from baseline to study week 13. The percentage of patients achieving more than 65% uNTx/Cr reduction, time to more than 65% uNTx/Cr reduction, patients experiencing one or more on-study skeletal-related events (SRE), and safety were also evaluated.
  
  
  RESULTS
  At study week 13, the median percent reduction in uNTx/Cr was 71% for the pooled denosumab groups and 79% for the IV BP group. Overall, 74% of denosumab-treated patients (157 of 211) achieved a more than 65% reduction in uNTx/Cr compared with 63% of bisphosphonate-treated patients (27 of 43). On-study SREs were experienced by 9% of denosumab-treated patients (20 of 211) versus 16% of bisphosphonate-treated patients (seven of 43). No serious or fatal adverse events related to denosumab occurred.
  
  
  CONCLUSIONS
  Subcutaneous denosumab may be similar to IV BPs in suppressing bone turnover and reducing SRE risk. The safety profile was consistent with an advanced breast cancer population receiving systemic therapy.
authors.affiliation: Penn State Milton S. Hershey Medical Center, Hershey, PA 17033-0850, USA. alipton@psu.edu
authors.forename: Allan
authors.initials: A
authors.lastname: Lipton
authors.forename: Guenther G
authors.initials: GG
authors.lastname: Steger
authors.forename: Jazmin
authors.initials: J
authors.lastname: Figueroa
authors.forename: Cristina
authors.initials: C
authors.lastname: Alvarado
authors.forename: Philippe
authors.initials: P
authors.lastname: Solal-Celigny
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Body
authors.forename: Richard
authors.initials: R
authors.lastname: de Boer
authors.forename: Rossana
authors.initials: R
authors.lastname: Berardi
authors.forename: Pere
authors.initials: P
authors.lastname: Gascon
authors.forename: Katia S
authors.initials: KS
authors.lastname: Tonkin
authors.forename: Robert
authors.initials: R
authors.lastname: Coleman
authors.forename: Alexander H G
authors.initials: AH
authors.lastname: Paterson
authors.forename: Mark C
authors.initials: MC
authors.lastname: Peterson
authors.forename: Michelle
authors.initials: M
authors.lastname: Fan
authors.forename: Amy
authors.initials: A
authors.lastname: Kinsey
authors.forename: Susie
authors.initials: S
authors.lastname: Jun
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers / Q000378:metabolism; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D001862:Bone Resorption / Q000517:prevention & control*; D001943:Breast Neoplasms / Q000473:pathology*; D024042:Collagen Type I / Q000187:drug effects / Q000378:metabolism; D003198:Computer Simulation; D000069448:Denosumab; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D010455:Peptides / Q000187:drug effects / Q000378:metabolism; D053245:RANK Ligand