title: Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial.
abstract: BACKGROUND
  Docetaxel plus prednisone is standard first-line chemotherapy for men with metastatic castrate-resistant prostate cancer. Aflibercept is a recombinant human fusion protein that binds A and B isoforms of VEGF and placental growth factor, thereby inhibiting angiogenesis. We assessed whether the addition of aflibercept to docetaxel and prednisone would improve overall survival in men with metastatic castrate-resistant prostate cancer compared with the addition of placebo to docetaxel and prednisone.
  
  
  METHODS
  VENICE was a phase 3, multicentre, randomised double-blind placebo-controlled parallel group study done in 31 countries (187 sites). Men with metastatic castrate-resistant prostate cancer, adequate organ function, and no prior chemotherapy were treated with docetaxel (75 mg/m(2) intravenously every 3 weeks) and oral prednisone (5 mg twice daily) and randomly allocated (1:1) to receive aflibercept (6 mg/kg) or placebo, intravenously, every 3 weeks. Treatment allocation was done centrally via an interactive voice response system, using a computer-generated sequence with a permuted-block size of four and stratified according Eastern Co-operative Group performance status (0-1 vs 2). Patients, investigators, and other individuals responsible for study conduct and data analysis were masked to treatment assignment. Aflibercept or placebo vials were supplied in identical boxes. The primary endpoint was overall survival using intention-to-treat analysis. This is the primary analysis of the completed trial. The study is registered with ClinicalTrials.gov, number NCT00519285 FINDINGS: Between Aug 17, 2007, and Feb 11, 2010, 1224 men were randomly allocated to treatment: 612 to each group. At final analysis, median follow-up was 35 months (IQR 29-41) and 873 men had died. Median overall survival was 22·1 months (95·6% CI 20·3-24·1) in the aflibercept group and 21·2 months (19·6-23·8) in the placebo group (stratified hazard ratio 0·94, 95·6% CI 0·82-1·08; p=0·38). We recorded a higher incidence of grade 3-4 gastrointestinal disorders (182 [30%] vs 48 [8·0%]), haemorrhagic events (32 [5·2%] vs ten [1·7%]), hypertension (81 [13%] vs 20 [3·3%]), fatigue (97 [16%] vs 46 [7·7%]), infections (123 [20%] vs 60 [10%]) and treatment-related fatal adverse events (21 [3·4%] vs nine [1·5%]) in the aflibercept group than in the placebo group.
  
  
  CONCLUSIONS
  Aflibercept in combination with docetaxel and prednisone given as first-line chemotherapy for men with metastatic castrate-resistant prostate cancer resulted in no improvement in overall survival and added toxicity compared with placebo. Docetaxel plus prednisone remains the standard treatment for such men who need first-line chemotherapy.
  
  
  BACKGROUND
  Sanofi and Regeneron Pharmaceuticals Inc.
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada. ian.tannock@uhn.ca
authors.forename: Ian F
authors.initials: IF
authors.lastname: Tannock
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.forename: Sergey
authors.initials: S
authors.lastname: Ivanov
authors.forename: Camilla Thellenberg
authors.initials: CT
authors.lastname: Karlsson
authors.forename: Aude
authors.initials: A
authors.lastname: Fléchon
authors.forename: Iwona
authors.initials: I
authors.lastname: Skoneczna
authors.forename: Francisco
authors.initials: F
authors.lastname: Orlandi
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Gravis
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Matveev
authors.forename: Sevil
authors.initials: S
authors.lastname: Bavbek
authors.forename: Thierry
authors.initials: T
authors.lastname: Gil
authors.forename: Luciano
authors.initials: L
authors.lastname: Viana
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Arén
authors.forename: Oleg
authors.initials: O
authors.lastname: Karyakin
authors.forename: Tony
authors.initials: T
authors.lastname: Elliott
authors.forename: Alison
authors.initials: A
authors.lastname: Birtle
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Magherini
authors.forename: Laurence
authors.initials: L
authors.lastname: Hatteville
authors.forename: Daniel
authors.initials: D
authors.lastname: Petrylak
authors.forename: Bertrand
authors.initials: B
authors.lastname: Tombal
authors.forename: Mark
authors.initials: M
authors.lastname: Rosenthal
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000077143:Docetaxel; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005060:Europe; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009656:North America; D009919:Orchiectomy; D011241:Prednisone / Q000008:administration & dosage; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D013020:South America; D043823:Taxoids / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D011993:Recombinant Fusion Proteins; D043823:Taxoids; C533178:aflibercept; D000077143:Docetaxel; D040262:Receptors, Vascular Endothelial Growth Factor; D011241:Prednisone