title: Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial.
abstract: BACKGROUND
  Src kinase-mediated interactions between prostate cancer cells and osteoclasts might promote bone metastasis. Dasatinib inhibits tyrosine kinases, including Src kinases. Data suggests that dasatinib kinase inhibition leads to antitumour activity, affects osteoclasts, and has synergy with docetaxel, a first-line chemotherapy for metastatic castration-resistant prostate cancer. We assessed whether dasatinib plus docetaxel in chemotherapy-naive men with metastatic castration-resistant prostate cancer led to greater efficacy than with docetaxel alone.
  
  
  METHODS
  In this double-blind, randomised, placebo-controlled phase 3 study, we enrolled men of 18 years or older with chemotherapy-naive, metastatic, castration-resistant prostate cancer, and adequate organ function from 186 centres across 25 countries. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive docetaxel (75 mg/m(2) intravenously every 3 weeks, plus oral prednisone 5 mg twice daily), plus either dasatinib (100 mg orally once daily) or placebo until disease progression or unacceptable toxicity. Randomisation was stratified by Eastern Cooperative Oncology Group performance status (0-1 vs 2), bisphosphonate use (yes vs no), and urinary N-telopeptide (uNTx) value (<60 μmol/mol creatinine vs ≥60 μmol/mol creatinine). All patients, investigators, and personnel involved in study conduct and data analyses were blinded to treatment allocation. The primary endpoint was overall survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00744497.
  
  
  RESULTS
  Between Oct 30, 2008, and April 11, 2011, 1522 eligible patients were randomly assigned to treatment; 762 patients were assigned to dasatinib and 760 to placebo. At final analysis, median follow-up was 19·0 months (IQR 11·2-25·1) and 914 patients had died. Median overall survival was 21·5 months (95% CI 20·3-22·8) in the dasatinib group and 21·2 months (20·0-23·4) in the placebo group (stratified hazard ratio [HR] 0·99, 95·5% CI 0·87-1·13; p=0·90). The most common grade 3-4 adverse events included diarrhoea (58 [8%] patients in the dasatinib group vs 27 [4%] patients in the placebo group), fatigue (62 [8%] vs 42 [6%]), and asthenia (40 [5%] vs 23 [3%]); grade 3-4 pleural effusions were uncommon (ten [1%] vs three [<1%]).
  
  
  CONCLUSIONS
  The addition of dasatinib to docetaxel did not improve overall survival for chemotherapy-naive men with metastatic castration-resistant prostate cancer. This study does not support the combination of dasatinib and docetaxel in this population of patients.
  
  
  BACKGROUND
  Bristol-Myers Squibb.
authors.affiliation: Department of Genitourinary Medical Onology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: johna@mdanderson.org.
authors.forename: John C
authors.initials: JC
authors.lastname: Araujo
authors.forename: Géralyn C
authors.initials: GC
authors.lastname: Trudel
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Armstrong
authors.forename: Evan Y
authors.initials: EY
authors.lastname: Yu
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.forename: John
authors.initials: J
authors.lastname: McCaffrey
authors.forename: Sergio V
authors.initials: SV
authors.lastname: Serrano
authors.forename: Vsevolod B
authors.initials: VB
authors.lastname: Matveev
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.forename: Stephane
authors.initials: S
authors.lastname: Oudard
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morris
authors.forename: Bruce
authors.initials: B
authors.lastname: Sizer
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Goebell
authors.forename: Axel
authors.initials: A
authors.lastname: Heidenreich
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.forename: Stephen
authors.initials: S
authors.lastname: Begbie
authors.forename: Jun H
authors.initials: JH
authors.lastname: Hong
authors.forename: Eduardo
authors.initials: E
authors.lastname: Richardet
authors.forename: Enrique
authors.initials: E
authors.lastname: Gallardo
authors.forename: Prashni
authors.initials: P
authors.lastname: Paliwal
authors.forename: Susan
authors.initials: S
authors.lastname: Durham
authors.forename: Shinta
authors.initials: S
authors.lastname: Cheng
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D000069439:Dasatinib; D018450:Disease Progression; D000077143:Docetaxel; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects; D017211:Treatment Failure
chemical_list: D014408:Biomarkers, Tumor; D011743:Pyrimidines; D043823:Taxoids; D013844:Thiazoles; D000077143:Docetaxel; D017430:Prostate-Specific Antigen; D000069439:Dasatinib