title: Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial.
abstract: BACKGROUND
  Enzalutamide significantly increased overall survival and radiographic progression-free survival compared with placebo in the PREVAIL trial of asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer. We report the effect of enzalutamide on health-related quality of life (HRQoL), pain, and skeletal-related events observed during this trial.
  
  
  METHODS
  In this phase 3, double-blind trial, patients were randomly assigned (1:1) to receive enzalutamide 160 mg/day (n=872) or placebo (n=845) orally. HRQoL was assessed at baseline and during treatment using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D questionnaires. Pain status was assessed at screening, baseline, week 13, and week 25 with the Brief Pain Inventory Short Form (BPI-SF). The primary analysis of HRQoL data used a mixed-effects model to test the difference between least square means change from baseline at week 61. We assessed change from baseline, percentage improvement, and time to deterioration in HRQoL and pain, the proportion of patients with a skeletal-related event, and time to first skeletal-related event. Analysis was done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01212991.
  
  
  RESULTS
  Median treatment duration was 16·6 months (IQR 10·1-21·1) in the enzalutamide group and 4·6 months (2·8-9·7) in the placebo group. The mixed-effects model analyses showed significant treatment differences in change from baseline to week 61 with enzalutamide compared with placebo for most FACT-P endpoints and EQ-5D visual analogue scale. Median time to deterioration in FACT-P total score was 11·3 months (95% CI 11·1-13·9) in the enzalutamide group and 5·6 months (5·5-5·6) in the placebo groups (hazard ratio [HR] 0·62 [95% CI 0·54-0·72]; p<0·0001). A significantly greater proportion of patients in the enzalutamide group than in the placebo group reported clinically meaningful improvements in FACT-P total score (327 [40%] of 826 vs 181 [23%] of 790), in EQ-5D utility index (224 [28%] of 812 vs 99 [16%] of 623), and visual analogue scale (218 [27%] of 803 vs 106 of [18%] 603; all p<0·0001). Median time to progression in BPI-SF pain at its worst was 5·7 months (95% CI 5·6-5·7) in the enzalutamide group and 5·6 months (5·4-5·6) in the placebo group (HR 0·62 [95% CI 0·53-0·74]; p<0·0001). Progression of pain at its worst was less common in the enzalutamide group than in the placebo group at week 13 (220 [29%] of 769 vs 257 [42%] of 610; p<0·0001), but not at week 25 (225 [32%] of 705 vs 135 [38%] of 360; p=0·068). 278 (32%) of 872 patients in the enzalutamide group and 309 (37%) of 845 patients in the placebo group had experienced a skeletal-related event by data cutoff. Median time to first skeletal-related events in the enzalutamide group was 31·1 months (95% CI 29·5-not reached) and 31·3 months (95% CI 23·9-not reached) in the placebo group (HR 0·72 [95% CI 0·61-0·84]; p<0·0001).
  
  
  CONCLUSIONS
  In addition to improving overall survival relative to placebo, enzalutamide significantly improves patient-related outcomes and delays occurrence of first skeletal-related event in chemotherapy-naive men with metastatic castration-resistant prostate cancer.
  
  
  BACKGROUND
  Astellas Pharma and Medivation.
authors.affiliation: Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif, France. Electronic address: yohann.loriot@gustaveroussy.fr.
authors.forename: Yohann
authors.initials: Y
authors.lastname: Loriot
authors.affiliation: Department of Urology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Kurt
authors.initials: K
authors.lastname: Miller
authors.affiliation: Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy.
authors.forename: Cora N
authors.initials: CN
authors.lastname: Sternberg
authors.affiliation: Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.affiliation: Drug Development Unit, Royal Marsden Hospital and Institute of Cancer Research, London, UK.
authors.forename: Johann S
authors.initials: JS
authors.lastname: De Bono
authors.affiliation: Department of Urology, Guys and St Thomas' Hospital, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.affiliation: Department of Early Clinical Development, Medivation, San Francisco, CA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Noonberg
authors.affiliation: Health Economics and Outcomes Research, Astellas Pharma Europe, Leiden, Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Holmstrom
authors.affiliation: Department of Medical Affairs, Medivation, San Francisco, CA, USA.
authors.forename: Harry
authors.initials: H
authors.lastname: Mansbach
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Perabo
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: De
authors.initials: D
authors.lastname: Phung
authors.affiliation: Consulting, Quintiles, Hoofddorp, Netherlands.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivanescu
authors.affiliation: Consulting, Quintiles, Barcelona, Spain; Department of Public Health, University of Barcelona, Barcelona, Spain.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Skaltsa
authors.affiliation: Division of Hematology and Medical Oncology, OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Beer
authors.affiliation: Department of Urology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Tombal
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001549:Benzamides; D018572:Disease-Free Survival; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009570:Nitriles; D010146:Pain / Q000188:drug therapy* / Q000473:pathology; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D011788:Quality of Life
chemical_list: D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide