title: Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial.
abstract: BACKGROUND
  In the AFFIRM trial of patients with metastatic castration-resistant prostate cancer after progression with docetaxel treatment, enzalutamide significantly increased overall survival compared with placebo. Here we present the prospectively defined analyses of some secondary endpoints, including occurrence of skeletal-related events, measures of pain control, and patient-reported health-related quality of life (HRQoL).
  
  
  METHODS
  In this phase 3, double-blind trial, patients were randomly assigned (2:1) to receive enzalutamide 160 mg/day or placebo orally, stratified by ECOG baseline performance status (0 or 1 vs 2) and mean pain score (Brief Pain Inventory-Short Form [BPI-SF] question 3 worst pain, score ≤3 vs ≥4). Secondary endpoints were time to first skeletal-related event (defined as radiation therapy or surgery to bone); change from baseline to week 13 in pain severity and interference; pain palliation and progression at week 13; time to pain progression; overall improvement in HRQoL; improvements in HRQoL domains; and time to HRQoL deterioration. Analysis was done on the intention-to-treat population for each endpoint. AFFIRM is registered with ClinicalTrials.gov, number NCT00974311.
  
  
  RESULTS
  Median time to first skeletal-related event in the enzalutamide (n=800) and placebo (n=399) groups was 16·7 months (95% CI 14·6 to 19·1) and 13·3 months (95% CI 9·9 to not yet reached), respectively (hazard ratio [HR] 0·69 [95% CI 0·57-0·84]; p=0·0001). Pain progression at week 13 occurred in 174 (28%) of 625 evaluable patients in the enzalutamide group versus 101 (39%) of 259 patients in the placebo group (difference -11·2%, 95% CI -18·1 to -4·3; p=0·0018). Median time to pain progression was not yet reached in the enzalutamide group (95% CI not yet reached to not yet reached) versus 13·8 (13·8 to not yet reached) months in the placebo group (HR 0·56 [95% CI 0·41 to 0·78]; p=0·0004). Mean treatment effects for pain severity (mean change from baseline in the enzalutamide group -0·15, 95% CI -0·28 to -0·02, vs placebo 0·50, 0·29 to 0·70; difference -0·65, 95% CI -0·89 to -0·41; p<0·0001) and interference (-0·01, -0·18 to 0·16, vs 0·74, 0·47 to 1·00; respectively, difference -0·74, 95% -1·06 to -0·43; p<0·0001) were significantly better with enzalutamide than with placebo. 22 (45%) of 49 evaluable patients in the enzalutamide group reported pain palliation at week 13 versus one (7%) of 15 in the placebo group (difference 38·2%, 95% CI 19·4-57·0; p=0·0079). Overall improvement in HRQoL was reported in more patients receiving enzalutamide (275 [42%] of 652) than in those receiving placebo (36 [15%] of 248; p<0·0001). Patients in the enzalutamide group had longer median time to HRQoL deterioration than did those in the placebo group (9·0 months, 95% CI 8·3-11·1, vs 3·7 months, 95% CI 3·0-4·2; HR 0·45, 95% CI 0·37-0·55; p<0·0001) in risk of deterioration.
  
  
  CONCLUSIONS
  Our results show that, in addition to improving overall survival, enzalutamide improves wellbeing and everyday functioning of patients with metastatic castration-resistant prostate cancer.
  
  
  BACKGROUND
  Astellas Pharma and Medivation.
authors.affiliation: Institut Gustave Roussy, University of Paris Sud, Villejuif, France. Electronic address: karim.fizazi@gustaveroussy.fr.
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.affiliation: Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
authors.affiliation: Charité Berlin, Berlin, Germany.
authors.forename: Kurt
authors.initials: K
authors.lastname: Miller
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Basch
authors.affiliation: San Camillo and Forlanini Hospitals, Rome, Italy.
authors.forename: Cora N
authors.initials: CN
authors.lastname: Sternberg
authors.affiliation: Department of Medical Social Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: David
authors.initials: D
authors.lastname: Cella
authors.affiliation: Medivation, San Francisco, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Forer
authors.affiliation: Medivation, San Francisco, CA, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hirmand
authors.affiliation: Royal Marsden Hospital and the Institute of Cancer Research, Sutton, UK.
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary*; D016001:Confidence Intervals; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009570:Nitriles; D059408:Pain Management / Q000379:methods; D010669:Phenylthiohydantoin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016016:Proportional Hazards Models; D011446:Prospective Studies; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D011788:Quality of Life; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide