title: Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial.
abstract: BACKGROUND
  Bone metastases are a major cause of morbidity in metastatic castration-resistant prostate cancer. Abiraterone acetate potently disrupts intracrine androgen receptor signalling pathways implicated in the progression of the disease, including bone metastases. We assessed data for pain control and skeletal-related events prospectively collected as part of the randomised, phase 3 COU-AA-301 trial of abiraterone acetate plus prednisone versus placebo plus prednisone in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy.
  
  
  METHODS
  The COU-AA-301 trial enrolled patients with metastatic castration-resistant prostate cancer in whom one or two lines of chemotherapy (one docetaxel based) had been unsuccessful and who had Eastern Cooperative Oncology Group performance statuses of 2 or less. Pain intensity and interference of pain with daily activities were assessed with the Brief Pain Inventory-Short Form questionnaire at baseline, day 15 of cycle 1, and day 1 of each treatment cycle thereafter until discontinuation. We assessed, with prospectively defined response criteria that incorporated analgesic use, clinically meaningful changes in pain intensity and interference with daily living. We measured time to first occurrence of skeletal-related events, which we defined as pathological fracture, spinal cord compression, palliative radiation to bone, or bone surgery, and regularly assessed them throughout the study. Pain palliation was assessed in patients who had clinically significant baseline pain, whereas all other analyses were done in the overall intention-to-treat population. COU-AA-301 is registered with ClinicalTrials.gov, number NCT00638690.
  
  
  RESULTS
  Median follow-up was 20·2 months (IQR 18·4-22·1). In patients with clinically significant pain at baseline, abiraterone acetate and prednisone resulted in significantly more palliation (157 of 349 [45·0%] patients vs 47 of 163 [28·8%]; p=0·0005) and faster palliation (median time to palliation 5·6 months [95% CI 3·7-9·2] vs 13·7 months [5·4-not estimable]; p=0·0018) of pain intensity than did prednisone only. Palliation of pain interference (134 of 223 [60·1%] vs 38 of 100 [38·0%], p=0·0002; median time to palliation of pain interference 1·0 months [95% CI 0·9-1·9] vs 3·7 months [2·7-not estimable], p=0·0004) and median duration of palliation of pain intensity (4·2 months [95% CI 3·0-4·9] vs 2·1 months [1·4-3·7]; p=0·0056) were significantly better with abiraterone acetate and prednisone than with prednisone only. In the overall population, median time to occurrence of first skeletal-related event was significantly longer with abiraterone acetate and prednisone than with prednisone only (25·0 months [95% CI 25·0-not estimable] vs 20·3 months [16·9-not estimable]; p=0·0001).
  
  
  CONCLUSIONS
  In patients with metastatic castration-resistant prostate cancer previously treated with docetaxel, abiraterone acetate and prednisone offer significant benefits compared with prednisone alone in terms of pain relief, delayed pain progression, and prevention of skeletal-related events.
  
  
  BACKGROUND
  Janssen Research & Development and Janssen Global Services.
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. clogothe@mdanderson.org
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
authors.forename: Ethan
authors.initials: E
authors.lastname: Basch
authors.forename: Arturo
authors.initials: A
authors.lastname: Molina
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.forename: Scott A
authors.initials: SA
authors.lastname: North
authors.forename: Kim N
authors.initials: KN
authors.lastname: Chi
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Jones
authors.forename: Oscar B
authors.initials: OB
authors.lastname: Goodman
authors.forename: Paul N
authors.initials: PN
authors.lastname: Mainwaring
authors.forename: Cora N
authors.initials: CN
authors.lastname: Sternberg
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Gagnon
authors.forename: Margaret
authors.initials: M
authors.lastname: Rothman
authors.forename: Yanni
authors.initials: Y
authors.lastname: Hao
authors.forename: Cameron S
authors.initials: CS
authors.lastname: Liu
authors.forename: Thian S
authors.initials: TS
authors.lastname: Kheoh
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Haqq
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
mesh_terms: D000069501:Abiraterone Acetate; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000008:administration & dosage*; D000730:Androstadienes / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000150:complications* / Q000556:secondary*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005598:Fractures, Spontaneous / Q000209:etiology / Q000517:prevention & control; D005938:Glucocorticoids / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D059408:Pain Management; D010147:Pain Measurement; D010166:Palliative Care; D011241:Prednisone / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D013117:Spinal Cord Compression / Q000209:etiology / Q000517:prevention & control; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*
chemical_list: D000726:Androgen Antagonists; D000730:Androstadienes; D005938:Glucocorticoids; D013254:Steroid 17-alpha-Hydroxylase; D000069501:Abiraterone Acetate; D011241:Prednisone