title: Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial.
abstract: BACKGROUND
  Orteronel is an investigational, partially selective inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic target for metastatic castration-resistant prostate cancer. We assessed orteronel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer.
  
  
  METHODS
  In this phase 3, double-blind, placebo-controlled trial, we recruited patients with progressive metastatic castration-resistant prostate cancer and no previous chemotherapy from 324 study centres (ie, hospitals or large urologic or group outpatient offices) in 43 countries. Eligible patients were randomly assigned in a 1:1 ratio to receive either 400 mg orteronel plus 5 mg prednisone twice daily or placebo plus 5 mg prednisone twice daily. Randomisation was done centrally with an interactive voice response system and patients were stratified by region (Europe, North America, and not Europe or North America) and the presence or absence of radiographic disease progression at baseline. The two primary endpoints were radiographic progression-free survival and overall survival, determined in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01193244.
  
  
  RESULTS
  From Oct 31, 2010, to June 29, 2012, 2353 patients were assessed for eligibility. Of those, 1560 were randomly assigned to receive either orteronel plus prednisone (n=781) or placebo plus prednisone (n=779). The clinical cutoff date for the final analysis was Jan 15, 2014 (with 611 deaths). Median follow-up for radiographic progression-free survival was 8·4 months (IQR 3·7-16·6). Median radiographic progression-free survival was 13·8 months (95% CI 13·1-14·9) with orteronel plus prednisone and 8·7 months (8·3-10·9) with placebo plus prednisone (hazard ratio [HR] 0·71, 95% CI 0·63-0·80; p<0·0001). After a median follow-up of 20·7 months (IQR 14·2-25·4), median overall survival was 31·4 months (95% CI 28·6-not estimable) with orteronel plus prednisone and 29·5 months (27·0-not estimable) with placebo plus prednisone (HR 0·92, 95% CI 0·79-1·08; p=0·31). The most common grade 3 or worse adverse events were increased lipase (137 [17%] of 784 patients in the orteronel plus prednisone group vs 14 [2%] of 770 patients in the placebo plus prednisone group), increased amylase (77 [10%] vs nine [1%]), fatigue (50 [6%] vs 14 [2%]), and pulmonary embolism (40 [5%] vs 27 [4%]). Serious adverse events were reported in 358 [46%] patients receiving orteronel plus prednisone and in 292 [38%] patients receiving placebo plus prednisone.
  
  
  CONCLUSIONS
  In chemotherapy-naive patients with metastatic castration-resistant prostate cancer, radiographic progression-free survival was prolonged with orteronel plus prednisone versus placebo plus prednisone. However, no improvement was noted in the other primary endpoint, overall survival. Orteronel plus prednisone was associated with increased toxic effects compared with placebo plus prednisone. On the basis of these and other data, orteronel is not undergoing further development in metastatic castration-resistant prostate cancer.
  
  
  BACKGROUND
  Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
authors.affiliation: Centre Hospitalier de l'Université de Montréal/CRCHUM, Montréal, QC, Canada. Electronic address: fred.saad@umontreal.ca.
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.affiliation: Institut Gustave Roussy, University of Paris Sud, Villejuif, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.affiliation: Universitatea de Medicina si Farmacie, Bucharest, Romania.
authors.forename: Viorel
authors.initials: V
authors.lastname: Jinga
authors.affiliation: University of Athens Medical School, Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.affiliation: Auckland City Hospital, Auckland, New Zealand.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Fong
authors.affiliation: Florida Cancer Specialists, Fort Myers, FL, USA.
authors.forename: Lowell L
authors.initials: LL
authors.lastname: Hart
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Jones
authors.affiliation: The Adelaide and Meath Hospital, Incorporating the National Children's Hospital, Dublin, Ireland.
authors.forename: Raymond
authors.initials: R
authors.lastname: McDermott
authors.affiliation: University Hospital Carl Gustav Carus Dresden, Dresden, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Wirth
authors.affiliation: Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: MacLean
authors.affiliation: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: The University of Tokyo Research Center for Advanced Science and Technology, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Akaza
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Nelson
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
authors.affiliation: Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Dreicer
authors.affiliation: Millennium Pharmaceuticals, Inc, Cambridge, MA, USA.
authors.forename: Iain J
authors.initials: IJ
authors.lastname: Webb
authors.affiliation: Erasmus University Medical Center, Rotterdam, Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: de Wit
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000556:secondary; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001208:Asia; D001315:Australia; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000008:administration & dosage; D018450:Disease Progression; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005060:Europe; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage; D009520:New Zealand; D009656:North America; D011241:Prednisone / Q000008:administration & dosage; D016016:Proportional Hazards Models; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D012307:Risk Factors; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D009281:Naphthalenes; D013254:Steroid 17-alpha-Hydroxylase; C571806:orteronel; D011241:Prednisone