title: Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial.
abstract: Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer.
  
  
  
  SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries. Patients were eligible for participation if they had: metastatic castration-resistant prostate cancer and had received no previous chemotherapy; prostate-specific antigen greater than 5 ng/mL; and a Karnofsky performance score of 70% or higher. Patients were randomly assigned 1:1 centrally to either the docetaxel, prednisone, and custirsen combination or docetaxel and prednisone alone. Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression. All patients received docetaxel 75 mg/m2intravenously with 5 mg of prednisone orally twice daily. Patients assigned docetaxel, prednisone, and custirsen received weekly doses of custirsen 640 mg intravenously after three loading doses of 640 mg. The primary endpoint was overall survival analysed in the intention-to-treat population. Patients who received at least one study dose were included in the safety analysis set. This trial is registered with ClinicalTrials.gov, number NCT01188187. The trial is completed and final analyses are reported here.
  
  
  
  Between Dec 10, 2010, and Nov 7, 2012, 1022 patients were enrolled to the trial, of whom 510 were assigned docetaxel, prednisone, and custirsen and 512 were allocated docetaxel and prednisone. No difference in overall survival was recorded between the two groups (median survival 23·4 months [95% CI 20·9-24·8] with docetaxel, prednisone, and custirsen vs 22·0 months [19·5-24·0] with docetaxel and prednisone; hazard ratio [HR] 0·93, 95% CI 0·79-1·10; p=0·415). The most common adverse events of grade 3 or worse in the docetaxel, prednisone and custirsen group (n=501) compared with the docetaxel and prednisone alone group (n=499) were neutropenia (grade 3, 63 [13%] vs 28 [6%]; grade 4, 98 [20%] vs 77 [15%]), febrile neutropenia (grade 3, 52 [10%] vs 31 [6%]; grade 4, four [1%] vs two [<1%]), and fatigue (grade 3, 53 [11%] vs 41 [8%]; grade 4, three [1%] vs one [<1%]). One or more serious adverse events were reported for 214 (43%) of 501 patients treated with docetaxel, prednisone, and custirsen and 181 (36%) of 499 receiving docetaxel and prednisone alone. Adverse events were attributable to 23 (5%) deaths in the docetaxel, prednisone, and custirsen group and 24 (5%) deaths in the docetaxel and prednisone alone group.
  
  
  
  Addition of custirsen to first-line docetaxel and prednisone was reasonably well tolerated, but overall survival was not significantly longer for patients with metastatic castration-resistant prostate cancer treated with this combination, compared with patients treated with docetaxel and prednisone alone.
  
  
  
  OncoGenex Technologies.
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of British Columbia, BC Cancer Agency, Vancouver Prostate Centre, Vancouver, BC, Canada. Electronic address: kchi@bccancer.bc.ca.
authors.forename: Kim N
authors.initials: KN
authors.lastname: Chi
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: Trial Architecture Consulting, Washington, DC, USA.
authors.forename: Brent
authors.initials: B
authors.lastname: Blumenstein
authors.affiliation: Centre Antoine Lacassagne, Nice, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Ferrero
authors.affiliation: Florida Cancer Specialists, Fort Myers, FL, USA.
authors.forename: James
authors.initials: J
authors.lastname: Reeves
authors.affiliation: Department of Urology, Tübingen, Germany.
authors.forename: Susan
authors.initials: S
authors.lastname: Feyerabend
authors.affiliation: Institut Paoli Calmette, Department of Cancer Medicine, Marseille, France.
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Gravis
authors.affiliation: Department of Urology, University Hospital Schleswig-Holstein, Lübeck, Germany.
authors.forename: Axel S
authors.initials: AS
authors.lastname: Merseburger
authors.affiliation: University of Tübingen, Tübingen, Germany.
authors.forename: Arnulf
authors.initials: A
authors.lastname: Stenzl
authors.affiliation: Netherlands Cancer Institute and Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands.
authors.forename: Andries M
authors.initials: AM
authors.lastname: Bergman
authors.affiliation: Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, ON, Canada.
authors.forename: Som D
authors.initials: SD
authors.lastname: Mukherjee
authors.affiliation: Durham Regional Cancer Centre, Oshawa, ON, Canada.
authors.forename: Pawel
authors.initials: P
authors.lastname: Zalewski
authors.affiliation: Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada.
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.affiliation: OncoGenex Pharmaceuticals, Bothell, WA, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Jacobs
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of British Columbia, BC Cancer Agency, Vancouver Prostate Centre, Vancouver, BC, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
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
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D018450:Disease Progression; D000077143:Docetaxel; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011241:Prednisone / Q000008:administration & dosage; D011379:Prognosis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D013873:Thionucleotides / Q000008:administration & dosage
chemical_list: C503781:OGX-011; D043823:Taxoids; D013873:Thionucleotides; D000077143:Docetaxel; D011241:Prednisone