title: Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial.
abstract: BACKGROUND
  Androgen-deprivation therapy is offered to men with prostate cancer who have a rising prostate-specific antigen after curative therapy (PSA relapse) or who are considered not suitable for curative treatment; however, the optimal timing for its introduction is uncertain. We aimed to assess whether immediate androgen-deprivation therapy improves overall survival compared with delayed therapy.
  
  
  METHODS
  In this randomised, multicentre, phase 3, non-blinded trial, we recruited men through 29 oncology centres in Australia, New Zealand, and Canada. Men with prostate cancer were eligible if they had a PSA relapse after previous attempted curative therapy (radiotherapy or surgery, with or without postoperative radiotherapy) or if they were not considered suitable for curative treatment (because of age, comorbidity, or locally advanced disease). We used a database-embedded, dynamically balanced, randomisation algorithm, coordinated by the Cancer Council Victoria, to randomly assign participants (1:1) to immediate androgen-deprivation therapy (immediate therapy arm) or to delayed androgen-deprivation therapy (delayed therapy arm) with a recommended interval of at least 2 years unless clinically contraindicated. Randomisation for participants with PSA relapse was stratified by type of previous therapy, relapse-free interval, and PSA doubling time; randomisation for those with non-curative disease was stratified by metastatic status; and randomisation in both groups was stratified by planned treatment schedule (continuous or intermittent) and treatment centre. Clinicians could prescribe any form and schedule of androgen-deprivation therapy and group assignment was not masked. The primary outcome was overall survival in the intention-to-treat population. The trial closed to accrual in 2012 after review by the independent data monitoring committee, but data collection continued for 18 months until Feb 26, 2014. It is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12606000301561) and ClinicalTrials.gov (NCT00110162).
  
  
  RESULTS
  Between Sept 3, 2004, and July 13, 2012, we recruited 293 men (261 with PSA relapse and 32 with non-curable disease). We randomly assigned 142 men to the immediate therapy arm and 151 to the delayed therapy arm. Median follow-up was 5 years (IQR 3·3-6·2) from the date of randomisation. 16 (11%) men died in the immediate therapy arm and 30 (20%) died in the delayed therapy arm. 5-year overall survival was 86·4% (95% CI 78·5-91·5) in the delayed therapy arm versus 91·2% (84·2-95·2) in the immediate therapy arm (log-rank p=0·047). After Cox regression, the unadjusted HR for overall survival for immediate versus delayed arm assignment was 0·55 (95% CI 0·30-1·00; p=0·050). 23 patients had grade 3 treatment-related adverse events. 105 (36%) men had adverse events requiring hospital admission; none of these events were attributable to treatment or differed between treatment-timing groups. The most common serious adverse events were cardiovascular, which occurred in nine (6%) patients in the delayed therapy arm and 13 (9%) in the immediate therapy arm.
  
  
  CONCLUSIONS
  Immediate receipt of androgen-deprivation therapy significantly improved overall survival compared with delayed intervention in men with PSA-relapsed or non-curable prostate cancer. The results provide benchmark evidence of survival rates and morbidity to discuss with men when considering their treatment options.
  
  
  BACKGROUND
  Australian National Health and Medical Research Council and Cancer Councils, The Royal Australian and New Zealand College of Radiologists, Mayne Pharma Australia.
authors.affiliation: Peter MacCallum Cancer Centre and Melbourne University, Melbourne, VIC, Australia. Electronic address: gillian.duchesne@petermac.org.
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Duchesne
authors.affiliation: Sydney Adventist Hospital Clinical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Henry H
authors.initials: HH
authors.lastname: Woo
authors.affiliation: Cancer Council Victoria, Melbourne, VIC, Australia.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Bassett
authors.affiliation: Deakin Biostatistics Unit, Faculty of Health, Deakin University, Melbourne, VIC, Australia.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Bowe
authors.affiliation: National Centre for Epidemiology and Population Health, Australian National University College of Medicine, Canberra, ACT, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: D'Este
authors.affiliation: Department of Surgery, Monash University Faculty of Medicine, Clayton, VIC, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Frydenberg
authors.affiliation: School of Psychology, Sydney Medical School and Chris O'Brien Lifehouse, University of Sydney, Sydney, NSW, Australia.
authors.forename: Madeleine
authors.initials: M
authors.lastname: King
authors.affiliation: Cancer Council Victoria, Melbourne, VIC, Australia.
authors.forename: Leo
authors.initials: L
authors.lastname: Ledwich
authors.affiliation: Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, ON, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Loblaw
authors.affiliation: The Ottawa Hospital, Ottawa, ON, Canada.
authors.forename: Shawn
authors.initials: S
authors.lastname: Malone
authors.affiliation: Radiation Oncology, Alfred Health, Melbourne, VIC, Australia.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Millar
authors.affiliation: Cancer Council Victoria, Melbourne, VIC, Australia.
authors.forename: Roger
authors.initials: R
authors.lastname: Milne
authors.affiliation: Cancer Council Victoria, Melbourne, VIC, Australia.
authors.forename: Rosemary G
authors.initials: RG
authors.lastname: Smith
authors.affiliation: Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
authors.forename: Nigel
authors.initials: N
authors.lastname: Spry
authors.affiliation: NHMRC Clinical Trials Unit, University of Sydney, Camperdown, NSW, Australia.
authors.forename: Martin
authors.initials: M
authors.lastname: Stockler
authors.affiliation: Department of Surgery, The Austin Hospital and University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Syme
authors.affiliation: Peter MacCallum Cancer Centre and Melbourne University, Melbourne, VIC, Australia.
authors.forename: Keen Hun
authors.initials: KH
authors.lastname: Tai
authors.affiliation: Department of Radiation Oncology, Crown Princess Mary Cancer Centre, Westmead, NSW, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Turner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D061665:Time-to-Treatment
chemical_list: D000726:Androgen Antagonists; D014408:Biomarkers, Tumor; D017430:Prostate-Specific Antigen