title: Locally advanced and metastatic prostate cancer treated with intermittent androgen monotherapy or maximal androgen blockade: results from a randomised phase 3 study by the South European Uroncological Group.
abstract: BACKGROUND
  Few randomised studies have compared antiandrogen intermittent hormonal therapy (IHT) with continuous maximal androgen blockade (MAB) therapy for advanced prostate cancer (PCa).
  
  
  OBJECTIVE
  To determine whether overall survival (OS) on IHT (cyproterone acetate; CPA) is noninferior to OS on continuous MAB.
  
  
  METHODS
  This phase 3 randomised trial compared IHT and continuous MAB in patients with locally advanced or metastatic PCa.
  
  
  METHODS
  During induction, patients received CPA 200 mg/d for 2 wk and then monthly depot injections of a luteinising hormone-releasing hormone (LHRH; triptoreline 11.25 mg) analogue plus CPA 200 mg/d. Patients whose prostate-specific antigen (PSA) was <4 ng/ml after 3 mo of induction treatment were randomised to the IHT arm (stopped treatment and restarted on CPA 300 mg/d monotherapy if PSA rose to ≥20 ng/ml or they were symptomatic) or the continuous arm (CPA 200 mg/d plus monthly LHRH analogue).
  
  
  METHODS
  Primary outcome measurement was OS. Secondary outcomes included cause-specific survival, time to subjective or objective progression, and quality of life. Time off therapy in the intermittent arm was recorded.
  
  
  CONCLUSIONS
  We recruited 1045 patients, of which 918 responded to induction therapy and were randomised (462 to IHT and 456 to continuous MAB). OS was similar between groups (p=0.25), and noninferiority of IHT was demonstrated (hazard ratio [HR]: 0.90; 95% confidence interval [CI], 0.76-1.07). There was a trend for an interaction between PSA and treatment (p=0.05), favouring IHT over continuous therapy in patients with PSA ≤1 ng/ml (HR: 0.79; 95% CI, 0.61-1.02). Men treated with IHT reported better sexual function. Among the 462 patients on IHT, 50% and 28% of patients were off therapy for ≥2.5 yr or >5 yr, respectively, after randomisation. The main limitation is that the length of time for the trial to mature means that other therapies are now available. A second limitation is that T3 patients may now profit from watchful waiting instead of androgen-deprivation therapy.
  
  
  CONCLUSIONS
  Noninferiority of IHT in terms of survival and its association with better sexual activity than continuous therapy suggest that IHT should be considered for use in routine clinical practice.
authors.affiliation: Department of Urology, Centro Hospitalar Lisboa Central, Lisbon, Portugal. Electronic address: secretariado@seug-gpgu.org.
authors.forename: Fernando
authors.initials: F
authors.lastname: Calais da Silva
authors.affiliation: Department of Urology, Centro Hospitalar Lisboa Central, Lisbon, Portugal.
authors.forename: Fernando Manuel
authors.initials: FM
authors.lastname: Calais da Silva
authors.affiliation: Department of Urology, Klinika Lfuk, Bratislava, Slovakia.
authors.forename: Frederico
authors.initials: F
authors.lastname: Gonçalves
authors.affiliation: Department of Urology, Hospital S. Marcos, Braga, Portugal.
authors.forename: Américo
authors.initials: A
authors.lastname: Santos
authors.affiliation: Department of Urology, Jessenius School of Medicine, Martin, Slovakia.
authors.forename: Jan
authors.initials: J
authors.lastname: Kliment
authors.affiliation: Department of Urology, Saint James University Hospital, Leeds, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Whelan
authors.affiliation: Department of Urology, Saint Bartholomew's, London, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Oliver
authors.affiliation: Department of Urology, Amalia Fleming Hospital, Melissa, Greece.
authors.forename: Nicos
authors.initials: N
authors.lastname: Antoniou
authors.affiliation: Department of Urology, Amalia Fleming Hospital, Melissa, Greece.
authors.forename: Spiro
authors.initials: S
authors.lastname: Pastidis
authors.affiliation: Department of Urology, Policlinico La Rosaleda, Santiago de Compostela, Spain.
authors.forename: Anton
authors.initials: A
authors.lastname: Marques Queimadelos
authors.affiliation: Department of Mathematics and Statistics, University of Strathclyde, Glasgow, UK; Health Protection Scotland, Glasgow, UK; International Prevention Research Institute, Lyon, France.
authors.forename: Chris
authors.initials: C
authors.lastname: Robertson
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000556:secondary*; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D017373:Cyproterone Acetate / Q000008:administration & dosage; D018450:Disease Progression; D005060:Europe; D006801:Humans; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D011788:Quality of Life; D019529:Sexuality; D015996:Survival Rate; D013997:Time Factors; D017329:Triptorelin Pamoate / Q000008:administration & dosage
chemical_list: D017329:Triptorelin Pamoate; D017373:Cyproterone Acetate; D017430:Prostate-Specific Antigen
keywords: Intermittent antiandrogen therapy; Maximal androgen blockade; Prostate cancer