title: Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09).
abstract: BACKGROUND
  There is evidence linking metformin to improved prostate cancer (PCa)-related outcomes.
  
  
  OBJECTIVE
  To evaluate treatment with metformin in patients with castration-resistant PCa (CRPC) and the effect of the treatment on progression-free survival (PFS) and PSA doubling time (PSA DT).
  
  
  METHODS
  Forty-four men with progressive metastatic CRPC from 10 Swiss centers were included in this single-arm phase 2 trial between December 2010 and December 2011.
  
  
  METHODS
  Patients received metformin 1000 mg twice daily until disease progression.
  
  
  METHODS
  The primary end point was the absence of disease progression at 12 wk. Simon two-stage optimal design was applied. With a 5% significance level and 90% power, 44 patients were required to test PFS at 12 wk ≤ 15% (H0) compared with ≥ 35% (H1).
  
  
  CONCLUSIONS
  Thirty-six percent of patients were progression-free at 12 wk, 9.1% were progression-free at 24 wk, and in two patients a confirmed ≥ 50% prostate-specific antigen (PSA) decline was demonstrated. In 23 patients (52.3%) we observed a prolongation of PSA DT after starting metformin. The homeostatic model assessment index fell by 26% from baseline to 12 wk, indicating an improvement in insulin sensitivity. There was a significant change in insulin-like growth factor-1 and insulin-like growth factor binding protein 3 from baseline to 12 wk. Sample size and lack of a control arm are the limitations of this trial; analyses are therefore exploratory.
  
  
  CONCLUSIONS
  Treatment with metformin is safe in nondiabetic patients, and it yields objective PSA responses and may induce disease stabilization. The activity of metformin in PCa, along with its low cost, favorable toxicity profile, and positive effect on metabolic parameters, suggests that further investigation of metformin as therapy for patients with PCa is of interest.
  
  
  RESULTS
  In this trial we assessed the use of the diabetes mellitus drug metformin in patients with advanced prostate cancer. We found disease stabilization and prolongation of prostate-specific antigen doubling time in some patients as well as effects on metabolic parameters.
  
  
  BACKGROUND
  This study is registered with ClinicalTrials.gov with the identifier NCT01243385.
  The study was presented at ESMO 2012 (abstract 1460).
authors.affiliation: Cantonal Hospital St. Gallen, St. Gallen, Switzerland. Electronic address: christian.rothermundt@kssg.ch.
authors.forename: Christian
authors.initials: C
authors.lastname: Rothermundt
authors.affiliation: SAKK Coordinating Center Bern, Bern, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hayoz
authors.affiliation: Cantonal Hospital St. Gallen, St. Gallen, Switzerland; SAKK Coordinating Center Bern, Bern, Switzerland.
authors.forename: Arnoud J
authors.initials: AJ
authors.lastname: Templeton
authors.affiliation: Cantonal Hospital Lucerne, Lucerne, Switzerland.
authors.forename: Ralph
authors.initials: R
authors.lastname: Winterhalder
authors.affiliation: Cantonal Hospital Chur, Chur, Switzerland.
authors.forename: Räto T
authors.initials: RT
authors.lastname: Strebel
authors.affiliation: SAKK Coordinating Center Bern, Bern, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bärtschi
authors.affiliation: Lady Davis Institute for Medical Research Jewish General Hospital Montréal, Montréal, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.affiliation: Lady Davis Institute for Medical Research Jewish General Hospital Montréal, Montréal, Canada.
authors.forename: Lillianne
authors.initials: L
authors.lastname: Lui
authors.affiliation: ProteoMediX, Schlieren, Switzerland.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Endt
authors.affiliation: ProteoMediX, Schlieren, Switzerland.
authors.forename: Ralph
authors.initials: R
authors.lastname: Schiess
authors.affiliation: Institute of Surgical Pathology University Hospital Zurich, Zurich, Switzerland.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Rüschoff
authors.affiliation: Cantonal Hospital Chur, Chur, Switzerland.
authors.forename: Richard
authors.initials: R
authors.lastname: Cathomas
authors.affiliation: Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
authors.forename: Silke
authors.initials: S
authors.lastname: Gillessen
mesh_terms: D000230:Adenocarcinoma / Q000097:blood* / Q000188:drug therapy*; D000368:Aged; D000951:Antigens, Neoplasm / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects; D002352:Carrier Proteins / Q000097:blood; D017242:Complement Factor H / Q000378:metabolism; D018450:Disease Progression; D018572:Disease-Free Survival; D006023:Glycoproteins / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood* / Q000188:drug therapy*; D016326:Extracellular Matrix Proteins
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D001786:Blood Glucose; D002352:Carrier Proteins; D017242:Complement Factor H; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I; D008687:Metformin; D017430:Prostate-Specific Antigen; C081856:LGALS3BP protein, human; D016326:Extracellular Matrix Proteins
keywords: Castration-resistant prostate cancer; Metabolic parameters; Metformin