Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09).
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).


DESIGN, SETTING, AND PARTICIPANTS
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.


INTERVENTION
Patients received metformin 1000 mg twice daily until disease progression.


OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
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).


RESULTS AND LIMITATIONS
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.


PATIENT SUMMARY
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.


TRIAL REGISTRATION
This study is registered with ClinicalTrials.gov with the identifier NCT01243385.


PREVIOUS PRESENTATION
The study was presented at ESMO 2012 (abstract 1460).
['Rothermundt|Christian|C|', 'Hayoz|Stefanie|S|', 'Templeton|Arnoud J|AJ|', 'Winterhalder|Ralph|R|', 'Strebel|Räto T|RT|', 'Bärtschi|Daniela|D|', 'Pollak|Michael|M|', 'Lui|Lillianne|L|', 'Endt|Kathrin|K|', 'Schiess|Ralph|R|', 'Rüschoff|Jan H|JH|', 'Cathomas|Richard|R|', 'Gillessen|Silke|S|']
D000230:Adenocarcinoma D000368:Aged D000951:Antigens, Neoplasm D014408:Biomarkers, Tumor D001786:Blood Glucose D002352:Carrier Proteins D017242:Complement Factor H D018450:Disease Progression D018572:Disease-Free Survival D006023:Glycoproteins D006801:Humans D007004:Hypoglycemic Agents D007328:Insulin D007333:Insulin Resistance D018972:Insulin-Like Growth Factor Binding Protein 3 D007334:Insulin-Like Growth Factor I D008297:Male D008687:Metformin D008875:Middle Aged D011446:Prospective Studies D017430:Prostate-Specific Antigen D064129:Prostatic Neoplasms, Castration-Resistant
Metformin Castration-resistant prostate cancer Metabolic parameters