917P - Metformin in chemotherapy-naïve castration resistant prostate cancer (CRPC): a multicenter phase II trial (SAKK 08/09)
|Date||29 September 2012|
|Event||ESMO Congress 2012|
|Session||Poster presentation I|
|Topics|| Prostate Cancer
C.A. Rothermundt1, R. Cathomas2, A.J. Templeton3, R.C. Winterhalder4, R. Strebel5, D. Baertschi6, M. Pollak7, L. Lui7, S. Crowe8, S. Gillessen9
Men with prostate cancer (PC) receiving androgen deprivation therapy (ADT) are at risk of developing insulin resistance. Hyperinsulinemia causes activation of insulin-like growth factor (IGF) signalling pathways, promoting progression of PC. Functional loss of PTEN leads to activation of the PI3K pathway, including Akt kinase and mTOR, critical components of PC cell survival and oncogenic function of IGF-1. The biguanide metformin is an inexpensive oral drug used as treatment for diabetes mellitus. Metformin, an activator of AMP-activated protein kinase, has antiproliferative effects on PC via reduction of systemic insulin levels and inhibition of mTOR.Methods
Patients (pts) with CPRC, PSA < 114 ng/ml, PSA-doubling time (PSA-DT) ≥ 55 days, no prior chemotherapy, and adequate organ function were eligible. ADT was continued in non-surgically castrated pts. Metformin was administered continuously at 1000mg bd in 4 week cycles. The primary endpoint was progression free survival at 12 weeks (PFS12) defined as absence of progression (PSA increase ≥ 25% above baseline, progression of measurable disease or bone lesions, clinical progression) or death. Simon's two-stage optimal design was applied. With 5% significance level and 90% power, 44 evaluable pts were required to test if PFS12 rate ≤ 15% (H0) vs ≥ 35% (H1). If ≥ 11 evaluable pts remain PFS12, the trial was deemed worth of further investigation.Results
44 pts were enrolled at 10 Swiss centres between 12/2010 and 12/2011. Median age was 70 (range 48-87) years; median PSA-DT at registration was 89 (range 55-438) days. In total, 186 cycles of metformin were administered; median 4 (range 1-13) cycles. Fourteen pts (31.8%, 95% CI: 18.6%-47.6%) had PFS12. Confirmed PSA response was seen in 2 pts (4.5%); both of whom had 50% PSA response. Median PFS was 2.1 (range 0.8-12.5) months. Treatment related adverse events were generally mild and manageable.Conclusion
To our knowledge this is the first trial reporting on metformin in CRPC. Metformin shows activity in this disease setting and some pts have prolonged stabilization of disease. Analysis of insulin and C-peptide levels and correlation to response will be presented.Disclosure
S. Gillessen: Advisory boards with honorarium Millennium Janssen-Cilag Sanofi-Aventis.
All other authors have declared no conflicts of interest.