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We observed tumor responses and prolonged survival. Patients had CRPC and
were chemotherapy-naïve. They received bi-weekly GVAX for a 24 week period
combined with monthly intravenous administrations of ipilimumab. Each cohort
of 3 patients received an escalating dose of ipilimumab at 0·3, 1·0, 3·0 or 5·0 mg/
kg. In an expansion cohort 16 patients were treated with GVAX and 3·0 mg/kg
ipilimumab. Since the teratment can be accompanied by side-effects (colitis,
hypophysitis), we looked for lymphoid and myeloid markers as well as antibody
formation. We observed a significantly prolonged OS for patients with high
pre-treatment frequencies of CD4 + CTLA-4 + , CD4 + PD-1 + , or differentiated
CD8+ T cells, or low pre-treatment frequencies of differentiated CD4+ T cells or
CD4 + CD25hiFoxP3+ regulatory T cells. In contrast, increased frequencies of
granulocytic Myeloid-Derived Suppressor Cells and high pre-treatment
frequencies of monocytic CD14 + HLA-DRlo/- MDSC were associated with
reduced OS. Antibody formation against PSMA, NRP2, and PNPO was
associated with prolonged survival and especially when multiple antibodies were
detected.
Conclusions: Together these data provide an immune profile to predict clinical
outcome; both pre-treatment CD4+ T-cells as well as antibody formation was
associated with prolonged survival. These potentially biomarkers for patient selection
should be validated in patients treated with ipilimumab.
Disclosure: W.R. Gerritsen: member of advisory board of BMS, K. Hege: former
employee of Cell Genesys, N. Sacks: former employee of Cell Genesys, I. Lowy:
former employee of Medarex, T. Harding: former emloyee of Cell Genesys, A.
van den Eertwegh: member advisory board BMS, T. De Gruijl: educational
grant from Cell Genesys. All other authors have declared no conflicts of
interest.
916P C-MYC EXPRESSION IS MODULATED BY STATINS USE AND
IT’S CORRELATED WITH TIME TO PROGRESSION (TTP) IN
MEN WITH LOCALISED PROSTATE CANCER TREATED WITH
RADICAL RADIOTHERAPY
D. Torrejon Castro 1 , I. De Torres 2 , G. Sánchez-Ollé 3 , X. Maldonado 4 ,
R. Morales-Barrera 1 , C. Suarez 1 , C. Valverde Morales 5 , I. Nunez Hernandez 6 ,
J. Morote 7 , J. Carles 1
1 Medical Oncology, Vall d´ Hebron University Hospital, Barcelona, SPAIN,
2 Pathology, Hospital Vall d’Hebron, Barcelona, SPAIN, 3 Oncology, Hospital Vall
d’Hebron, Barcelona, SPAIN, 4 Radiotherapy, Vall Hebron Univerity Hospital,
Barcelona, SPAIN, 5 Medical Oncology, Vall Hebron Univerity Hospital, Barcelona,
SPAIN, 6 Oncologia M, Vall d’Hebron University Hospital Institut d’Oncologia,
Barcelona, SPAIN, 7 Urology Department, Hospital Vall d’Hebrón, Barcelona,
SPAIN
Background: Although statins do not affect the incidence of prostate cancer (PCa),
its use reduces the risk of clinical progression and mortality. The mechanism by
which statins reduce PCa progression is unknown. MYC phosphorylation is a critical
mechanism by which the inhibition of HMG-CoA reductase by statins, thereby
resulting in MYC dephosphorylation and inactivation, which is essential for their
anticancer therapeutic effect. The aim of this study was to correlate statins use with
the c-MYC levels in PCa patients treated with radical radiotherapy (RT) with
concurrent androgen deprivation.
Methods: A total of 85 patients with paraffin-embedded prostate tissue specimens
were investigated immunohistochemically for c-MYC overexpression, diagnosed
with PCa between 2000 and 2005. Clinical and pathological variables were
compared between statin users and non-users and correlates with expression of
c-MYC. Disease-free survival (DFS) and time to progression (TTP) were
analysed.
Results: Mean age was 71 (56-82) years and median follow-up was 75 months.
Three (3.5%), 14 pts (16.5%) and 68 pts (80%) were classified as low, medium
and high risk respectively. Of those, 20 patients (24%) were using statins,
either during initial consultation or during follow-up. No statistical differences
were found between treatment groups regarding median age, risk category,
clinical T stage, Gleason score or median radiation dose. Median percentage
value of c-MYC was 20 (5-80) of statin users vs. 35 (5-100) of non-users (p
= 0.057) and elevated c-MYC expression was not significantly associated with
shorterDFS(p=0.5).Atthetimeofanalysis,only13pts(15.3%)had
biochemical relapse (1 low risk, 3 intermediate, and 9 high risk). Statins use
(38%) was significantly associated with improved TTP (55.2 vs. 30.6 months,
p = 0.016).
Conclusions: In our analysis, statins use was associated with a significant
improvement in TTP, in all risk groups. Although no differences in DFS according
cMYC values, there is a tendency towards a lower expression in statins users. Our
findings warrant further investigation.
Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
917P METFORMIN IN CHEMOTHERAPY-NAïVE CASTRATION
RESISTANT PROSTATE CANCER (CRPC): A MULTICENTER
PHASE II TRIAL (SAKK 08/09)
C.A. Rothermundt 1 , R. Cathomas 2 , A. Templeton 1 , R.C. Winterhalder 3 ,
R. Strebel 4 , D. Baertschi 5 , M. Pollak 6 , L. Lui 6 , S. Crowe 7 , S. Gillessen 1
1 Medical Oncology, Kantonsspital St. Gallen, St. Gallen, SWITZERLAND,
2 Medical Oncology, Kantonspital Graubünden, Chur, SWITZERLAND, 3 Medical
Oncology, Luzerner Kantonsspital, Luzern, SWITZERLAND, 4 Urology,
Kantonsspital Chur, Chur, SWITZERLAND, 5 Trial Coordination, SAKK, Bern,
SWITZERLAND, 6 Lady Davis Institute for Medical Research, Jewish General
Hospital, Montreal, QC, CANADA, 7 Statistics, SAKK, Bern, SWITZERLAND
Background: 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.
918P PHASE 2 RESULTS FROM A PHASE 1/2 STUDY OF TAK-700
(ORTERONEL), AN ORAL, INVESTIGATIONAL, NONSTEROIDAL
17,20-LYASE INHIBITOR, WITH DOCETAXEL AND
PREDNISONE (DP) IN METASTATIC CASTRATION-RESISTANT
PROSTATE CANCER (MCRPC)
D.P. Petrylak 1 , J.G. Gandhi 2 , W.R. Clark 3 , E.I. Heath 4 , J. Lin 5 , W.K. Oh 6 ,
D.B. Agus 7 , B. Carthon 8 , S. Moran 9 , G. Liu 10
1 Oncology, Columbia University Medical Center, New York, NY, UNITED STATES
OF AMERICA, 2 Oncology and Hematology, Associates in Oncology and
Hematology, Chattanooga, TN, UNITED STATES OF AMERICA, 3 Oncology,
Alaska Clinical Research Center, Anchorage, AK, UNITED STATES OF AMERICA,
4 Oncology, Karmanos Cancer Institute, Detroit, MI, UNITED STATES OF
AMERICA, 5 Medical Oncology, Thomas Jefferson University, Philadelphia, PA,
UNITED STATES OF AMERICA, 6 Oncology, Mt. Sinai Hospital, New York, NY,
UNITED STATES OF AMERICA, 7 Molecular Medicine, University of Southern
California, Keck School of Medicine, Beverly Hills, CA, UNITED STATES OF
AMERICA, 8 Hematology, Winship Cancer Institute, Emory University, Atlanta,
GA, UNITED STATES OF AMERICA, 9 Oncology, Millennium Pharmaceuticals,
Inc., Cambridge, MA, UNITED STATES OF AMERICA, 10 Oncology, University of
Wisconsin Carbone Cancer Center, Madison, WI, UNITED STATES OF
AMERICA
Background: The investigational agent TAK-700 (orteronel) is a selective 17,20-lyase
inhibitor that blocks androgen production. Since DP is currently standard
chemotherapy in mCRPC, this phase 1/2 study examined TAK-700 + DP in men
with mCRPC.
Methods: The primary phase 2 objective is tolerability of TAK-700 400 mg BID + D
(75 mg/m q3w) + P (5 mg BID) in castrate men (testosterone [T]