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945 BONE TURNOVER MARKERS AND POTENTIAL CORRELATION
WITH OUTCOMES IN PATIENTS WITH GENITOURINARY
CANCER (PROSTATE) AND BONE METASTASIS (RESULTS OF
TUGAMO STUDY)
J. Bellmunt 1 , C. De La Piedra 2 ,A.Gómez Caamaño 3 , M.J. Ribal 4 , F. Vázquez 5 ,
U. Anido 6 , E. Solsona 7 , P. Samper 8 , E. Esteban 9 , J. Morote 10
1 Medical Oncology Department, Hospital del Mar, Barcelona, SPAIN, 2 Clinical
Biochemistry Department, Instituto de Investigación Sanitaria Fundación Jiménez
Díaz, Madrid, SPAIN, 3 Radiation Oncology Department, Complexo Hospitalario
Universitario de Santiago de Compostela, A Coruña, SPAIN, 4 Urology
Department, Hospital Clínic, Barcelona, SPAIN, 5 Urology Department, Hospital
Universitario Virgen de las Nieves, Granada, SPAIN, 6 Oncology Department,
Complexo Hospitalario Universitario de Santiago de Compostela, A Coruña,
SPAIN, 7 Urology Department, Instituto Valenciano de Oncología, Valencia,
SPAIN, 8 Urology Department, Hospital Central de la Defensa Gómez Ulla,
Madrid, SPAIN, 9 Medical Oncology Department, Hospital Universitario Central de
Asturias, Oviedo, SPAIN, 10 Urology Department, Hospital Vall d’Hebrón,
Barcelona, SPAIN
Background: Levels of bone turnover markers (BTM) might be correlated with
outcome in terms of skeletal related events (SRE), disease progression and death. The
aim of this study was to determine the possible correlation between BTM, disease
progression, SREs and death in patients with genitourinary cancer and bone
metastases (BM) treated with zoledronic acid (ZA).
Methods: Observational, prospective, multicenter study. Patients with genitourinary
cancer (prostate, renal, bladder) and BM were included. BTM determined were:
carboxiterminal telopeptide of type I collagen (β-CTX) and bone specific alkaline
phosphatase (BALP) by ELISA (immunoenzymatic assay, IDS UK), and
aminoterminal propeptide of type I collagen (P1NP) by automatised assays (Elecsys,
Roche). All BTM were determined at baseline (V0) and every 3 mo of treatment
until Month 18 (V6). All patients started treatment with ZA 4 mg IV every 3-4
weeks at the beginning of the study.
Results: Data of 168 patients with genitourinary cancer were analyzed. In this work
data of prostate cancer patients (n = 95) are presented. Population basal
characteristics [35 new, without previous treatment (N) / 60 pre-treated, with
anti-hormonal treatment (P)]: mean age (years): 72.1; median time from tumor
diagnosis (months): 7.6 (N) / 11.6 (P); ECOG 0-1: 90% (N) / 87.5% (P). Patients
with pathologic baseline levels were: 47.1% β-CTX, 64.7% BALP and 57.1% P1NP
(N) and 48.3% β-CTX, 80.7% BALP and 60% P1NP (P). After 6 mo.: 28%, 48% and
32% (N) and 32%, 59.4% and 31.3% (P) presented pathologic values of β-CTX,
BALP and P1NP respectively. Normalized levels remained steady throughout 18 mo
follow-up. Reductions from baseline to month 3 in BALP levels correlated with lower
risk of death (p = 0.0219) (Cox regression analysis).
Conclusions: Elevation of baseline BTM levels is frequently present in advanced
prostate cancer with bone metastasis. Addition of AZ to standard systemic therapy
reduces BTM levels, even though in those highly hormone sensitive ones. A
significant association was observed between elevated levels of BALP and death
throughout follow-up.
Disclosure: All authors have declared no conflicts of interest.
946 CABAZITAXEL (CBZ) SHOWS SUPERIOR ANTITUMOR
EFFICACY OVER DOCETAXEL IN A HORMONE-RESISTANT
PROSTATE TUMOR XENOGRAFT MODEL (HID28)
L. Bourré 1 , D. Nicolle 1 , M. Legrier 2 , V. Yvonnet 3 , J. Charpentier 3 , M. Poupon 4 ,
P. Vrignaud 5 , S. Oudard 6 , J-G. Judde 3
1 Contract Research Department, XenTech, Evry, FRANCE, 2 R & D, XenTech,
Evry, FRANCE, 3 XenTech, Evry, FRANCE, 4 Scientific Advisory Board, XenTech,
Fresnes, FRANCE, 5 Translational and Experimental Medicine, Sanofi Oncology,
Vitry-sur-Seine, FRANCE, 6 Medical Oncology Department, Hopital Europeen
Georges Pompidou, Paris, FRANCE
Background: Docetaxel (D) was the first cytotoxic treatment demonstrating a
survival benefit in metastatic castration-resistant prostate cancer (mCRPC) patients.
Recently, the novel taxane cabazitaxel and the CYP17 inhibitor abiraterone acetate
have demonstrated a significant survival benefit in mCRPC patients progressing after
receiving a D-containing regimen. Here we compare the antitumour efficacy of D,
cabazitaxel and abiraterone acetate in the HID28 hormone-resistant human prostate
carcinoma xenograft.
Methods: HID28 tumour-bearing nude mice received 20 mg/kg of D (IP, Q3W x 2),
cabazitaxel at 15 and 20 mg/kg (IP, Q3W x 2) and abiraterone acetate at 50 mg/kg
(PO, QD x 21). Median tumour growth inhibition (T/C%) was evaluated, as well as
time-course androgen receptor expression (4, 8 and 24 h post-dosing) by western
blot analysis.
Results: D inhibited tumour growth with a T/C% = 16.7% at day 35, 2 partial (PR)
and 1 complete (CR) tumour regressions, and with relapse of all tumours (3/3)
observed at day 42. Cabazitaxel demonstrated dose-dependent efficacy at day 35 with
T/C% = 10.8% and 1.4% for 15 and 20 mg/kg doses, respectively. At a cabazitaxel
dose of 15 mg/kg, 4/10 PR and 3/10 CR were observed, whereas 4/10 PR and 6/10
Annals of Oncology
CR were observed at 20 mg/kg. At day 42, 6/6 tumour relapses were observed at 15
mg/kg, whereas only 3/6 relapses were observed at 20 mg/kg. No anti-tumour activity
was demonstrated with abiraterone acetate as well as no significant decreases in
testosterone levels compared with the vehicle group. Tolerability was good for all
treatment groups, with a transitory maximum mean body weight loss of 12%, 6 days
after treatments.Androgen receptor western blot expression analysis after 4, 8 and 24
h post-dosing demonstrated no significant difference between groups and over time.
Conclusions: Cabazitaxel demonstrated superior antitumour efficacy and a similar
tolerability compared with D at equivalent dosing in the HID28 hormone-resistant
tumour model. The model did not respond to abiraterone. These results support the
clinical development of cabazitaxel in first-line treatment of mCRPC patients.This
research was funded by Sanofi.
Disclosure: L. Bourré: Is a Xentech employee, D. Nicolle: Is a Xentech employee,
M. Legrier: Is a Xentech employee, V. Yvonnet: Is a Xentech employee, J.
Charpentier: Is a Xentech employee, M. Poupon: Has acted as an uncompensated
consultant and has provided expert testimony. Is a Xentech employee, P. Vrignaud:
Is a Sanofi employee (Research Investigator) and owns Sanofi stocks and shares, S.
Oudard: Has acted as an advisor for, and received honoraria from Pfizer Oncology,
Bayer Schering Pharma, Roche, GSK, Novartis and Sanofi, J-G. Judde: Is a Xentech
employee.
947 AUGMENTATION OF THE CYTOTOXICITY OF IBANDRONATE
BY Y-27632 IN PROSTATE CANCER CELL LINES
A. Ata 1 , A. Özçimen 2 , H. Kurt 3 , N. Tiftik 4 ,A.Arıcan 5 , K. Büyükafs¸ar 4
1 Dept of Medical Oncology, Mersin State Hospital, Mersin, TURKEY, 2 Biology,
Mersin University Science and Art Faculty, Mersin, TURKEY, 3 Dept of
Pharmacology, Mersin University School of Medicine, Mersin, TURKEY, 4 Dept of
Pharmacology, Mersin University School of Medicine, Mersin, TURKEY, 5 Dept. of
Medical Oncology, Mersin University School of Medicine, Mersin, TURKEY
Background: Bisphosphonates, which have been used for the treatment of the
metastatic bone disease and malignant hypercalcemia due many cancers. These
drugs also inhibit mevalonate pathway that results in the reduction of Ras
prenylation, which eventually inhibits tumor growth. Rho/Rho kinase signaling has
a fundamental role in cancer cell proliferation, migration and metastasis. In this
study, we aimed to investigate the effects of y-27632 (a Rho-kinase inhibitor) and
ibandronate (a bisphosphonate) and their combination on cell proliferation in
prostate cell lines.
Methods: The adherent prostate cell line, PC-3, was grown in RPMI-1640
supplemented with 10% fetal bovine serum, 1% L-glutamine, 1% penicillin
(10.000U/ml) and streptomycin (10.000 mg/ml) in a humidified atmosphere
of 5% CO2 at 37 o C for confluency. The cells were seeded in the wells of E-plates
(24,000 cells/well) that allowed a real-time-monitoring of the cell index reflected
cell growth and proliferation (xCELLigence, Roche). The cell index was evaluated at
the different points of time (post-treatment 12, 24, 36, 48, 60 and 72 h) in the
groups of, y-27632, ibandronate, the combination of these drugs and time-course
control.
Results: Both ibandronate alone (10-100 mM) and y-27632 alone (50-100 mM)
markedly decreased cell index. But the combination of ibandronate with y-27632
(in differrent concentrations but especially in higher concentrations) resulted in
potentiation of cytotoxicity in prostate cell line.
Conclusions: Rho kinase inhibitors, bisphosphonates and their combinations may be
used for the treatment of prostate cancer in the future, according to the possible
beneficial results of clinical trials.
Disclosure: All authors have declared no conflicts of interest.
948 ANALYSIS OF THE USA POSTMARKETING SAFETY PROFILE
OF CABAZITAXEL IN THE TREATMENT OF METASTATIC
CASTRATE-RESISTANT PROSTATE CANCER (MCRPC)
PREVIOUSLY TREATED WITH A DOCETAXEL-CONTAINING
TREATMENT REGIMEN
L. Nicacio 1 , P. Raina 2 , R. Sands 3 , S. Neibart 4
1 NA Oncology, Sanofi-Aventis U.S. LLC, Inc., a Sanofi Company, Bridgewater,
NJ, UNITED STATES OF AMERICA, 2 US Pharmacovigilance, sanofi-aventis U.S.
LLC, Inc., a Sanofi Company, Bridgewater, NJ, UNITED STATES OF AMERICA,
3 Global Oncology, sanofi-aventis U.S. LLC, Inc., a Sanofi Company, Cambridge,
MA, UNITED STATES OF AMERICA, 4 Global Pharmacovigilance, sanofi-aventis
U.S. LLC, Inc., a Sanofi Company, Bridgewater, NJ, UNITED STATES OF
AMERICA
Background: Cabazitaxel (Jevtana®) in combination with prednisone was licensed in
the United States (USA) in June 2010 for the treatment of mCRPC in patients (pts)
previously treated with a docetaxel-containing treatment regimen. We estimate that
over 13,000 patients have since been treated in the US. This research analyzes the
post-marketing safety profile of cabazitaxel based on spontaneously reported
pharmacovigilance (PV) Adverse Events (AEs) in the USA. As such reports depend
ix312 | Abstracts Volume 23 | Supplement 9 | September 2012