869P - Pharmacogenetic study of cabazitaxel in advanced or metastatic transitional cell carcinoma (TCC): The SOGUG 2011-04 trial

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Pharmacology
Urothelial Cancers
Presenter Ignacio Duran
Citation Annals of Oncology (2014) 25 (suppl_4): iv280-iv304. 10.1093/annonc/mdu337
Authors I. Duran1, C. Hagen2, J.A. Arranz Arija3, M. Apellaniz4, B. Pérez-Valderrama1, N. Sala Gonzalez5, N. Lainez6, X. Garcia Del Muro7, E. Nogueron8, M. Climent9, P. Maroto10, A. Font11, J. Garcia-Donas12, E. Gallardo13, P. Lopez Criado14, A. Gonzalez Del Alba15, M.I. Saez16, S. Vazquez17, R. Luque18, C. Rodriguez-Antona4
  • 1Departamento De Oncologia, Hospital Universitario Virgen del Rocio, 41013 - Sevilla/ES
  • 2Translational Research, Spanish Oncology Genitourinary Group, MADRID/ES
  • 3Servicio De Oncologia Medica, Hospital General Univ. Gregorio Marañon, 28007 - Madrid/ES
  • 4Human Genetic, Spanish National Cancer Research Center, Madrid/ES
  • 5Medical Oncology, ICO Josep Trueta, Girona/ES
  • 6Medical Oncology, Complejo Hospitalario de Navarra, Pamplona/ES
  • 7Medical Oncology, Institut Catal, ES-08907 - L'Hospitalet de Llobregat/ES
  • 8Dept. Of Medical Oncology, Complejo Hospitalario Universitario de Albacete, Albacete/ES
  • 9Medical Oncology, Instituto Valenciano de Oncologia, 46009 - Valencia/ES
  • 10Dept. Of Medical Oncology, Hospital de la Sta. Creu i St. Pau, ES-08025 - Barcelona/ES
  • 11Medical Oncology, Catalan Institute of Oncology ICO Badalona Hospital Germans Trias i Pujol, Medical Oncology, 08916 - Badalona/ES
  • 12Madrid, Hospital Madrid Norte San Chinarro Centro Integral Oncologico Clara Campal, 28050 - Madrid/ES
  • 13Oncologia Medica, Hospital de Sabadell Corporacis Parc Tauli, ES-08208 - Sabadell/ES
  • 14Medical Oncology, MD ANDERSON MADRID, MADRID/ES
  • 15Medical Oncology, Hospital Universitario Son Espases, Palma de Mallorca/ES
  • 16Medical Oncology, Hospital Universitario Virgen de la Victoria, Malaga/ES
  • 17Oncoloxia Médica, Hospital Universitario Lucus Augusti de Lugo, Lugo/ES
  • 18Medical Oncology Unit, Hospital Universitario Virgen de las Nieves, 18014 - Granada/ES

Abstract

Aim

Cabazitaxel (Cab) is a novel tubulin-binding taxane active in preclinical models against docetaxel-sensitive and resistant tumors. Cab is approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) after docetaxel failure; however, its activity against other cancers remains unexplored. SOGUG 2011-04 is a phase II clinical trial designed to explore the efficacy of Cab in advanced genitourinary TCC after progression to a platinum-based regime. As part of this trial, a pharmacogenetic study to identify single-nucleotide polymorphisms (SNPs) predictive of Cab toxicity and response was conducted.

Methods

DNA was extracted from blood samples from 45 patients in this trial. Nine key SNPs in genes involved in the pharmacokinetic and pharmacodynamic pathways of Cab (CYP3A4 rs35599367; CYP3A5 rs776746; CYP2C8 rs11572080 and rs1113129 ABCB1 rs1045642, rs1128503 and rs2032582; TUBB1 rs6070697 and rs463312) were genotyped using standard techniques. Logistic regression was used to study toxicity and response, and Cox regression to analyze progression free survival (PFS) and overall survival (OS), using an additive genetic model. Preliminary results are presented.

Results

CYP3A5 rs776746 (splicing defect) protected against gastrointestinal (GI) toxicity (OR = 0.06, 95%CI = 0.007-0.63, P = 0.018) and was associated with reduced PFS (HR = 4.4, 95%CI = 1.6-11.7, P = 0.0032). Adjusting for patient prognosis, according to Bellmunt's classification, did not change the results. Furthermore ABCB1 rs1128503, rs1045642 and rs2032582 were associated with the total number of Grade 3-4 toxicity events (P values of 0.009, 0.041, and 0.043, respectively, multivariable analysis). TUBB1 Q43P missense polymorphism was associated with reduced OS (P = 0.0023) although only three patients carried this variant.

Conclusions

Polymorphisms in CYP3A5 may define a subset of patients with decreased Cab activity resulting in less GI adverse events and shorter PFS. Additionally, variation in ABCB1 may be associated with the severity of Cab toxicity. These results need to be validated in larger and independent series but suggest potential markers for Cab treatment optimization. * This study has been supported by an unrestricted educational grant of Sanofi-Aventis to the Spanish GU Oncology Group (SOGUG)

Disclosure

I. Duran: has participated in compensated Advisory Boards for Sanofi-Aventis; M. Climent: has participated in compensated Advisory Boards for Sanofi-Aventis. All other authors have declared no conflicts of interest.