Mieux prédire la durée du bénéfice aux inhibiteurs de PARP dans les cancers de l’ovaire

Objectif(s) de la recherche et intérêt pour la santé publique

Finalité de l'étude

Objectifs poursuivis

Domaines médicaux investigués

Bénéfices attendus

The efficacy of the Myriad myChoice® Homologous Recombination Deficiency (HRD) test to guide use of PARP inhibitors in ovarian cancer has been demonstrated in several phase III trials. Nonetheless most PARPi-treated patients will develop a resistance. Current tests predict the primary response to PARP inhibitors (mostly driven by an HR proficiency) but the evaluation of the propensity to develop an acquired resistance is not yet part of the clinical routine. The overall objectives of this project are :
1. To better characterize the BRCAwt subpopulation with a short-term response to olaparib+bevacizumab in order to propose a test with predictive power for primary and acquired resistance to PARPi. HRP: non-responders, HRD-mid: short-term responders (response to olaparib but high probability of developing an acquired resistance), HRD-high: long-term responders),
2. To publish, in collaboration with the group that generated the RNA-seq data, the first opendata cohort of an Olaparib phase 3 clinical trial with whole-genome copy number variation and gene expression data that will lay the foundation for the next generation of HRD tests.

To this end, the ThermoFisher Oncoscan CNV assay will be performed on the DNA of 297 patients enrolled in the PAOLA-1 trial "Randomized, Double-Blind, Phase III Trial of Olaparib versus Placebo in Patients with Advanced FIGO Stage IIIB–IV High-Grade Serous or Endometrioid Ovarian, Fallopian Tube, or Primary Peritoneal Cancer treated with standard first-line platinum–taxane chemotherapy plus bevacizumab, followed by maintenance therapy". The oncoscanR software, validated on through the ENGOT initiative and currently used for clinical routine at the Geneva University Hospitals, will be used to compute the HRD score. BRCA mutations with respect to their localization in the gene,copy number variation profiles and gene expression data will be combined and analyzed to distinguish primary resistance from acquired resistance using the progression-free survival and overall survival.

The progression-free survival of short-term responders (PFS < 12 months) vs long-term (PFS ≥ 24 months) with respect to the test status will be investigated through Fisher Exact tests. The hazard ratio of olaparib vs placebo for the overall survival and progression-free survival of the three categories will be assessed (with 95% confidence intervals) and the differences in the Kaplan-Meier curves tested via a log-rank test.