Etude de la relation entre le niveau d’instabilité génomique de la tumeur (score HRD) et le bénéfice du traitement par inhibiteur de PARP dans le cancer 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

These findings established BRCA mutation and HRD status as a key predictive biomarkers for PARP inhibitor benefit in the frontline setting. However, the magnitude of clinical benefit may be more precisely estimated using mathematical modeling.

The objectives of this project are to :
- to explore the continuous relationships between the GIS generated by the Myriad myChoice® assay, analyzed as a continuous variable, and the treatment effect of olaparib plus bevacizumab versus bevacizumab plus placebo on progression-free survival (PFS) and overall survival (OS), using generalized additive mathematical models ;
- to evaluate whether these relationships differ according to BRCA mutation status (mutated vs wild-type) ;
- to assess potential relationship modification by treatment setting, comparing patients treated with neoadjuvant chemotherapy versus primary surgery followed by adjuvant chemotherapy ;
- to explore differences in these relationships according to baseline disease risk (low-risk vs high-risk) ;
- to compare the shapes and magnitudes of these relationships across the different assays that provided continuous HRD-related output values.

Such exploratory analyses may help more precisely characterize the magnitude of expected benefit of the mainteannce treatment with PARP inhibitor therapy combined with bevacizumab in patients with ovarian cancer with or without BRCA mutation.

For that, about 806 patients with clinical and biological data will be analyzed from the PAOLA-1 clinical trial "Randomized, Double-Blind, Phase III Trial of Olaparib vs. Placebo in Patients with Advanced FIGO Stage IIIB – IV High Grade Serous or Endometrioid Ovarian, Fallopian Tube, or Peritoneal Cancer treated with standard First-Line Treatment, Combining Platinum-Taxane Chemotherapy and Bevacizumab Concurrent with Chemotherapy and in Maintenance".

Treatment effects on progression-free survival (PFS) and overall survival (OS) will be assessed using Cox proportional hazards models incorporating generalized additive models to flexibly model the non-linear association between the GIS, analyzed as a continuous variable, and the treatment hazard ratio. Interaction terms between treatment assignment and GIS will be used to estimate how the treatment effect varies across the GIS spectrum.

Results will be presented as hazard-ratio curves with corresponding confidence intervals across the range of GIS values. The impact of the integration of the radiological response observed during the initial chemotherapy on the accuracy of prediction will be assessed using adequate statistical tests.

Analyses will be performed in the overall population and stratified by predefined subgroups, including BRCA mutation status, treatment setting (neoadjuvant vs adjuvant), and disease risk category. Similar analyses will be performed with the other HRD asays provided as continuous covariates.