Prexasertib and Olaparib: overcoming PARPi resistance in high-grade serous ovarian carcinoma

Abstract

BACKGROUND Ovarian cancer is the 1st cause of death due to gynecological cancer and is the 5th cause of cancer death in woman . Since the approval of PARPi the progression free survival and the global survival rates have improved significantly in patients with HGS C, ultimately revolutionizing the management of this patients. But with the increasing number of patients using PARPi, an increasing number of patients who are developing PARPi resistance has been observed as well . One of the main reasons for this resistance is the acquisition of mutations that restore the homologous recombination mechanism, which was previously de ficient. This, unables the fun ctioning of the PARPi and led s to the cell becoming PARPi resistant. The strategy of combining different drugs (e.g. PARPi + DNA damaging drug) to re sensitize PARPi resistant cells to PARPi is a topic now starting to arise interest and, although there’s enough motives and justifications to start investigating, there is little to no evidence yet. OBJECTIVES The main objective of this study is to det ermine whether the combination strategy of Olaparib (PARP inhibitor) and Prexasertib (Chk1 inhibitor) is better in terms of survival free progression than the current treatment based on chemotherapy, in the context of patients with HGSC and BRCA 1,2 mutation wh o have a documented progression on PARPi within the first 2 years of maintenance treatment and are considered PARPi resistant Secondary objectives aim to determine patient acceptability and, although it is not developed in this project, to analyze t he effect of the Olaparib and Prexasertib combination on the mutations that regained the HR functions. DESIGN AND METHODOLOGY This study was designed as a randomized, open label, multicentered, prospective , controlled clinical trial, aiming to determine the optimal treatment in HGSC BRCA mutated patients who have progressed during the first two years of maintenance treatment and became PARPi resistant . It will be a multicenter study with 6 centers from around Catalonia. PARTICIPANTS Patients with HGSC and BRCA mutated profile admitted to a medical oncology facility for a progression in their disease