EUDARIO/ENGOTov-48: A European multicenter randomised phase II trial on the combination of the HSP90 inhibitor ganetespib with carboplatin followed by maintenance treatment with niraparib (+/- ganetespib) compared to platinum-based combination-chemotherapy followed by niraparib in relapsed platinum-sensitive ovarian cancer patients.

Abstract

TPS5605 Background: Carboplatin (C) mainly acts by forming interstrand crosslinks (ICL) within the DNA double helix, which can only be removed by the Fanconi Anemia (FA) pathway. HSP90 inhibitors destabilise a number of HSP90 client proteins, such as those governing the FA DNA repair pathway and the G2/M checkpoint (e.g. Chk1 and Wee1). Kramer et al. (Cell Death Differ, 2017) showed that the HSP90 inhibitor Ganetespib (G) virtually eliminates a functional FA DNA repair complex, therewith preventing the repair of DNA ICL in vitro and vivo. In parallel, G abrogated Chk1 and Wee1 expression and circumvented a G2/M arrest. Consequently, cells with unrepaired DNA damage rushed into mitosis, which resulted in massive tumour cell death. Furthermore, HSP90 inhibition has been shown to reduce the amount of BRCA1 in the cell therewith broadening sensitivity towards PARPi and preventing acquired PARP resistance. Our trial approach is tested in ovarian carcinomas with a mutant p53 background. EUDARIO (EUDRACT 017-004058-40) is funded by the European Commission (FP7 project GANNET53). Methods: Eligible patients have relapsed platinum-sensitive ovarian cancer, no limits in prior lines, high-grade (but clear cell) histology or carcinosarcoma, disease measurable or evaluable according to RECIST 1.1. Patients are randomised into 3 treatment arms (1:1:1), a) control arm: C+Gemcitabine or C+Paclitaxel (q3w, 6 cycles, investigator`s choice) followed by Niraparib, b+c) 2 experimental arms: C (AUC5, d1) + G (150mg/m2, d1) q3w 6 cycles followed by either Niraparib alone (arm b) or by Niraparib+G (arm c; G at 100mg/m2 weekly, limited to 9 months). Niraparib (200/300mg/day) is given in case of SD, PR or CR after platinum-based treatment until disease progression. The main analysis will combine both experimental arms b+c and jointly compare them against arm a using log-rank test. Primary endpoint is PFS, secondary endpoints are PFS2, TFST, TSST, safety, ORR, PRO, OS. The first patient was dosed in January 2019. Clinical trial information: NCT03783949.