Abstract CT201: Ceralasertib and olaparib in the treatment of homologous recombination repair (HRR)-deficient platinum-sensitive ovarian cancer after progression on PARP inhibitors
Authors: Shapiro Geoffrey I. , Basu Bristi , El-Khoueiry Anthony , Postel-Vinay Sophie , Im Seock-Ah , Rha Sun Young , Friedman Claire F. , Italiano Antoine , Kim Yong Man , Lim Myong Cheol , Roux Rene , Liu Joyce F. , Sanai Elhan , Smith Simon A. , Smith Claire , Farhi Sarah El , Lau Alan , Lukashchuk Natalia , Dean Emma , Krebs Matthew G. 
Published: June 2022

Abstract
Background: The majority of BRCA-mutant or HRR-deficient ovarian cancers are initially sensitive to PARP inhibitors (PARPis) but eventually develop resistance. The most commonly reported PARPi resistance mechanisms are (1) reversal of HRR deficiency through (a) reversion mutations in BRCA or other HRR genes (eg, RAD51C/D) or (b) DNA end resection rewiring with loss of 53BP1, REV7, or Shieldin complex components; or (2) stabilization of stalled replication forks through loss of PTIP or EZH2, preventing nuclease recruitment. The only confirmed PARPi resistance mechanism in the clinic to date is reversion mutations.
Combined ATR and PARP inhibition is an attractive strategy that may overcome PARPi resistance, as has been shown in PARPi-resistant cell lines and patient-derived xenograft models (Yazinski et al Genes Dev 2017; Murai et al Oncotarget 2016; Kim et al Nat Commun 2020; data on file, AstraZeneca). The PARPi olaparib 300 mg twice daily (BID) continuously in combination with the ATR inhibitor ceralasertib 160 mg daily on days 1-7 of a 28-day cycle has demonstrated promising activity in the CAPRI study in patients with ovarian cancer who had progressed on PARPis (Wethington et al J Clin Oncol 2021). However, preclinical models of PARPi resistance suggest that a higher dose or duration of ceralasertib with a lower dose of olaparib may be more beneficial (data on file, AstraZeneca).
Methods: D5330C00004 (NCT02264678) is a multicenter, modular, phase 1 study assessing ceralasertib in combination with other anti-cancer agents in adults with advanced solid malignancies. In Module 2, a lower dose of olaparib (150 mg BID continuous) and a longer duration of ceralasertib (80 mg BID, days 1-14 of a 28-day cycle) is now being explored in 2 expansion cohorts in patients with platinum-sensitive, high-grade, serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer with deleterious or suspected deleterious germline or somatic BRCA or RAD51C/D mutations, or HRR deficiency by Myriad MyChoice® or FoundationOne® CDx (F1CDx) assays. Patients will have progressed on prior PARPis after ≥6 months in the maintenance or treatment setting (≥12 months after first-line maintenance). Cohort 1 is enrolling ~30 patients immediately after progression on a PARPi; Cohort 2 is recruiting ~30 PARPi-treated patients after intervening platinum-based chemotherapy. Study endpoints include safety, tumor response by RECIST 1.1, and duration of response. Exploratory analyses include genomic and functional analysis of HRR restoration in tumor and circulating tumor DNA, and analysis of replication fork stability in organoid cultures established from mandatory fresh tumor biopsy samples. Recruitment began in July 2021 with the first patient dosed in August 2021.
Citation Format: Geoffrey I. Shapiro, Bristi Basu, Anthony El-Khoueiry, Sophie Postel-Vinay, Seock-Ah Im, Sun Young Rha, Claire F. Friedman, Antoine Italiano, Yong Man Kim, Myong Cheol Lim, Rene Roux, Joyce F. Liu, Elhan Sanai, Simon A. Smith, Claire Smith, Sarah El Farhi, Alan Lau, Natalia Lukashchuk, Emma Dean, Matthew G. Krebs. Ceralasertib and olaparib in the treatment of homologous recombination repair (HRR)-deficient platinum-sensitive ovarian cancer after progression on PARP inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT201.