Abstract CT232: Phase I combination study of the CHK1 inhibitor prexasertib (LY2606368) and olaparib in patients with high-grade serous ovarian cancer and other advanced solid tumors
Authors: Do Khanh T. , Hill Sarah J. , Kochupurakkal Bose , Supko Jeffrey G. , Gannon Courtney , Anderson Adrienne , Muzikansky Alona , Wolanski Andrew , Hedglin Jennifer , Parmar Kalindi , Lazaro Jean-Bernard , Liu Joyce , Campos Susana , Matulonis Ursula A. , D'Andrea Alan D. , Shapiro Geoffrey I. 
Published: August 2019

Abstract
Background: Checkpoint kinase 1 (CHK1) plays a central role in replication fork stabilization and homologous recombination repair (HRR) through modulation of cell cycle checkpoints and phosphorylation of HRR proteins. BRCA-deficient cancers frequently upregulate CHK1 for protection of stalled replication forks. Prexasertib is an ATP-competitive inhibitor of CHK1. Addition of prexasertib to olaparib, an oral PARP inhibitor, may allow for combinatorial synergy and sensitization to PARP inhibition among tumors with de novo or acquired resistance.
Methods: We conducted an open-label phase 1 study following a 3+3 design. Patients (pts) received a 7-day lead-in of olaparib alone (C0), followed by 28-day cycles with prexasertib administered on days 1 and 15 and olaparib on days 1-5 and 15-19 with starting dose of prexasertib at 80mg/m2 and olaparib at 200mg. The MTD was defined as the highest dose level at which less than 1/3rd of at least 6 pts experienced a DLT during C0+C1. Pharmacokinetic blood samples were obtained at C0, C1, and C2. Pts enrolled to the expansion phase of the study underwent tumor biopsies during C0 and on C1D16 after the combination for pharmacodynamic assessment of target effects on HRR. Patient-derived organoid cultures with functional assays for HRR proficiency and replication fork stability were conducted in parallel as an exploratory objective.
Results: Twenty-one pts have been treated, 19 in the dose escalation phase. Three of 6 pts experienced DLTs at the starting dose and included Gr 3 neutropenia and Gr 3 febrile neutropenia. Lower doses for both agents were evaluated; the MTD is prexasertib at 70mg/m2 IV on days 1 and 15 in combination with olaparib at 100 mg PO BID D1-5 and 15-19. No DLTs were observed at this dose level. Drug-related adverse events occurring in ≥ 50% of pts included leukopenia, neutropenia, thrombocytopenia, anemia, and nausea. Three pts with BRCA1-mutant high-grade serous ovarian cancer (HGSOC) achieved PRs, two of whom had progressed on a prior PARP inhibitor. Tumor biopsies from pts in the expansion cohort demonstrated decreased RAD51 foci after prexasertib exposure. Pre-prexasertib patient-derived organoid cultures were successfully established and subjected to a DNA fiber assay to assess replication fork stability. The organoid derived from tumor from a non-responding patient had stable replication forks, whereas the organoid from a responding patient demonstrated baseline fork instability.
Conclusion: Prexasertib in combination with an abbreviated course of olaparib has preliminary clinical activity in patients with BRCA-mutant HGSOC who have previously progressed on a PARP inhibitor. A functional assay for HRR in tumor biopsies indicates that prexasertib can compromise RAD51 focus formation, consistent with the role of CHK1 in RAD51 phosphorylation and filament formation. Preliminary data in patient-derived organoid cultures parallels that of clinical responses and confirms previously published data suggesting replication fork instability contributes to response to prexasertib. An expansion cohort in the BRCA-mutant, PARP inhibitor-resistant HGSOC population is being enrolled to further assess efficacy of the combination and to obtain additional pharmacodynamic determinants of response and resistance.
Citation Format: Khanh T. Do, Sarah J. Hill, Bose Kochupurakkal, Jeffrey G. Supko, Courtney Gannon, Adrienne Anderson, Alona Muzikansky, Andrew Wolanski, Jennifer Hedglin, Kalindi Parmar, Jean-Bernard Lazaro, Joyce Liu, Susana Campos, Ursula A. Matulonis, Alan D. D'Andrea, Geoffrey I. Shapiro. Phase I combination study of the CHK1 inhibitor prexasertib (LY2606368) and olaparib in patients with high-grade serous ovarian cancer and other advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT232.