Abstract CT113: A phase II study of prexasertib, a cell cycle checkpoint kinase 1 (CHK1) inhibitor, in platinum-resistant recurrent high-grade serous ovarian cancer (HGSOC) with BRCA wild-type (BRCAwt)

Abstract

Abstract Background: Platinum-resistance is associated with a poor prognosis in HGSOC and has limited treatment options. Inhibition of CHK1 has shown activity in BRCAwt HGSOC. Here, we report the clinical activity and tolerability of the second generation CHK1 inhibitor, prexasertib, in platinum-resistant BRCAwt HGSOC (NCT02203513). Methods: Eligibility included platinum-resistant recurrent HGSOC women without germline or somatic BRCA mutation, ECOG PS 0-2, good end organ function, and measurable disease. The primary endpoint was response rate (RR). Secondary endpoints were progression-free survival (PFS) and safety. Prexasertib was given at 105 mg/m2 IV every 14 days in a 28-day cycle. CT scans were performed every 2 cycles for RECIST v1.1 evaluation, and safety evaluation using CTCAE v4.0 every cycle. CBC was performed on day 8 of cycle 1 for ANC nadir. Pretreatment clinical samples were collected for biomarker analysis including HR deficiency and circulating tumor cells (CTC). Results: Between January 2017 and November 2020, 49 patients (median age 64.1 years [IQR 56.8 - 69.9]) received at least one dose. 12 (24.5%) patients were primary platinum-resistant, and 37 (75.5%) were secondary platinum-resistant. All were heavily pretreated (median 4 prior systemic therapies [IQR 3 - 7]), including bevacizumab (79%), PARP inhibitors (44%), and both (2%). 39 patients were evaluable by RECIST and RR was 30.7%. The median PFS was 5.8 months (range 1.7-26.4 months). The median duration of response among PRs was 5.5 months (range 1-19.8 months). The clinical benefit rate (PR+CR+SD >4 months) was 84.6%. 10 patients were inevaluable due to: withdrawal of consent (n=2), intercurrent illness related to disease (tumor invasion of mainstem bronchus (n=1) or vaginal wall (n=1), small bowel obstruction (n=2), infection (n=2), failure to thrive (n=1), and pneumothorax secondary to thoracentesis (n=1) during cycle 1. The common (>10%) grade 3 or 4 adverse events (AEs) included neutropenia (85%, 42/49) based on the cycle 1 day 8 CBC at the time of ANC nadir, lymphocytopenia (46%, 23/49), thrombocytopenia (40%, 20/49), anemia (30%, 15/49), and febrile neutropenia (12%, 5/49). 83% (41/49) of patients received growth factors support to avoid subsequent treatment delays. There were no deaths on the study. No significant difference of RECIST response or PFS was observed in patients with high (≥2) vs low (<2) CTC at baseline. Conclusions: Prexasertib monotherapy resulted in clinical benefit in subgroups of heavily pretreated BRCAwt platinum-resistant HGSOC. Prexasertib was well tolerated with manageable grade 3/4 AEs. Further studies on predictive biomarkers are ongoing. Citation Format: Grant Zurcher, Ann McCoy, Brooke Solarz, Jay Nair, Min-Jung Lee, Jane B. Trepel, Christina M. Annunziata, Jung-Min Lee. A phase II study of prexasertib, a cell cycle checkpoint kinase 1 (CHK1) inhibitor, in platinum-resistant recurrent high-grade serous ovarian cancer (HGSOC) with BRCA wild-type (BRCAwt) [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 CT113.