BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor-resistant BRCA-mutant ovarian cancer

PARP inhibitors (PARPis) have changed the treatment paradigm in BRCA-mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for novel therapeutic strategies. Using high throughput drug screens, we identified ATR/CHK1 pathway inhibitors as cytotoxic, and further validated monotherapy activity of the CHK1 inhibitor (CHK1i), prexasertib, in PARPi-resistant BRCA-mutant HGSC cells and animal models. As a proof-of-concept trial, we conducted a phase II study of prexasertib in BRCA-mutant HGSC patients. The treatment was well-tolerated but yielded an objective response rate of 6% (1/17; 1 PR) in patients with prior PARPi treatment. Exploratory biomarker analyses revealed that replication stress and fork stabilization were associated with clinical benefit to CHK1i. In particular, overexpression of BLM, and CCNE1 overexpression or copy number gain/amplification were seen in patients deriving durable benefit from CHK1i. Our findings suggest replication fork-related biomarkers should be further evaluated for CHK1i sensitivity in HGSC. Clinical Trial Registration ID #: NCT02203513.