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.