The most common type of ovarian cancer, high-grade serous ovarian cancer, has a dismal prognosis, and new treatments are desperately needed for individuals with platinum-resistant or -refractory disease. Inhibition of CHK1 with prexasertib is one example of a new therapeutic approach targeting cell cycle checkpoints that has the potential to enhance clinical response and overcome resistance. The Phase 2 multicenter trial (NCT03414047) randomized 169 patients with ovarian cancer into 4 groups: Platinum-resistant, BRCA-wildtype patients with more than or equal to 3 prior lines of therapy; platinum-resistant, BRCA-mutated patients who have previously been treated with a PARP inhibitor; platinum-refractory, BRCA-mutated or BRCA-wildtype patients who have received any number of prior lines of therapy.
The objective response rate (ORR) was the primary goal, whereas the disease control rate (DCR) and safety were secondary. Biomarkers were found by sequencing DNA extracted from tumor tissues. Patients in Cohorts 1-3 who were resistant to platinum had an ORR of 12.1%, while those who were refractory to platinum had an ORR of 6.9%. The DCR in platinum-resistant patients was 37.1%, and this rate was stable between studies. DCR was 31.0% in platinum-resistant individuals. Thrombocytopenia, neutropenia, fatigue, nausea, and anemia were the most common treatment-related side events across all grades, which is consistent with the prexasertib mechanism of action.
In a subset of patients with recurrent ovarian cancer, prexasertib displayed sustained single agent efficacy regardless of clinical features, BRCA status, or prior treatments, including PARPi. Responders and non-responders did not show any clear link with genetic modifications, highlighting the need for further biomarker approaches to determine who will respond.