Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA wild-type recurrent high-grade serous ovarian cancer: a first in class, proof-of-concept, single arm phase 2 study

BACKGROUND: High-grade serous ovarian carcinoma (HGSOC) is characterized by TP53 mutations, DNA repair defects, and genomic instability. We hypothesized that prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, would be active in BRCA wild-type HGSOC. METHODS: In this open label, single centre, two-stage proof-of-concept phase 2 study, women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma were enrolled. All patients must have had either a negative family history of hereditary breast and ovarian cancer or known BRCA wild-type for BRCA wild-type cohort. Other key eligibility criteria were an Eastern Cooperative Oncology Group performance status of 0 or 1 or 2, and adequate haematological, renal, and hepatic function. Patients received intravenous prexasertib 105mg/m(2) once every 2 weeks until disease progression, unacceptable toxicity or patient withdrawal of consent. The primary endpoint was investigator-assessed tumour response per protocol based on Response Evaluation Criteria in Solid Tumors, version 1·1 in evaluable patients. The final analysis of this cohort is reported here. This ongoing trial is registered with ClinicalTrials.gov (NCT02203513) and enrolling the patients of BRCA mutation cohort. FINDINGS: Between January 2015 and November 2016, 28 women (median age 64-year-old [IQR 58–69·5], with median 5 prior systemic therapies [IQR 2·5–5]) were enrolled and received at least one dose of prexasertib. Eight of 24 evaluable patients had a partial response (PR; 33%, 95% CI: 16–55) and 50% had a GCIG CA125 response. The RR in the intention-to-treat population was 29% (8/28, 95% CI: 13–49). The common (>10%) grade 3 or 4 treatment-emergent adverse events were neutropenia (26 [93%] patients), thrombocytopenia (seven [25%] patients), and anaemia (three [11%] patients). Grade 4 neutropenia occurred in 22 (79%) patients after the first dose and was transient ≤ 7 days (median 6 days [IQR 4–8]) without growth factor support; the incidence of febrile neutropenia was 7% (2/28). INTERPRETATION: We demonstrate clinical activity of prexasertib in BRCA wild-type HGSOC, especially patients with platinum-resistant or refractory ovarian cancer. These results warrant further development for this unmet patient need. FUNDING: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, USA.