A cell cycle checkpoint kinase inhibitor known as prexasertib showed promising activity and was reasonably well tolerated in a phase II study of high-grade, heavily pretreated, BRCA wild-type serous ovarian carcinoma.
“High-grade serous ovarian carcinoma is the most lethal gynecologic malignancy in the US,” wrote study authors led by Jung-Min Lee, MD, of the National Cancer Institute in Bethesda, Maryland. The malignancy is characterized by TP53 mutations, DNA repair defects, and genetic instability, and the authors hypothesized that prexasertib, which targets checkpoint kinases 1 and 2, could be active in this setting.
The new study was an open-label, single-center, proof-of-concept phase II trial, including 28 women with a median age of 64 years. Of those, all received at least one dose of prexasertib, but only 24 were available for efficacy assessment. The patients had received a median of 5.0 previous systemic therapies, and 75% were platinum resistant. Results of the study were published online ahead of print in Lancet Oncology.
For the 24 assessable patients, the median treatment duration was 7.4 months. Eight patients (33%) had a partial tumor response; among only those who responded, the median treatment duration was 11.4 months, and three were still undergoing treatment with prexasertib. Six of the 19% patients with platinum-resistant or –refractory disease had partial responses, and five had stable disease for at least 6 months, for a clinical benefit rate of 58% in those patients.
The median progression-free survival in the 24 patients assessable for efficacy was 7.4 months. In total, 19 patients had a disease progression event (79%), and another died due to progression.
All patients who received the study drug had at least one treatment-emergent adverse event of any grade. The most common grade 3 or 4 treatment-emergent adverse events included neutropenia (93%), reduced white blood cell count (82%), thrombocytopenia (25%), and anemia (11%). Two patients had dose reductions, one due to recurrent grade 4 neutropenia and one due to recurrent grade 3 anemia. The two treatment-related serious adverse events were both grade 3 febrile neutropenia cases.
A separate phase II study of prexasertib is now enrolling patients with recurrent high-grade serous ovarian carcinoma and BRCA mutations. “The encouraging antitumor activity that we recorded in patients with platinum-resistant or platinum-refractory high-grade serous ovarian carcinoma warrants further development in a randomized trial that includes assessment of patient-reported outcomes,” the authors concluded.