Prexasertib Promising in BRCA Wild-Type Ovarian Cancer


Prexasertib (LY2606368) induced a 29% response rate with acceptable tolerability in women with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma.

Prexasertib (LY2606368), a cell cycle checkpoint kinase 1 and 2 inhibitor, induced a 29% response rate with acceptable tolerability in women with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma.

In the intention-to-treat population (ITT), 29% (95% CI, 13-49) of 28 patients had partial response (PR), meeting the primary endpoint.

Four patients were not assessable for RECIST response per the study protocol. Among the 24 assessable patients, the median duration of treatment was 7.4 months (IQR, 2.1-9.7) and the PR rate was 33% (95% CI, 16-55), all of which were identified at the first tumor reassessment. The median duration of treatment among the responders was 11.4 months (IQR, 8.5 to not estimable). Treatment was still ongoing in 3 patients, at 12.5, 13.5, and 16.5 months.

In the open-label, single-center, 2-stage, proof-of-concept phase II study, 28 adult women received 105 mg/m2 of intravenous prexasertib monotherapy every 14 days in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent.

All patients received at least 1 dose of prexasertib from January 2015 to November 2016. Four women were not evaluable for RECIST response and 4 were still receiving treatment at the July 1, 2017, data cutoff.

The median age was 64 years (IQR, 58.0-69.5) and participants had undergone a median of 5.0 (IQR, 2.5-5.0) systemic therapies. Most patients (79%) had platinum-resistant or platinum-refractory disease. All patients had a negative family history of hereditary breast and ovarian cancer or known BRCA wild-type status, measurable disease according to RECIST v1.1, ECOG performance status score of 0 to 2, and adequate hematological, renal, hepatic, and bone-marrow function.

Six of 19 patients (32%; 95% CI, 13-57) with platinum-resistant or platinum-refractory disease in the per-protocol population had a PR. Five patients (26%; 95% CI, 9-51) had stable disease for at least 6 months with a median treatment duration of 9.5 months (IQR, 8.5-9.8). Investigators determined that 58% of patients with platinum-resistant or platinum-refractory disease derived a clinical benefit from prexasertib treatment.

The median progression-free survival in th evaluable population was 7.4 months (95% CI, 2.1-9.4).

Nineteen (79%) of 24 evaluable patients experienced a disease progression event and another patient died of tumor progression. In the posthoc exploratory analysis, half of assessable patients had a CA-125 response (≥50% reduction in CA-125 during treatment), 92% of whom also had PR or stable disease for longer than 6 months.

All 28 women were included in the safety analysis and all experienced at least 1 any-grade treatment-emergent adverse event (TEAE). The most common (>10%) grade 3/4 TEAEs were neutropenia (93%), reduced white blood cell count (82%), thrombocytopenia (25%), and anemia (11%). The most common grade 4 AE was transient neutropenia (79%) that resolved without growth-factor support. The median duration was 6 days (IQR, 4-8). The lowest absolute neutrophil count, as assessed in cycle 1, occurred consistently at around 1 week after each dose.

Twenty-two (79%) patients received prophylactic granulocyte colony-stimulating factor after the first cycle to avoid treatment delays or dose reductions. Two (7%) patients had dose reductions, 1 because of recurrent grade 4 neutropenia lasting longer than 7 days during cycle 4 despite the use of filgrastim (Neupogen), and 1 because of recurrent grade 3 anemia during cycle 6 that was refractory to blood transfusion. No patients discontinued treatment because of a TEAE.

Lee J, Nair J, Zimmer A, et al. 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 phase 2 study. Lancet Oncol. 2018; 19:207-215. doi: 10.1016/ S1470-2045(18)30009-3.

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