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

Abstract

Background: High-grade serous ovarian carcinoma is characterised by TP53 mutations, DNA repair defects, and genomic instability. We hypothesised that prexasertib (LY2606368), a cell cycle checkpoint kinase 1 and 2 inhibitor, would be active in BRCA wild-type disease.

Methods: In an open-label, single-centre, two-stage, proof-of-concept phase 2 study, we enrolled women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma. All patients had a negative family history of hereditary breast and ovarian cancer or known BRCA wild-type status, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status score 0-2, and adequate haematological, renal, hepatic, and bone-marrow function. Patients received intravenous prexasertib 105 mg/m² administered over 1 h every 14 days in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint of investigator-assessed tumour response, based on RECIST version 1.1, was assessed per protocol (assessable patients who had undergone CT imaging at baseline and attended at least one protocol-specified follow-up) and by intention to treat. The final analysis of this cohort of patients with BRCA wild-type high-grade serous ovarian carcinoma is reported here. This ongoing trial is registered with ClinicalTrials.gov, number NCT02203513, and continues to enrol patients for the BRCA-mutated ovarian cancer cohort.

Findings: Between Jan 20, 2015, and Nov 2, 2016, we enrolled 28 women with a median age of 64 years (IQR 58·0-69·5) who had previously received a median of 5·0 (IQR 2·5-5·0) systemic therapies. Most patients (22 [79%]) had platinum-resistant or platinum-refractory disease. All women received at least one dose of prexasertib, but four (14%) of 28 patients were not assessable for RECIST response. Eight (33%, 95% CI 16-55) of 24 patients assessable per protocol had partial responses. In the intention-to-treat population, eight (29%, 95% CI 13-49) of 28 had a partial responses. The most common (in >10% patients) grade 3 or 4 treatment-emergent adverse events were neutropenia in 26 (93%) of 28 patients, reduced white blood cell count in 23 (82%), thrombocytopenia in seven (25%), and anaemia in three (11%). Grade 4 neutropenia was reported in 22 (79%) patients after the first dose of prexasertib and was transient (median duration 6 days [IQR 4-8]) and recovered without growth-factor support in all cases. The treatment-related serious adverse event of grade 3 febrile neutropenia was reported in two (7%) patients. One patient died during the study due to tumour progression.

Interpretation: Prexasertib showed clinical activity and was tolerable in patients with BRCA wild-type high-grade serous ovarian carcinoma. This drug warrants further development in this setting, especially for patients with platinum-resistant or platinum-refractory disease.

Funding: Intramural Research Program of the National Institutes of Health and National Cancer Institute.

Figure 1

Consort diagram.

Figure 2. Clinical benefit

(A) Duration on treatment of 28 enrolled patients. Blue: platinum-sensitive; grey: platinum-resistant; yellow: platinum-refractory disease. The red dot indicates PR and red arrows indicate ongoing treatment at data lock. (B) Baseline and serial CA125 measurements from 24 evaluable patients. Blue: platinum-sensitive; grey: platinum-resistant; yellow: platinum-refractory disease. Patients with PR by RECIST v1·1 criteria are marked as a red square. Red cross indicates those receiving drug at data lock.

Figure 3. Integrated treatment outcome and mutations in DNA repair genes and CCNE1 amplification or overexpression in pretreatment tumours

Top: 24 patients with baseline and subsequent imaging reassessment are shown. Best RECIST response is graphed for each patient. Blue: platinum-sensitive; grey: platinum- resistant; yellow: platinum-refractory disease. Red cross indicates those receiving drug at data lock. Middle: PFS (months), number of prior lines of therapy, and presence of mutations in DNA damage repair genes (black) are listed for each patient. Bottom: pretreatment CCNE1 copy number variations, mRNA expression, and protein expression are shown for each patient. Tumors are classified by CCNE1 copy number as follows; CCNE1 mean copy number >3: amplification (red) and 2·1–3: copy number gain (yellow). Tumors are considered as CCNE1 mRNA upregulation (pink) if log2 CPM >2 by RNA-Seq. CCNE1 protein expression by IHC is marked as positive (positive or strong positive nuclear staining; black) or negative (grey). Study ID 48’s core biopsy sample consisted of normal liver tissue with suboptimal quantity of tumor tissue. Abbreviations: PFS = progression-free survival, CPM = counts per million