Abstract A011: Rationale for the use of Azenosertib in Early Line Treatment of Cyclin E1-Positive High-Grade Serous Ovarian Cancer

Abstract High tumoral cyclin E1 protein expression—driven by CCNE1 gene amplification, impaired degradation, or increased transcription—is associated with poor prognosis in high grade serous ovarian cancer (HGSOC) patients, including shorter survival and reduced response to standard of care (SOC) chemotherapy. By leveraging the cell cycle checkpoint vulnerability induced by cyclin E1 overexpression, the WEE1 inhibitor azenosertib has demonstrated promising efficacy in patients with cyclin E1-positive, platinum-resistant ovarian cancer. The potential benefit of WEE1 inhibition in earlier lines of treatment - when most patients are not yet resistant to platinum therapy - warrants further investigation. Using prior systemic therapy records of 120 patients enrolled in azenosertib clinical studies, we determined that patients with cyclin E1-positive tumors required second-line treatment - a surrogate endpoint for first relapse – sooner than patients with cyclin E1-negative tumors (median time to subsequent treatment 8.8 vs 13.8 months, HR=1.47, p<0.05) irrespective of BRCA status or use of maintenance therapy. Among patients with cyclin E1-positive tumors, those also with CCNE1 amplification tended to have shorter time to treatment. Reciprocally, in patients with a shorter time to subsequent therapy following first relapse, tumors were more likely to be cyclin E1-positive (72% and 53% prevalence for patients below and above median time to subsequent treatment, respectively). In an independent study of patients treated with neoadjuvant chemotherapy (N=102), patients with cyclin E1-positive tumors had significantly worse progression free survival than those with cyclin E1-negative tumors confirming its role as a poor prognostic marker as early as the first line (1L) treatment. Although BRCA-mutated tumors were less likely to have CCNE1 amplification, the level of cyclin E1 protein expression and proportion of positive tumors were similar between BRCA wildtype and BRCA mutated tumors. These findings support the evaluation of azenosertib in patients with cyclin E1-positive tumors who relapse following 1L therapy, regardless of BRCA status. To evaluate if combining azenosertib with SOC bevacizumab offers an advantage in 1L maintenance, we tested the combination in two homologous recombination proficient, cyclin E1-high xenograft models (OVCAR3, OV5308) with differing sensitivities to anti-VEGF. The combination with azenosertib was well tolerated and enhanced tumor growth inhibition compared to either single agent in both models, while also resulting in deeper tumor regressions and better duration of response in the model that was sensitive to anti-VEGF monotherapy (OVCAR3). Safety and tolerability of the combination is currently being assessed in the maintenance setting of an ongoing phase 1b study (NCT04516447). The preclinical and retrospective clinical data support developing azenosertib in cyclin E1-positive HGSOC patients in an early treatment setting, with preclinical evidence suggesting added benefit when combined with SOC anti-VEGF in 1L maintenance. Citation Format: Mona Abed, Catherine Lee, Alexandra Levy, Doris Kim, Nandini Molden, Changhwan Shim, Divya Rajendran, Elisa Yaniz-Galende, Felix Blanc-Durand, Christophe Desauw, Philippe Follana, Nathalie Bonichon-Lamichhane, Stéphane Oudard, Véronique D'Hondt, Céline Gavoille, Leslie M. Randall, Fiona Simpkins, Funda Meric-Bernstam, Danielle D. Jandial, Alexandra Leary, Olivier Harismendy. Rationale for the use of Azenosertib in Early Line Treatment of Cyclin E1-Positive High-Grade Serous Ovarian Cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A011.