Abstract B013: Cyclin E1 Positive Protein Status is a Predictive Biomarker of Azenosertib Benefit in Platinum-Resistant Ovarian Cancer: Part 2 of the DENALI Study (GOG-3066)

Abstract Background: Cyclin E1 positive protein expression comprises a significant portion of patients with platinum resistant ovarian cancer (PROC) and has been associated with poor prognosis in ovarian cancer patients. Currently, there are no approved therapies specifically for cyclin E1 positive-PROC, presenting a significant unmet need. Azenosertib is a potential best-in-class, highly selective oral WEE1 kinase inhibitor. Cyclin E1 protein overexpression has been shown to directly correlate with an increased reliance on the G2/M checkpoint in the cell cycle and is a predictive biomarker of azenosertib sensitivity in preclinical models of ovarian cancer (Kim D, et al. NPJ Precis Oncol. 2025;9[1]:3). Azenosertib demonstrated clinically meaningful response rates and duration of response in heavily pretreated patients with cyclin E1 positive-PROC in DENALI Part 1b (Simpkins F, et al. SGO Annual Meeting 2025: Abstract 814654). In addition, azenosertib has shown to have a manageable safety profile with a low rate of serious treatment-related adverse events.These results indicate that cyclin E1 protein expression is a clinically relevant biomarker associated with response to azenosertib monotherapy, warranting further investigation with azenosertib in patients with cyclin E1 positive-PROC. The objective of DENALI Part 2 is to evaluate the efficacy and safety of azenosertib in patients prospectively screened and selected for cyclin E1 positive-PROC status based on Sponsor’s central immunohistochemistry (IHC) assay. Study Design & Methods: DENALI (NCT05128825, GOG-3066) is a Phase 2 open-label, multicenter, 2-part (Part 1b & Part 2a/b) study assessing the safety and efficacy of azenosertib in patients with PROC (including fallopian tube and primary peritoneal). In Part 2 of the study, which is currently enrolling, eligible patients are required to have measurable disease per RECIST v1.1, cyclin E1 positive-PROC by IHC per Sponsor’s central assay (pre-screening can be performed during current therapy), and ECOG PS 0-1. Prior therapy requirements include bevacizumab, PARPi for patients harboring BRCA 1/2 mutation or HRD, and mirvetuximab for patients with high folate receptor alpha expression. Between 1-3 prior lines of therapy are permitted; a 4th prior line is permitted for patients treated with prior mirvetuximab. In the dose confirmation portion of the study (Part 2a), patients with Cyclin E1 positive-PROC are being randomized 1:1 to receive either azenosertib 300 mg or 400 mg once a day (target enrollment of approximately 30 patients at each dose) on an intermittent schedule (5 days on 2 days off). Upon dose confirmation in Part 2a, Part 2b will continue enrollment of patients at the confirmed Part 2a dose, targeting approximately 100 patients across Part 2a and 2b combined. The endpoints are objective response rate, duration of response, progression-free survival and clinical benefit rate by RECIST v1.1, CA-125 response by Gynecologic Cancer Intergroup criteria, and safety. An Independent Data Monitoring Committee has been chartered for this study. Citation Format: Alexandra Leary, Lyndsay Willmott, Bradley J. Monk, Jean-Sébastien Frenel, David C. Starks, Meena Okera, Angeles Alvarez Secord, David M. O’Malley, Lainie Martin, Kaissa Ouali, Martin K. Oehler, Jeffrey C. Goh, Brian M. Slomovitz, Peter C. Lim, Catherine M. Shannon, Robert Neff, Floor J. Backes, Divya Rajendran, Heekyung Chung, Doris Kim, Hailun Li, Danielle Jandial, Fiona Simpkins. Cyclin E1 Positive Protein Status is a Predictive Biomarker of Azenosertib Benefit in Platinum-Resistant Ovarian Cancer: Part 2 of the DENALI Study (GOG-3066) [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 B013.