Announcement • May 07
Zentalis Pharmaceuticals Announces First Patient Dosed in Aspenova Phase 3 Trial of Azenosertib in Patients with Cyclin E1-Positive Platinum-Resistant Ovarian Cancer
Zentalis Pharmaceuticals, Inc. had announced that the first patient has been dosed in the Phase 3 ASPENOVA clinical trial (NCT07546500, GOG-3147, ENGOT-ov109, APGOT-OV27) evaluating azenosertib in patients with Cyclin E1-positive platinum-resistant ovarian cancer (PROC). ASPENOVA is a randomized, controlled Phase 3 trial designed to confirm the clinical benefit of azenosertib and support full approval as part of Zentalis' dual-track regulatory strategy. The company is pursuing accelerated approval based on the ongoing registration-intended DENALI Phase 2 trial, with a topline readout expected by year-end 2026, while simultaneously advancing ASPENOVA as the confirmatory study to satisfy FDA requirements for conversion to full approval. Both trials are evaluating azenosertib at 400mg once daily on a 5-days-on, 2-days-off schedule (400mg QD 5:2), the dose selected based on the DENALI Part 2a interim analysis announced in April 2026. The planned interim analysis showed a meaningful, clearly differentiated response rate at 400mg QD 5:2 over 300mg QD 5:2 and comparable safety profiles between the two dose groups. The ASPENOVA trial is being conducted in collaboration with The GOG Foundation, Inc. (GOG-F), the European Network of Gynaecological Oncological Trial groups (ENGOT), and Asia-Pacific Gynecologic Oncology Trials Group (APGOT), reflecting the global clinical and scientific community's recognition of the significant unmet need in this patient population. ASPENOVA (NCT07546500, GOG-3147, ENGOT-ov109) is a Phase 3 randomized, confirmatory clinical trial designed to support full approval of azenosertib in patients with Cyclin E1-positive platinum-resistant ovarian cancer (PROC). The trial is expected to enroll approximately 420 patients and compare azenosertib monotherapy at 400mg QD 5:2 to investigator's choice of standard-of-care single-agent chemotherapy (paclitaxel, pegylated liposomal doxorubicin [PLD], gemcitabine, or topotecan) in this biomarker-selected population. The primary endpoint is progression-free survival (PFS); key secondary endpoints include overall survival (OS) and overall response rate (ORR). The trial design was aligned with the U.S. Food and Drug Administration (FDA) to meet requirements for the accelerated approval pathway and potential conversion to full approval. DENALI is a multi-part Phase 2 registration-intended clinical trial (NCT05128825) studying azenosertib in PROC patients. Part 1b enrolled patients with PROC regardless of Cyclin E1 protein expression, all treated at 400mg QD 5:2. Part 2 is prospectively enrolling PROC patients with Cyclin E1 protein overexpression based on Zentalis' proprietary immunohistochemistry cutoff. Part 2, in total, is designed to support accelerated approval, pending study outcome and discussions with the FDA. The study design consists of the following parts: Part 2a: Dose confirmation evaluated two doses, 300mg QD 5:2 and 400mg QD 5:2, with approximately 30 patients enrolled per dose group. 400mg QD 5:2 was selected as the optimal monotherapy dose. Recruitment at the 300mg QD 5:2 dose level has been discontinued. All patients enrolled in Part 2a will contribute to the overall safety database submitted to the FDA. Part 2b: Enrollment expansion at the selected 400mg QD 5:2 dose up to approximately 100 patients, including patients at this dose in Part 2a. This cohort is currently enrolling. Part 2c: Broadening study population to include approximately 40 patients previously treated with a taxane-containing regimen for PROC. This cohort is currently enrolling. Zentalis expects to complete enrollment in all cohorts of DENALI Part 2 (2a, 2b, 2c) and provide a topline readout by year-end 2026. Azenosertib is an investigational, potentially first-in-class, selective, and orally bioavailable inhibitor of WEE1 currently being evaluated in clinical studies in ovarian cancer and additional tumor types. WEE1 acts as a master regulator of the G1-S and G2-M cell cycle checkpoints, through negative regulation of both CDK1 and CDK2, to prevent replication of cells with damaged DNA. By inhibiting WEE1, azenosertib enables cell cycle progression, despite high levels of DNA damage, thereby resulting in the accumulation of DNA damage and leading to mitotic catastrophe and cancer cell death. Azenosertib is in late-stage development as a potential treatment for Cyclin E1-positive platinum-resistant ovarian cancer (PROC). There is currently no approved treatment option specifically for this biomarker-selected population which comprises approximately 50% of PROC patients. Cyclin E1 protein overexpression has been established as a sensitive and specific predictive biomarker for identifying patients who could potentially derive benefit from azenosertib treatment, based on retrospective analysis of azenosertib studies in PROC. Validation of the Cyclin E1 companion diagnostic assay is ongoing in the DENALI and ASPENOVA trials. Azenosertib has been granted Fast Track Designation by the U.S. FDA for the treatment of patients with Cyclin E1-positive platinum-resistant ovarian cancer. Fast Track Designation is intended to facilitate the development and expedite the review of therapies that have the potential to treat serious conditions and address unmet medical needs.
