On March 17, 2025 Zentalis Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage biopharmaceutical company developing a potentially first-in-class and best-in-class WEE1 inhibitor for patients with ovarian cancer and other tumor types, reported updated clinical data from Part 1b of the ongoing DENALI clinical trial of azenosertib in patients with PROC in an oral presentation at the Society of Gynecologic Oncology (SGO) 2025 Annual Meeting on Women’s Cancer (Press release, Zentalis Pharmaceuticals, MAR 17, 2025, View Source [SID1234651193]).
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DENALI Part 1b is a Phase 2 single-arm study that evaluated azenosertib monotherapy at the 400mg QD 5:2 dose (once daily, five days on, two days off, or the "intermittent schedule") in patients with PROC (n=102).
As of the January 13, 2025 data cutoff, patients with Cyclin E1+ PROC tumors who were response-evaluable (patients who had at least one scan after receiving azenosertib) demonstrated an ORR of 34.9% (15/43; 95% CI: 21.0 – 50.9). In the intent-to-treat patients with Cyclin E1+ PROC (patients who received at least one dose of azenosertib), the ORR was 31.3% (15/48; 95% CI: 18.7 – 46.3), and an mDOR of 6.3 months (95% CI: 2.7 – not estimable). The mDOR is subject to change since there were patients with ongoing responses as of the cutoff date.
The presentation also demonstrates Cyclin E1 protein overexpression, regardless of CCNE1 gene amplification, as a sensitive and specific predictive biomarker that can be used to identify patients who could potentially derive benefit from azenosertib. Zentalis estimates that about half of PROC patients overexpress Cyclin E1 based on its proprietary immunohistochemistry cutoff.
As of the January 13, 2025 data cutoff, the safety and tolerability profile was consistent with the safety and tolerability profile from the Company’s January 29, 2025 investor event, which included data based off a cutoff date of December 2, 2024, with no new safety findings. Gastrointestinal toxicities and fatigue were found to be the most common treatment-related adverse events.
"The presentation of the updated DENALI Part 1b data at the SGO Annual Meeting supports our continued development of azenosertib," said Ingmar Bruns, M.D., Chief Medical Officer of Zentalis. "The clear anti-tumor activity and durable response observed highlights the potential of azenosertib to become an important treatment option for patients with Cyclin E1+ PROC. We are proud to have shared these data with many of the world’s leading gynecologic oncologists at SGO as part of our continued commitment to patients living with PROC."
"Platinum-resistant ovarian cancer is one of the most challenging types of ovarian cancer to treat. Tumors overexpressing Cyclin E1 protein exhibit poorer outcomes after standard of care chemotherapy regimens," said Fiona Simpkins, M.D., Director of Clinical & Translational Gynecologic Oncology Research at the University of Pennsylvania, and lead principal investigator in the DENALI study. "Developing new therapies for this subset of ovarian cancer patients is urgently needed. DENALI Part 1b results are exciting as they show that the WEE1 inhibitor, azenosertib, is active in a Cyclin E1 biomarker selective population potentially addressing a clinical unmet need."
The Company is on track to initiate enrollment of DENALI Part 2 in the first half of 2025 and expects to disclose topline data from DENALI Part 2 by year end 2026. DENALI Part 2, if successful, has the potential to support an accelerated approval, subject to FDA review. Zentalis plans to treat the same patient population in a Phase 3 randomized confirmatory study, subject to FDA review, which the Company plans to enroll concurrently with DENALI Part 2b.
Tomorrow, the Company will also present preclinical data of azenosertib during a poster presentation at the SGO Annual Meeting. The poster data highlights synergistic effects and significantly improved tumor growth inhibition in in vitro and in vivo preclinical models using a combination of azenosertib and microtubule inhibitor-based ADCs. Together with the previous data that azenosertib synergized with TOPO1 inhibitor based ADCs, these results indicate that azenosertib could be used as a generalizable combination partner with ADCs for improving responses in patients with advanced solid tumors.
The oral presentation and poster can be accessed through the "Publications" section of the Zentalis website.
About Azenosertib
Azenosertib is a novel, selective, and orally bioavailable inhibitor of WEE1 currently being evaluated as a monotherapy and combination 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.