First Patient Dosed With Azenosertib in Cyclin E1+ Ovarian Cancer

The first patient with Cyclin E1-positive platinum-resistant ovarian cancer has been dosed with azenosertib in part 2a of the phase 2 registration-intent, DENALI clinical trial, according to a news release from Zentalis Pharmaceuticals, Inc.

The announcement went on to share that topline data from part 2 of the DENALI study are expected to be shared by the end 2026. This data, subject to U.S. Food and Drug Administration (FDA) feedback, may potentially support an accelerated approval of the agent.

“Dosing the first patient in part 2 of the DENALI study is an important milestone for Zentalis as we continue the clinical development of azenosertib,” said Dr. Ingmar Bruns, chief medical officer of Zentalis. “We are proud that azenosertib is one step closer to our goal of addressing a tremendous unmet need. We are grateful to our patients and their families for participating in this trial, which has the potential to result in a treatment option for thousands of women diagnosed with Cyclin E1-positive platinum-resistant ovarian cancer.”

More Information on the DENALI Clinical Trial

The Company previously announced that they had aligned with the U.S. FDA on the design of part 2 of the DENALI study, allowing for a seamless transition to enrollment for both parts of the trial.

Part 2a of the clinical trial will dose patients with azenosertib at either 300 or 400 milligrams on an intermittent daily dosing schedule of five days on, two days off. This part of the phase 2 study aims to confirm the primary dose-of-interest of azenosertib with a target enrollment of approximately 30 patients at each of dose levels.

Importantly, results from part 2a of the two-part phase 2 study will inform part 2b, which aims to enroll approximately 70 additional patients at the selected dose optimal dose, subject to FDA feedback.

Prior to this announcement, the Company shared findings from part 1b of the DENALI study; these findings showed clinically meaningful results in patients with Cyclin E1-positive positive platinum-resistant ovarian cancer. At the data cutoff of January 13, 2025, there were 43 response-evaluable patients, and the objective response rate among these individuals was 34.9%. Additionally, there was also a median duration of response of 6.3 months. However, the median duration of response is subject to change, according to the news release, as there were patients with ongoing responses as of the cutoff date.

Moreover, in the news release, the Company emphasized that these data established Cyclin E1 protein overexpression as a sensitive and specific predictive biomarker for response to azenosertib, regardless of CCNE1 gene amplification. This biomarker can be used to identify individuals who may potentially derive benefit from treatment with this therapeutic agent.

The Company has estimated, based on its proprietary immunohistochemistry threshold, that approximately 50% of patients with platinum-resistant ovarian cancer exhibit Cyclin E1 overexpression, demonstrating the importance of this biomarker in patient selection.

What is Azenosertib?

The novel, selective and orally bioavailable inhibitor of WEE1, azenosertib is being evaluated both as a monotherapy and in combination with other agents across clinical studies in ovarian cancer, as well as in additional tumor types.

The news release goes on to explain that WEE1 is a master regulator of the G1-S and G2-M cell cycle checkpoints. This is important because the agent then inhibits WEE1 to enable cell cycle progression and prevent the replication of cells with damaged DNA. Inhibition of WEE1 results in the accumulation of DNA damage and leads to mitotic catastrophe and cancer cell death.

For more information regarding the DENALI trial, please visit www.clinicaltrials.gov using the identifier: NCT05128825.

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