Zentalis Pharmaceuticals is advancing azenosertib, a WEE1 inhibitor, as a potential treatment for Cyclin E1-positive platinum-resistant ovarian cancer (PROC). Updated clinical data from the ZN-c3-001, MAMMOTH, and DENALI studies were presented at a recent corporate event, outlining a path for future clinical development and registration plans. The FDA has granted Fast Track Designation to azenosertib, underscoring the unmet medical need in this patient population.
Promising Monotherapy Results
Data from the DENALI Part 1b trial showed an objective response rate (ORR) of approximately 35% in response-evaluable, heavily pretreated patients with Cyclin E1+ PROC. In the intent-to-treat (ITT) cyclin E1-positive population, the ORR was 31.3% (95% CI, 18.7%-46.3%). The median duration of response (DOR) in the ITT population was approximately 5.5 months (95% CI, 2.7-not evaluable) and still maturing.
Ingmar Bruns, MD, chief medical officer of Zentalis, stated, "In a patient population with a clear unmet medical need, the monotherapy data showed a meaningful and consistent improvement in responses as compared to historical data from current monotherapy chemotherapy standard of care, across multiple studies, in heavily pretreated patients at the 400mg once daily [5 days on, 2 days off] intermittent dose."
Safety and Tolerability
Across monotherapy cohorts in key clinical studies, azenosertib demonstrated a well-characterized safety and tolerability profile with no new safety signals. The safety findings from the azenosertib monotherapy cohorts of DENALI and other trials, including the phase 1 ZN-c3-001 and the phase 2 MAMMOTH trials, in patients with ovarian cancer and other solid tumors, have been consistent with each other and have shown that the agent appears safe and tolerable. Two treatment-related grade 5 adverse effects (AEs) in 2 patients from DENALI part 1b have been previously reported.
DENALI Trial Details and Future Plans
The single-arm DENALI part 1b trial investigated azenosertib monotherapy at intermittent daily dosing of 400 mg (5 days on, 2 days off) in 102 patients with high-grade serous platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer. Approximately 50% of enrolled patients were cyclin E1 positive.
The DENALI Part 2 study is planned to begin enrollment in the first half of 2025 and will consist of 2 parts. Part 2a aims to confirm the primary dose of interest of azenosertib, which is intermittent daily dosing at 400 mg for 5 days on and 2 days off. Part 2b plans to enroll approximately 70 patients at a single dose, which will be selected based on findings from Part 2a. Topline data from Part 2 are planned to be reported by the end of 2026. The company has aligned with the FDA on the design of its DENALI Part 2 study in patients with Cyclin E1+ PROC, which allows for seamless enrollment across Parts 2a and 2b.
Julie Eastland, chief executive officer of Zentalis, added, "Notably, approximately 50% of patients with platinum-resistant ovarian cancer are cyclin E1 positive, and we believe that the therapeutic and commercial opportunity in this population, which tends to be especially treatment refractory, is substantial. Looking ahead at continued azenosertib development, we believe that DENALI Part 2, if successful, has the potential to support an accelerated product approval, subject to FDA feedback."
Fast Track Designation
On January 9, 2025, the FDA granted fast track designation to azenosertib for the treatment of patients with Cyclin E1–positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.
