Azenosertib Monotherapy Appears Safe and Effective in Ovarian Cancer

Azenosertib (ZN-c3) monotherapy elicited an overall response rate (ORR) of 34.9% (95% CI, 21.0%-50.9%) in response-evaluable, heavily pretreated patients with cyclin E1–positive platinum-resistant ovarian cancer (n = 43), according to updated findings from part 1b of the phase 2 DENALI trial (NCT05128825).1

Additional findings showed that at the December 2, 2024, data cutoff, in the intention-to-treat (ITT) cyclin E1–positive population (n = 48), the ORR was 31.3% (95% CI, 18.7%-46.3%). The median duration of response (DOR) in the ITT population was still maturing and was approximately 5.5 months (95% CI, 2.7-not evaluable).

Furthermore, safety findings from the azenosertib monotherapy cohorts of DENALI and other trials, including the phase 1 ZN-c3-001 (NCT04158336) and the phase 2 MAMMOTH (NCT05198804) 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.

“We are excited to outline a clear path for Zentalis to bring azenosertib to patients with cyclin E1–positive platinum-resistant ovarian cancer,” Ingmar Bruns, MD, chief medical officer of Zentalis, stated in a news release. “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. The results demonstrate a median DOR of approximately 5.5 months that continues to mature with patients remaining on therapy. In addition, with over 350 patients treated at clinically active monotherapy doses (total daily dose ≥ 300 mg) across our studies, we have observed a well-characterized safety profile and no new safety signals since our last report. Our data have also confirmed cyclin E1 overexpression as a predictor of sensitivity to azenosertib monotherapy in platinum-resistant ovarian cancer, and we intend to pursue further development in this patient population.”

The single-arm DENALI part 1b trial investigated azenosertib monotherapy at intermittent daily dosing of 400 mg on a schedule of 5 days on, 2 days off in 102 patients with high-grade serous platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer.1,2 Patients were allowed to have received 1 to 5 prior lines of therapy, and needed to have measurable disease per RECIST 1.1 criteria and adequate hematologic and organ function.2

Primary end points included the frequency and severity of treatment-emergent AEs, the incidence of dose modifications, and ORR. Secondary end points included DOR, progression-free survival, clinical benefit rate, and time to response.

All patients were required to provide tissue samples for biomarker assessment, and a retrospective analysis showed that approximately 50% of enrolled patients were cyclin E1 positive.1

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 2a has a target enrollment of approximately 30 patients at each of 2 dose levels: the primary dose of interest, and 300 mg on the same schedule.

Part 2b plans to enroll approximately 70 patients at a single dose, which will be selected based on findings from Part 2a. The final Part 2b dose selection and findings will be subject to FDA feedback. Topline data from Part 2 are planned to be reported by the end of 2026.

“We are very pleased with the azenosertib results obtained to date and believe we have a clear path to advancing this product candidate to patients,” Julie Eastland, chief executive officer of Zentalis, added in the news release. “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.”

Notably, 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.3

References

1. Zentalis Pharmaceuticals shares updated clinical data demonstrating meaningful azenosertib activity in Cyclin E1+, platinum-resistant ovarian cancer. News release. Zentalis Pharmaceuticals, Inc. January 29, 2025. Accessed January 29, 2025. https://www.globenewswire.com/news-release/2025/01/29/3017038/0/en/Zentalis-Pharmaceuticals-Shares-Updated-Clinical-Data-Demonstrating-Meaningful-Azenosertib-Activity-in-Cyclin-E1-Platinum-Resistant-Ovarian-Cancer.html
2. A study of ZN-c3 in subjects with high-grade serous ovarian, fallopian tube or primary peritoneal cancer. ClinicalTrials.gov. Updated June 25, 2024. Accessed January 29, 2025. https://clinicaltrials.gov/study/NCT05128825
3. Zentalis Pharmaceuticals announces azenosertib fast track designation and virtual corporate event to present updated data from azenosertib clinical studies. News release. Zentalis Pharmaceuticals, Inc. January 9, 2025. Accessed January 29, 2025. https://ir.zentalis.com/news-releases/news-release-details/zentalis-pharmaceuticals-announces-azenosertib-fast-track