Cyclin E1 Positivity Predicts Response to Azenosertib in Platinum-Resistant Ovarian Cancer

Cyclin E1 positivity was a predictive biomarker of response to azenosertib in patients with platinum-resistant ovarian cancer, according to data from part 1b of the phase 2 DENALI trial (NCT05128825) presented during the 2025 SGO Annual Meeting on Women’s Cancer.1

At the January 13, 2025, data cutoff, the overall response rate (ORR) among all response-evaluable patients who received azenosertib (n = 93) was 20.4% (95% CI, 12.8%-30.1%), and the ORR in the intention-to-treat (ITT) population (n = 102) was 18.6% (95% CI, 11.6%-27.6%). Comparatively, in response-evaluable patients with cyclin E1 positivity per immunohistochemistry (IHC; n = 43) the ORR was 34.9% (95% CI, 21.0%-50.9%); the ORR in the ITT population of patients with cyclin E1 positivity (n = 48) was 31.3% (95% CI, 18.7%-46.3%).

The median duration of response (DOR) was 6.3 months (95% CI, 2.7-not evaluable), and the median progression-free survival (PFS) was 4.1 months (95% CI, 2.8-6.8) among cyclin E1–positive patients in the ITT. Four patients were ongoing in response at the data cutoff.

“High-grade serous ovarian cancers with CCNE1 amplification are an unmet need, and new therapies are critically needed,” Fiona Simpkins, MD, said during the presentation. “Cyclin E1 protein overexpression results in complete cell cycle dysregulation. Cells enter S phase early, leading to high levels of replication stress and critical reliance on the G2-M checkpoint. WEE1 is a critical regulator of the G1 and G2-M checkpoints. Targeting WEE1 with azenosertib results in the loss of these checkpoints, leading to mitotic catastrophe and cell death.”

Simpkins is the Hilarie L. and Mitchell L. Morgan President's Distinguished Professor in Women's Health at the University of Pennsylvania Perelman School of Medicine in Philadelphia; an attending physician of Gynecologic Oncology in the Department of Ob/Gyn in the Hospital of the University of Pennsylvania; director of Clinical & Translational Gynecologic Oncology Research at the Penn Medicine Health System; and active staff of Gynecologic Oncology in the Department of Ob/Gyn at Chester County Hospital in West Chester, Pennsylvania.

In January 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.2

DENALI Study Design and Patient Baseline Characteristics

Part 1b of DENALI enrolled 102 patients with platinum-resistant ovarian cancer who had received 1 to 5 prior lines of therapy, including prior bevacizumab (Avastin). The trial included all patients irrespective of cyclin E1 status. Eligible patients received azenosertib at a dose of 400 mg daily on a 5-days-on, 2-days-off weekly dosing schedule.

The primary end points were the frequency and severity of treatment-emergent adverse effects (AEs), incidence of dose modifications, and ORR per revised RECIST 1.1 criteria and by independent review committee.3 Secondary end points included DOR, PFS, clinical benefit rate, and time to response.

At baseline, patients had a median age of 66 years (range, 34-82).1 Most patients were White (69%), had an ECOG performance status of 0 (52%), and had positive cyclin E1 status by IHC (51%). The median number of prior lines of therapy was 3 (range, 1-5); patients had received 1 to 2 (34%), 3 to 4 (56%), or 5 (10%) previous lines of treatment. Prior therapies consisted of bevacizumab (91%), PARP inhibitors (56%), and mirvetuximab soravtansine-gynx (Elahere; 15%).

Safety Findings and Next Steps

In terms of safety, common grade 1/2 treatment-related AEs (TRAEs) occurring in at least 10% of patients included nausea (66%), fatigue (60%), diarrhea (51%), thrombocytopenia (35%), anemia (29%), and decreased appetite (23%). Grade 3 or higher TRAEs included fatigue (16%), thrombocytopenia (12%), anemia (11%), and neutropenia (11%). TRAEs leading to dose reduction (43.1%), dose interruption (57.8%), and treatment discontinuation (21.6%) were reported. TRAEs leading to death and serious TRAEs occurred at rates of 2.0% and 21.6%, respectively.

Part 2 of DENALI will enroll patients with platinum-resistant ovarian cancer who are cyclin E1 positive per IHC. Patients need to have received 1 to 3 prior lines of therapy; 4 prior lines are permitted if patients have received prior mirvetuximab soravtansine. In part 2a, patients will be randomly assigned 1:1 to receive azenosertib at a dose of 400 mg or 300 mg daily on a 5-days-on, 2-days-off weekly dosing schedule. Following the interim analysis, patients will receive azenosertib at a to-be-determined dose. The outcomes are ORR, DOR, PFS, and safety and tolerability.

“Cyclin E1 [positivity] by IHC doubles the eligible patient population [for azenosertib] beyond CCNE1 amplification,” Simpkins said. “Cyclin E1 [positivity] by IHC is a predictive biomarker of response to azenosertib. Gastrointestinal toxicity and fatigue are the most common AEs; although less common, hematologic toxicities will require close monitoring. Azenosertib warrants further development in this biomarker-positive population and is ongoing in part 2 of DENALI.”

Disclosures: Simpkins reported performing consulting/advisory roles with AstraZeneca, GlaxoSmithKline, Repare Therapeutics, and FoRx Therapeutics; and receiving research funding from AstraZeneca, AstraZeneca/MedImmune, Instill Bio, Repare Therapeutics, and Sierra Oncology.

References

1. Simpkins F, Leary A, Willmott L, et al. Cyclin E1 is a predictive biomarker of azenosertib benefit in platinum-resistant ovarian cancer (PROC): outcomes from part 1b of the DENALI study (GOG-3066). Presented at: 2025 SGO Annual Meeting on Women’s Cancer. March 14-17, 2025; Seattle, WA. Abstract 814654.
2. Zentalis Pharmaceuticals announces azenosertib fast track designation and virtual corporate event to present updated data from azenosertib clinical studies. News release. Zentalis Pharmaceuticals. January 9, 2025. Accessed March 15, 2025. https://ir.zentalis.com/news-releases/news-release-details/zentalis-pharmaceuticals-announces-azenosertib-fast-track
3. 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 March 15, 2025. https://clinicaltrials.gov/study/NCT05128825