Cyclin E1 Positivity May Enhance Patient Selection for Azenosertib in Platinum-Resistant Ovarian Cancer

Fiona Simpkins, MD

Given the association of CCNE1 amplification and cyclin E1 overexpression with poor treatment outcomes in high-grade serous ovarian cancer and the limited treatment arsenal for platinum-resistant disease, the potential use of cyclin E1 overexpression as a predictive biomarker of response to azenosertib is an important therapeutic avenue warranting further investigation, according to Fiona Simpkins, MD.

Results from part 1b of the phase 2 DENALI trial (NCT05128825), which were presented at the 2025 SGO Annual Meeting on Women’s Cancer, showed that in the subgroup of patients with cyclin E1–positive tumors, azenosertib produced an overall response rate (ORR) of 34.9% (95% CI, 21.0%-50.9%) in response-evaluable patients (n = 43) and 31.3% (95% CI, 18.7%-46.3%) in the intention-to-treat (ITT) population (n = 48).1 For cyclin E1–positive patients in the ITT group, 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).

“The ORR and median DOR months [achieved] with azenosertib in a heavily pretreated population was remarkable and warrants further evaluation of this therapy,” Simpkins stated in an interview with OncLive®.

Notably, azenosertib was granted FDA fast track designation in January 2025 for the treatment of patients with cyclin E1–positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.2

In the interview, Simpkins discussed results supporting the predictive utility of cyclin E1–positivity for azenosertib response; emphasized the potential benefit of this agent for a patient subset with poor prognosis with existing therapies; and outlined the ongoing investigation of optimized azenosertib dosing in patients with cyclin E1–positive tumors in part 2 of the DENALI trial, which aims to support the agent’s accelerated FDA approval.

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; the director of Clinical & Translational Gynecologic Oncology Research at the Penn Medicine Health System; and an active staff member of Gynecologic Oncology in the Department of Ob/Gyn at Chester County Hospital in Chester County, Pennsylvania.

OncLive: What is the scientific rationale for targeting WEE1 in cyclin E1–overexpressing ovarian cancer, and how could this approach address unmet needs in this patient population?

Simpkins: CCNE1 amplification—or cyclin E1 overexpression—in high-grade serous ovarian cancers is associated with significantly worse outcomes. [These patients] have worse PFS and overall survival [outcomes] after [receiving] standard therapies that are currently available. This is clearly an unmet need.

Cyclin E1 overexpression results in complete cell cycle dysregulation. Cells enter the S phase too early, leading to high levels of replication stress and critical reliance on the G2M checkpoint for DNA repair. WEE1 is a key regulator of the G1S and the G2M checkpoints, so targeting WEE1 with azenosertib, for example, leads to the loss of these critical cell cycle checkpoints, leading to mitotic catastrophe and cell death. There’s a strong scientific rationale for targeting WEE1 in cyclin E1–overexpressing ovarian cancers.

What is important to know about the design and methodology of the DENALI study?

DENALI is a multicenter study evaluating azenosertib in platinum-resistant ovarian cancer. [This trial enrolled] biomarker-unselected patients. However, cyclin E1 protein [expression] and CCNE1 amplification were evaluated retrospectively in a planned analysis. Patients were treated with azenosertib at 400 mg on a 5-days on/2-days off schedule in 21-day cycles. [Treatment continued] until disease progression. The primary end point is safety, and secondary end points [include] ORR and PFS.

What findings from part 1b of this trial were reported at the meeting?

The results from part 1b [showed that] in all 102 treated patients, irrespective of biomarker [expression], the ORR in evaluable patients was [20.4%]. In the ITT population, [composed of] those having received 1 dose of the drug, it was [18.6%]. However, in the population [of response-evaluable patients who were] cyclin E1–positive by immunohistochemistry [IHC], the ORR was [34.9%]; in the [cyclin E1–positive] ITT population, it was [31.3%]. These are exciting results suggesting that cyclin E1 protein expression is predictive of response to azenosertib.

What was the agent’s safety profile?

Grade 3/4 hematological and nonhematologic toxicities were [present in approximately] 11% and 12% [of patients, respectively]. [The incidence of] gastrointestinal [toxicities] was low. However, grade 3/4 fatigue was identified in 16% of patients.

[Treatment-related adverse effects (AEs) leading to] dose reduction [occurred in] 43.1% of patients. There were 2 deaths on this study, secondary to neutropenic sepsis. The dose interruption and dose reduction rates were similar to those of other oral agents, but there was a slightly higher dose discontinuation rate [compared with those seen in other studies]. [Accordingly, AE] mitigation strategies have been implemented to improve safety.

What next steps are planned for the evaluation of azenosertib in this patient population?

Cyclin E1 protein [overexpression] by IHC represents approximately 50% of platinum-resistant ovarian cancers. This expands the [identification of] patients who could be eligible for such an agent [beyond the presence of] CCNE1 amplification by copy number.

Part 2 of DENALI is launching now. It’s a phase 2 portion evaluating azenosertib in cyclin E1–positive, platinum-resistant ovarian cancer. [This patient population will be] biomarker selected, and patients will be randomly assigned to [1 of] 2 [azenosertib] dose levels: 400 mg vs 300 mg for dose optimization. This trial will then be further expanded, for an approximate total of 110 patients to be treated at the selected optimized dose with the ultimate goal of accelerated FDA approval [of the agent for this population].

Disclosures: Simpkins reported performing consulting/advisory roles with AstraZeneca, GlaxoSmithKline, Zentalis, Repare Therapeutics, and FoRx Therapeutics; and receiving institutional research funding from AstraZeneca, AstraZeneca/MedImmune, Instil 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, Inc. January 9, 2025. Accessed April 15, 2025. https://ir.zentalis.com/news-releases/news-release-details/zentalis-pharmaceuticals-announces-azenosertib-fast-track