Exploiting the Vulnerabilities of High-Grade Serous Ovarian Cancer Through WEE1 Inhibition

Although recent advances have added more targeted agents to the ovarian cancer armamentarium and improved outcomes for patients, the disease still carries a relatively poor prognosis with a 5-year relative survival rate of 50.9%.¹ In the search to continue developing safe and effective novel targeted agents for these patients, investigators have turned their attention to WEE1 as a potentially targetable pathway in high-grade serous ovarian cancer (HGSOC).

WEE1 is a protein kinase that plays a major role in cell cycle regulation and mitosis. Specifically, it is a gatekeeper of the G2/M and S-phase checkpoints and is primarily localized in the nucleus of the cell.^2,3

“Cancer cells require a lot of regulation of the cell cycle because they have problems with repairing their DNA, they’re under a lot of stress, and there are a lot of drivers that cause them to try to move [through it] faster,” Joyce F. Liu, MD, MPH, explained in an interview with OncologyLive. “WEE1 regulates the G2/M checkpoint; as the cells are moving quickly through G1/S toward mitosis, there’s a second checkpoint right before mitosis that WEE1 helps to regulate. If cells are not ready to divide, they stop at that point. [However], cells that have cyclin E amplification, or are otherwise under high replication stress, can be very dependent upon that G2/M checkpoint. A drug that blocks WEE1 allows that cell to escape that checkpoint and move very quickly into mitosis. [Because] some of those cells are not ready to divide, as they enter mitosis, they undergo a mitotic catastrophe.”

Liu is the associate chief and the director of clinical research in the Division of Gynecologic Oncology and an associate clinical research officer at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School, all in Boston, Massachusetts.

Approximately 20% of ovarian cancers display amplification of CCNE1, the gene that codes for the cyclin E protein, and the disease feature is almost entirely mutually exclusive with homologous recombination–deficient tumors. Moreover, CCNE1 amplification can be further enriched in ovarian tumors that are refractory to platinum-based treatments. Targeting cyclins directly with small molecule inhibitors is currently considered unlikely and not feasible by investigators due to their status as regulatory subunits.^4,5 Instead, WEE1-directed therapies could potentially offer a route to targeting the vulnerabilities present in high cyclin E-expressing cancers to affect cancer cell death.

Azenosertib Displays Preliminary Efficacy in HGSOC

Although there are currently no FDA-approved WEE1 inhibitors, azenosertib (formerly ZN-c3) is the agent in this class that is furthest along in the development process and has to date shown the most activity with a tolerable safety profile in ovarian cancer, specifically HGSOC. HGSOC makes up approximately 70% of all instances of ovarian cancer and represents approximately 80% of deaths from the disease.^6,7

“Azenosertib has been studied in phase 1 clinical trials now, looking at the dosing, and in early studies has shown activity in ovarian cancers that have higher levels of cyclin E, uterine serous cancers, and platinum-resistant ovarian cancers,” Liu noted.

In the phase 1 ZN-c3-001 study (NCT04158336), azenosertib monotherapy is being evaluated in patients with heavily pretreated HGSOC or uterine serous carcinoma. Patients in the uterine serous carcinoma (n = 6) group received a median of 3.5 (range, 1-6) prior lines of therapy, including a previous PARP inhibitor (16.7%), VEGF inhibitor (83.3%), and anti–PD-1/PD-L1 therapy (100%), and most patients (83.3%) had platinum-resistant disease. In the HGSOC group (n = 13), the median number of prior lines of treatment was 6 (range, 2-11) and patients also previously received a PARP inhibitor (76.9%), investigational agent (38.5%), VEGF inhibitor (84.6%), and/or anti–PD-1/PD-L1 therapy (7.7%); most patients (61.5%) had platinum-refractory disease and the remaining 38.5% were platinum resistant.^8,9

Updated findings from ZN-c3-001 announced in November 2023 by azenosertib’s developer, Zentalis Pharmaceuticals, showed that at the October 25, 2023, data cutoff, efficacy-evaluable patients (n = 19) achieved an objective response rate (ORR) of 36.8%, including 4 patients in the HGSOC group who experienced a complete or partial response, 2 of whom were still in response at the data cutoff; the other 9 patients with HGSOC achieved stable disease. Three patients with uterine serous carcinoma responded and no responses were ongoing at the data cutoff. The median progression-free survival (PFS) among all patients was 6.5 months (95% CI, 2.79-6.87).

Regarding safety, no febrile neutropenia or sepsis was observed. Twenty-four percent of patients needed dose reductions of azenosertib, 35% experienced dose interruptions, and no patients discontinued treatment with the agent. Treatment-related adverse effects (TRAEs) of any severity included diarrhea (47.8%), nausea (43.5%), vomiting (17.4%), dehydration (10.9%), and decreased appetite (8.7%). Any-grade hematologic TRAEs included anemia (23.9%), thrombocytopenia (19.6%), and neutropenia (19.6%). Study authors determined that the recommended phase 2 dose of azenosertib monotherapy was 400 mg daily on a weekly dosing schedule of 5 days on, 2 days off.

In light of the positive initial data observed in ZN-c3-001, investigators initiated the phase 2 open-label, multicenter DENALI trial (NCT05128825), which will evaluate azenosertib monotherapy in patients with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Eligible patients must be at least aged 18 years, have measurable disease per RECIST 1.1 criteria, and have adequate hematologic and organ function. To be included, patients must have also received 1 to 4 prior lines of therapy, including bevacizumab (Avastin), and have platinum-resistant disease.¹⁰

The coprimary end points are safety and ORR by RECIST 1.1 criteria per independent central review. Secondary end points consist of PFS, ORR by investigator assessment, duration of response, clinical benefit rate, and time to response. DENALI is recruiting patients, with an estimated enrollment of approximately 90 patients, and is projected to be completed in October 2025.

The final results of the ZN-c3-001 study of azenosertib monotherapy in solid tumors are expected in the second half of 2024 and topline data from DENALI are expected in the first half of 2025. Moreover, the first new drug application for azenosertib in a gynecologic malignancy is projected to be submitted in 2026.¹¹

There has also been interest from investigators in using azenosertib as a component of combination regimens. During the 2023 American Society of Clinical Oncology Annual Meeting, Liu and coauthors presented findings from a phase 1b study (NCT04516447) examining the correlation of cyclin E1 expression and clinical outcomes in patients with platinum-resistant or refractory epithelial ovarian, peritoneal, or fallopian tube cancer who received azenosertib in combination with chemotherapy.¹²

Response-evaluable patients (n = 94) who received azenosertib in combination with paclitaxel (n = 22), carboplatin (n = 28), gemcitabine (n = 13), or pegylated liposomal doxorubicin (n = 31), achieved a confirmed ORR of 34.0% and a median duration of response (DOR) of 8.3 months (95% CI, 5.6-12.4). The median PFS was 9.0 months (95% CI, 5.8-13.7).

Additionally, response-evaluable patients with a cyclin E1 immunohistochemistry (IHC) status of over 50 (n = 70) achieved an ORR of 40.0%. The median PFS of patients with an IHC over 50 (n = 78) was 9.86 months compared with 3.25 months for patients with an IHC of 50 or less (n = 12; HR, 0.37; 95% CI, 0.18-0.79; log-rank P = .0078).

“We saw that many of these combinations had activity in this setting,” Liu said. “These are small numbers of patients and it’s not a randomized trial, but in this selection of patients we see some degree of activity that might have been more than we expect with chemotherapy alone. [This is] encouraging and something that we would want to study more in future trials. In addition to this evidence of activity, it seemed that the highest activity occurred when patients had tumors that had high levels of cyclin E.”

Adavosertib Reaches the End of the Line

Beyond azenosertib, the investigational WEE1 inhibitor adavosertib (formerly MK-1775) was also being explored for the treatment of patients with gynecologic cancers. “Azenosertib has a slightly more specific profile for WEE1 [with] fewer off-target effects compared with adavosertib. The toxicity profile [of azenosertib] is a little bit better in terms of its ability to be dosed on a more continuous basis than adavosertib, without the same number of AEs. The most prominent AEs that we’ve seen with WEE1 inhibitors include effects on blood counts, fatigue, and diarrhea; that was what we saw published in the trials of adavosertib,” Liu said.

During the 2023 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer, Liu and coauthors presented findings from the phase 2b ADAGIO trial (NCT04590248) examining adavosertib in patients with recurrent or persistent uterine serous carcinoma who were previously treated with platinum-based chemotherapy. The ORR among efficacy-evaluable patients (n = 104) was 26.0% (95% CI, 17.9%-35.5%) and the disease control rate was 51.4% (95% CI, 41.6%-61.1%). The median DOR was 4.7 months (95% CI, 3.8-8.3).¹³

However, patients had to discontinue treatment due to disease progression (n = 64), followed by AEs (n= 19), patient decision (n = 10), investigator decision (n = 2), death (n = 1), or other reasons (n = 6). AEs leading to dose reduction included anemia (11.0%), nausea (11.0%), and fatigue (10.1%); AEs leading to dose interruption consisted of fatigue (13.8%) and asthenia (11.9%). Serious AEs occurred at a rate of 26.6% and 1 patient died due to AEs. During her presentation of the findings, Liu noted that adavosertib displayed a narrow therapeutic window.

The agent had also been investigated in the phase 2 EFFORT trial (NCT03579316) with or without the PARP inhibitor olaparib (Lynparza) in patients with PARP inhibitor–resistant ovarian cancer. Patients who received adavosertib monotherapy (n = 35) achieved an ORR of 23% (90% CI, 12%-38%), a DOR of 5.5 months (95% CI, 2.8-not estimable), and a median PFS of 5.5 months (90% CI, 3.9-6.9). In the combination arm, these figures were 29% (90% CI, 16%-44%), 6.4 months (2.8-14.6), and 6.8 months (90% CI, 4.3-8.3), respectively.¹⁴

In terms of safety, grade 3 or 4 AEs were reported in 51% of patients treated in the monotherapy arm and included neutropenia (13%), thrombocytopenia (10%), and diarrhea (8%); dose interruptions (72%) and reductions (51%) were also needed. Patients in the combination arm experienced grade 3 or 4 AEs at a rate of 76%, and required dose interruption or reduction at a rate of 88% and 71%, respectively. Investigators noted the toxicities on both arms were generally manageable with supportive care. In 2022 AstraZeneca discontinued the development of adavosertib due to an internal decision at the company,15 but EFFORT is still recruiting patients to an arm evaluating the ataxia telangiectasia and rad3 related kinase inhibitor ceralasertib in combination with olaparib and is estimated to be completed in December of this year.^14,16

“There was activity of adavosertib by itself as well as in the olaparib combination in this setting. This was a very heterogeneous mix of patients, but [these findings were] very intriguing in terms of the activity that was seen and whether there’s a [scenario] where resistance to PARP inhibition is increasing sensitivity to drugs like WEE1 inhibitors,” Liu said.

References

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3. Ghelli Luserna di Rorà A, Cerchione C, Martinelli G. A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target. J Hematol Oncol. 2020;13(1):126. doi:10.1186/s13045-020-00959-2
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8. Zentalis Pharmaceuticals reports third quarter 2023 financial results and operational updates. News release. Zentalis Pharmaceuticals. November 6, 2023. Accessed May 8, 2024. bit.ly/3TWI6iP
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12. Liu JF, Fu S, Richardson GE, et al. Correlation of cyclin E1 expression and clinical outcomes in a phase 1b dose-escalation study of azenosertib (ZN-c3), a WEE1 inhibitor, in combination with chemotherapy (CT) in patients (pts) with platinum-resistant or refractory (R/R) epithelial ovarian, peritoneal, or fallopian tube cancer (EOC). J Clin Oncol. 2023;41(suppl 16):5513. doi:10.1200/JCO.2023.41.16_suppl.5513
13. Liu JF, Colombo N, Oza A, et al. ADAGIO: a phase IIb, open-label, single-arm, multicenter study assessing the efficacy and safety of adavosertib (AZD1775) as treatment for recurrent or persistent uterine serous carcinoma. Presented at: 2023 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 25-28, 2023; Tampa, FL. Abstract 219.
14. Westin SN, Coleman RL, Fellman BM, et al. EFFORT: EFFicacy Of adavosertib in parp ResisTance: a randomized two-arm non-comparative phase II study of adavosertib with or without olaparib in women with PARP-resistant ovarian cancer. J Clin Oncol. 2021;39(suppl 15):5505. doi:10.1200/JCO.2021.39.15_suppl.5505
15. H1 2022 results. News release. AstraZeneca. July 29, 2022. Accessed May 8, 2024. bit.ly/4b1oiSB
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