More Potent and Tolerable, Azenosertib Advances as the Leading WEE1 Inhibitor

Nearly a decade ago, I met a remarkable patient: Wesley Hall was living with gastric cancer, and across several interviews, he shared the ups and downs of taking part in 3 clinical trials over 4 years through Florida Cancer Specialists & Research Institute. In particular, he spoke about a targeted therapy called a WEE1 kinase inhibitor, which he said caused adverse effects intolerable that “I could set the clock by when the symptoms were going to start [and] when they were going to stop.”¹

Development of that drug, adavosertib, ended in 2022 after AstraZeneca found that too many patients shared Hall’s assessment.²

But the concept behind the therapy endures. So, this year, it was exciting to see a new generation of more selective, less toxic WEE1 inhibitors featured at the American Society of Clinical Oncology (ASCO) Annual Meeting. The one closest to reaching patients is azenosertib, from Zentalis Pharmaceuticals, which has shown encouraging clinical activity in a group of patients with unmet need.^3,4 

“We have been continuing our development and finding a therapeutic dose in a patient population that is incredibly underserved today, which is ovarian cancer, and in particular in patients who have platinum-resistant ovarian cancer [PROC], where they have very limited options,” said Zentalis CEO Julie Eastland, MBA, in an interview with The American Journal of Managed Care.®

Specifically, azenosertib is being evaluated in patients who are cyclin E1–positive, who account for 50% of patients with PROC; these patients have no approved treatments.^3,4

How Do WEE1 Inhibitors Work?

As Dillon et al explained in 2014, WEE1 is a tyrosine kinase that serves as a master regulator of the G1/S and G2/M cell cycle checkpoints. Normally, it halts cell division when DNA is damaged due to the loss of p53, giving cells time to repair. Cancer cells, which accumulate high levels of DNA damage and often lack intact repair machinery, are particularly dependent on this gatekeeper mechanism of WEE1.^5-7

Thus, inhibiting WEE1 eliminates this protection, forcing cancer cells to divide despite unresolved genomic damage and triggering what Eastland called “mitotic catastrophe,” or cellular collapse, as replication errors mount. Azenosertib has been shown to be highly selective for WEE1 over other kinases, limiting the risk of unintended off-target binding compared with adavosertib, making this new drug more potent and more tolerable.⁸

The PROC Opportunity and MUIR Results

As Eastland explained, PROC is one of oncology’s most persistent unmet needs. After surgery and platinum-based chemotherapy, most patients eventually develop resistance, at which point the standard of care reverts to single-agent chemotherapy. This is typically paclitaxel, with response rates around 30% and a median progression-free survival (PFS) of roughly 4 months.

The MUIR trial (NCT04516447) is a multipart phase 1b study evaluating azenosertib in combination with 4 chemotherapy drugs. Data presented at ASCO focused on the paclitaxel arm across 46 patients, all of whom had received prior paclitaxel. Across all 4 dose cohorts, the combination achieved an overall response rate (ORR) of 39.1%, a clinical benefit rate of 58.7%, and a median PFS of 7.3 months. The 250-mg intermittent dose (5 days on, 2 days off) emerged as the potentially optimal therapeutic dose, achieving a 50% ORR, including 1 complete response and a median duration of response of 9.2 months.^3,4

Responses were similar in cyclin E1–positive and cyclin E1–negative tumors, suggesting that in the combination setting, the activity may not depend on the biomarker that drives monotherapy benefit.^3,4 Eastland explained that this likely reflects the fact that paclitaxel itself induces replication stress; adding a WEE1 inhibitor then amplifies that effect regardless of baseline biomarker status.

On safety, the most common treatment-related adverse events (TRAEs) were fatigue (61%), anemia (59%), nausea (52%), and neutropenia (50%); grade 3 or higher events were led by neutropenia (30%) and anemia (20%).⁴ Serious TRAEs occurred in approximately 20% of patients. Eastland noted that gastrointestinal AEs, although common, are typically low-grade, manageable with standard antiemetics and antidiarrheals, and tend to ease after the first few cycles—a contrast from the tolerability problems that characterized the first wave of WEE1 inhibitors.

Registration Studies and Future Plans

Zentalis has sponsored 2 registration trials of azenosertib as monotherapy in cyclin E1–positive PROC. The phase 2 DENALI trial (NCT05128825) is designed to support accelerated approval; ASPENOVA (NCT07546500), a randomized phase 3 trial, is enrolling globally to support full approval. Azenosertib holds FDA fast track designation for this indication.²

Looking ahead, Eastland said Zentalis is also eyeing breast cancer, particularly triple-negative disease, which also has limited treatment options. Preclinical data presented at the American Association of Cancer Research in April 2026 showed near-complete tumor regression when azenosertib was combined with paclitaxel and an antibody-drug conjugate.⁹ Given paclitaxel’s broad footprint across tumor types, Eastland said, “as much as we want to get away from chemotherapy, if we’re going to use chemotherapy, let’s use it so…it’s more durable.”

References

1. Caffrey M. The clinical trial and the patient’s voice: “I’m extremely lucky to be alive.” Am J Manag Care. 2018;24(spec 2):SP53-SP54.
2. Taylor NP. AstraZeneca axes Moderna-partnered, phase 2 heart disease drug plus a Wee inhibitor. Fierce Biotech. July 29, 2022. Accessed June 24, 2026. https://www.fiercebiotech.com/biotech/astrazeneca-axes-moderna-partnered-phase-2-heart-disease-drug-amid-other-wee-pipeline
3. Zentalis Pharmaceuticals to present phase 1b MUIR trial data showing encouraging clinical activity and manageable safety profile of azenosertib plus paclitaxel in platinum-resistant ovarian cancer at ASCO 2026. News release. Zentalis. May 21, 2026. Accessed June 24, 2026. https://bit.ly/4ws37DJ
4. Okera M, Shannon CM, Richardson GE, et al. Azenosertib plus paclitaxel for platinum-resistant ovarian cancer: results from a phase 1b study. J Clin Oncol. 2026;44(suppl 16):5529. doi:10.1200/JCO.2026.44.16_suppl.5529
5. Dillon MT, Good JS, Harrington KJ, et al. Selective targeting of the G2/M cell cycle checkpoint to improve the therapeutic index of radiotherapy. Clin Oncol (R Coll Radiol). 2014;26(5):257-265. doi:10.1016/j.clon.2014.01.009
6. Jin T, Xu W, Chen R, et al. Discovery of potential WEE1 inhibitors via hybrid virtual screening. Front Pharmacol. 2023;14:1298245. doi:10.3389/fphar.2023.1298245
7. Hu J, Wang T, Xu J, et al. WEE1 inhibition induces glutamine addiction in T-cell acute lymphoblastic leukemia. 2021;106(7):1816-1827. doi:10.3324/haematol.2019.231126
8. Ma J, Liu W, Li J, et al. Azenosertib is a potent and selective WEE1 kinase inhibitor with broad antitumor activity across a range of solid tumors. Mol Cancer Ther. 2025;24(8):1171-1185. doi:10.1158/1535-7163.MCT-24-1194
9. Lee C, Levy A, Abed M, Chung H, Harismendy O, Kim D. WEE1 inhibition as a therapeutic strategy in triple-negative breast cancer: evaluating single agent and combination activity of azenosertib in preclinical models. Presented at: American Association for Cancer Research, April 20, 2026; San Diego, CA: Poster 2012.