Zentalis Pharmaceuticals (NASDAQ:ZNTL) executives outlined a strategy centered on advancing its WEE1 inhibitor azenosertib toward potential approval in platinum-resistant ovarian cancer (PROC), emphasizing a targeted approach in patients with high cyclin E1 protein expression. Speaking at a Guggenheim fireside chat, President and CEO Julie Eastland and Chief Medical Officer Ingmar Bruns said the company’s near-term priorities are to complete enrollment activities across key trials, select a registration dose, and deliver expected clinical updates over the next 12–18 months.
Strategy focused on azenosertib in cyclin E1-high PROC
Eastland said the leadership team brought a “very focused strategy” to the company: “to bring azenosertib to patients as quickly as possible.” The current focus is PROC patients whose tumors have high expression of cyclin E1, a biomarker the company believes identifies a subgroup likely to benefit.
Positioning versus ADCs: oral, non-chemotherapy option
Asked about increasing competition in PROC—particularly antibody-drug conjugates (ADCs)—Eastland argued the field will likely support multiple therapies. She said azenosertib is differentiated as an oral agent (versus infused ADCs) and a non-chemotherapy option that may provide patients a “chemo break.” She also emphasized the drug’s use in a biomarker-defined population (high cyclin E1 expression), which she said has shown benefit with azenosertib in prior work.
Tolerability discussion and dose selection in DENALI
The executives addressed historical concerns around tolerability for WEE1 inhibitors as a class. Eastland cited data presented in January 2025 from historical monotherapy studies using 300 mg and 400 mg once-daily dosing on a 5-days-on/2-days-off schedule, describing the tolerability profile as “very manageable.”
Bruns added that, compared with standard-of-care therapies and even ADCs, the company believes azenosertib has a favorable profile, citing “10% high-grade neutropenia” and mostly low-grade gastrointestinal and fatigue adverse events that he said are manageable with supportive care. He also described a “data-driven approach” in which the clinical organization reviews data daily and proactively contacts investigators to help manage emerging adverse events during the trial.
On trial progress, Eastland said DENALI Part 2A—up to 60 patients split between the two dose cohorts (30 each)—has been enrolled. The study has a seamless design: the company will continue enrolling both doses until it has enough follow-up to select the dose, then complete enrollment to approximately 100 patients at the selected dose in Part 2B. Eastland said Zentalis expects to announce the dose selection in the first half of the year.
Bruns said dose selection will be based on an overall risk-benefit profile, with an emphasis on overall response rate; he also noted a PK/PD model being built primarily for regulators. He said tolerability differences between 300 mg and 400 mg have not appeared “materially different,” although 400 mg has looked “a little bit more pronounced” historically.
Biomarker assay development and patient selection
Zentalis said it developed an immunohistochemistry (IHC) assay for cyclin E1 protein expression. Eastland said the cutoff used for prospective screening in DENALI Part 2 and ASPENOVA was derived from retrospective analyses across prior azenosertib studies, including archived tumor tissue from early trials and subsequent monotherapy cohorts. She said the cutoff was determined using data “across several hundred patients” and has been discussed with regulators. The company expects the ongoing trials to validate the assay for commercial companion diagnostic purposes.
Eastland said prior trials have shown roughly 50% of PROC patients meet the assay cutoff, and the company expects that rate to remain consistent, subject to what is observed in ongoing studies.
ASPENOVA confirmatory trial design and accelerated approval considerations
Bruns said ASPENOVA will use the same eligibility criteria as DENALI Part 2. He cited two reasons: leveraging the prior data set and aligning with the FDA’s preference that confirmatory trials enroll the same population as the accelerated approval study.
Executives also described an adaptive feature in ASPENOVA that can include a dose-confirmation component, resulting in a three-arm depiction. Bruns said this design was intended to allow an “immediate start” operationally without waiting for final dose confirmation from DENALI, and that the FDA confirmed the company could enroll only a small number of patients (or potentially none) in the adaptive portion, with DENALI providing most of the evidence for dose selection.
Eastland added the approach is intended to accelerate timelines, build a randomized control arm dataset specifically in cyclin E1-high PROC, and support requirements around accelerated approval, including enrolling the majority of the Phase 3 trial by the PDUFA date.
On efficacy expectations for accelerated approval, Bruns said the regulatory threshold has not changed in the company’s view, describing a target around “30% ORR” and “something between 5 and 6 months” duration of response. He noted the company has previously observed up to 35% overall response rate and a median duration of response of 6.3 months.
Looking beyond ovarian cancer, Eastland said the company is interested in combination approaches, including with cytotoxic agents and potentially ADCs, citing preclinical work suggesting combinations may be compelling in ovarian cancer and other tumor types.
The executives also briefly discussed the company’s TETON study in uterine serous carcinoma (USC). Eastland said the trial was fully enrolled as of the company’s Q3 update and data are planned this year, but she described USC as a smaller indication with a meaningfully changed landscape and not a top commercial priority. Bruns characterized the dataset as roughly 40 patients and said azenosertib appears active in the indication, while reiterating it is not a primary focus.
Finally, Eastland said the company’s longer-term strategy beyond azenosertib will be considered after key upcoming milestones, noting there is “nothing on the horizon” currently and that any additional program would need to fit company capabilities and investor interest, particularly given the capital requirements.
About Zentalis Pharmaceuticals (NASDAQ:ZNTL)
Zentalis Pharmaceuticals, Inc is a clinical-stage biopharmaceutical company focused on discovering and developing small molecule therapeutics for oncology. Leveraging a proprietary structure-based drug discovery platform, the company designs selective inhibitors aimed at critical cancer targets. Zentalis’ research and development efforts center on delivering differentiated therapies that address unmet medical needs in solid tumors and hematologic malignancies.
The company’s lead product candidate, ZN-c3, is an orally administered inhibitor of the p53-MDM2 interaction, currently being evaluated in Phase I clinical trials for advanced solid tumors and hematologic cancers.
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