DENALI Study Seeks to Prove Efficacy of Azenosertib in High-Grade Serous Ovarian Cancer

High-grade serous ovarian cancer (HGSOC) is the most common and deadliest variation of ovarian cancer, constituting approximately 70% of all ovarian cancer cases and almost 80% of deaths.^1,2 As such, investigators are hoping to expand safe and effective treatment options for patients with HGSOC and are examining the investigational agent azenosertib (formerly ZN-c3) with the initiation of the phase 2 DENALI trial (NCT05128825).³

“Azenosertib is a WEE1 inhibitor; WEE1 is a checkpoint that allows progression of the cell cycle through its typical mitosis,” Shannon N. Westin, MD, MPH, FACOG, explained in an interview with OncologyLive. “It regulates the G2/M checkpoint, [which] is important in and of itself. If you block that, you allow a cell that’s damaged to continue to replicate, and the cell has cellular catastrophe and death, so that can work on its own. But it’s especially important in TP53-mutated tumors because TP53 regulates the G1/S checkpoint. If that is mutated, then you become dependent on that G2/M checkpoint where WEE1 sits. You’re already collecting damage, and you’re not fixing your damage and going through the cell cycle. If you knock out TP53 at baseline and then you take out WEE1 with a WEE1 inhibitor, the cell has no opportunities to repair its damage and it has complete cellular catastrophe and cell death. It’s a neat way to specifically target cancer cells.” Westin is director of early drug development and phase 1 trials and professor in the Department of Gynecologic Oncology and Reproductive Medicine in the Division of Surgery at The University of Texas MD Anderson Cancer Center in Houston.

Azenosertib Demonstrates Preliminary Efficacy in Gynecologic Malignancies

In November 2023, Zentalis Pharmaceuticals, the developer of azenosertib, announced updated findings from the phase 1 ZN-c3-001 study (NCT04158336) of azenosertib monotherapy in heavily pretreated patients with uterine serous carcinoma (n = 6) or HGSOC (n = 13). In the uterine serous carcinoma group, the median number of prior lines of therapy received was 3.5 (range, 1-6), which included prior treatment with a PARP inhibitor (16.7%), VEGF inhibitor (83.3%), and anti–PD-1/PD-L1 therapy (100%); 83.3% of patients had platinum-resistant disease. Patients with HGSOC received a median of 6 (range, 2-11) prior lines of therapy, including a PARP inhibitor (76.9%), experimental agents (38.5%), VEGF inhibitor (84.6%), and anti–PD-1/PD-L1 therapy (7.7%). The HGSOC group consisted of patients who had platinum-resistant (38.5%) and platinum-refractory disease (61.5%).^4,5

At the data cutoff of October 25, 2023, the objective response rate (ORR) across all treated patients (n = 19) was 36.8%. Four patients with HGSOC experienced a complete or partial response, and 2 patients were still in response at the data cutoff, with 1 patient with platinum-refractory disease. The remaining 9 patients experienced stable disease. In the uterine serous carcinoma group, 3 patients achieved responses, none of which were ongoing at the data cutoff. One patient in the uterine serous carcinoma group experienced progressive disease, and 2 patients experienced stable disease. Additionally, the median progression-free survival (PFS) in the overall population was 6.5 months (95% CI, 2.79-6.87).

In terms of safety, any-grade gastrointestinal treatment-related adverse effects (TRAEs) included diarrhea (47.8%), nausea (43.5%), vomiting (17.4%), dehydration (10.9%), and decreased appetite (8.7%); these TRAEs occurred at grade 3 or 4 severity at rates of 8.7%, 4.3%, 2.2%, 0%, and 2.2%, respectively. Any-grade and grade 3 or 4 fatigue was reported at rates of 39.1% and 10.9%, respectively. Furthermore, any-grade hematologic TRAEs consisted of anemia (23.9%), thrombocytopenia (19.6%), and neutropenia (19.6%); these TRAEs occurred at grade 3 or 4 severity at rates of 10.9%, 8.7%, and 15.2%, respectively.

“When we use azenosertib, we also use prophylactic antibiotics just like we would with chemotherapy to try to get out in front of the nausea and make sure that it’s tolerable for patients. Fatigue is always an issue with these different tyrosine kinase inhibitors, especially in patients who have had multiple lines of therapy. The fatigue is cumulative,” Westin commented.

Notably, no instances of febrile neutropenia or sepsis were reported. No patients discontinued treatment with azenosertib; 24% required dose reductions, and 35% had dose interruptions. Following the encouraging efficacy and tolerability data seen with azenosertib monotherapy in the phase 1 trial, the recommended phase 2 dose of azenosertib monotherapy was determined to be 400 mg daily on a weekly schedule of 5 days on, 2 days off.

Details of the DENALI Trial

DENALI is an open-label, multicenter study of azenosertib in patients with HGSOC as well as fallopian tube or primary peritoneal cancer. To be eligible for the trial, patients need to be 18 years or older, have measurable disease per RECIST v1.1 criteria, and have adequate hematologic and organ function. Regarding prior therapy, patients must have undergone treatment with 1 to 4 prior lines of therapy including bevacizumab (Avastin) and they must have platinum-resistant disease.³

“A TP53 mutation is almost pathognomonic in tumors that are high-grade serous—it’s a high proportion, [approximately] 98%,” Westin noted. “We’re selecting a patient population who likely has the biggest benefit from this type of inhibitor. Of course, it’s [also] a huge unmet need, because we need good drugs for patients with recurrent ovarian cancer.”

Patients who received major surgery within 28 days, any chemotherapy or targeted tumor therapy within 14 days or 5 half-lives, radiation therapy within 21 days, autologous or allogeneic stem cell transplant within 3 months, and/or any other investigational therapy less than 28 days or 5 half-lives prior to day 1 of cycle 1 are not eligible for enrollment in DENALI. Additionally, those who received prior therapy with azenosertib or another WEE1, ATR, or CHK1/2 inhibitor will be excluded from the trial.

The coprimary end points are safety by frequency and severity of treatment-emergent AEs, incidences of dose modification, and ORR per RECIST 1.1 criteria by independent central review. Secondary end points include PFS, ORR by investigator assessment, duration of response, clinical benefit rate, and time to response. The study is currently recruiting patients, with a target enrollment of approximately 90, and is estimated to be completed in October 2025.

“This study originally was driven mostly by the biomarker CCNE1, which, when amplified, seems to make tumors even more sensitive to WEE1 inhibition,” Westin said. “Now we are allowing any patient with platinum-resistant [HGSOC to enroll], but there are different cohorts based on biomarkers. We’ll have a cohort who has that CCNE1 amplification, so the highest chance of potentially benefiting from azenosertib, and then a group who does not have amplification but [has] protein-positive [results] on immunohistochemistry for cyclin E1. Finally, there will be a group who doesn’t have amplification [of CCNE1 and] doesn’t have protein expression of that cyclin E1. [We will be] looking at each of the groups and determining whether there’s differential activity. The primary end points are around the first 2 cohorts, but they’re still going to look at that third group. Certainly if there’s a signal there, that could expand the group of patients who are able to receive this drug.”

In February 2024, Zentalis announced that the final results of the ZN-c3-001 study of azenosertib monotherapy in solid tumors were expected in the second half of 2024 and top-line data from DENALI were expected in the first half of 2025. They also projected the first new drug application for azenosertib in a gynecologic malignancy would be submitted in 2026.⁶

“Azenosertib is a very intriguing agent, and there’s a collection now of trials that are exploring it,” Westin said in conclusion. “If the single agent is tolerable and effective, that would be ideal. But there are also combination strategies looking at this drug with PARP inhibitors and with chemotherapy. We’re trying to figure out the best place to use this. If there is activity in the platinum-resistant setting as a single agent, it may be reasonable to move it to earlier lines of therapy or even into maintenance strategies for patients who don’t have good options. We don’t know what direction things are going to go in, [but] we’re excited by what we’ve seen so far. Hopefully, over the next few years as these trials read out, we’ll have a better understanding of exactly where this agent fits.”

References

1. Kleinmanns K, Bjørge L. Enhancing precision oncology in high-grade serous carcinoma: the emerging role of antibody-based therapies. npj Womens Health. 2024;2:7. doi:10.1038/s44294-024-00010-6
2. Wang Y, Duval AJ, Adli M, Matei D. Biology-driven therapy advances in high-grade serous ovarian cancer. J Clin Invest. 2024;134(1):e174013. doi:10.1172/JCI174013
3. A study of ZN-c3 in subjects with high-grade serous ovarian, fallopian tube or primary peritoneal cancer. ClinicalTrials.gov. April 3, 2024. Accessed April 11, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05128825
4. Zentalis Pharmaceuticals reports third quarter 2023 financial results and operational updates. News release. Zentalis Pharmaceuticals. November 6, 2023. Accessed April 12, 2024. bit.ly/3TWI6iP
5. Corporate Presentation. Zentalis Pharmaceuticals. April 2024. Accessed April 12, 2024. bit.ly/4b5qRTg
6. Zentalis Pharmaceuticals reports full year 2023 financial results and operational updates. News release. Zentalis Pharmaceuticals. February 27, 2024. Accessed April 12, 2024. bit.ly/4cVI2bB.