Azenosertib may be effective at treating cyclin E1+ PROC: Study
About a third of women responded to experimental therapy
About a third of women with cyclin E1+ platinum-resistant ovarian cancer (PROC) responded to treatment with azenosertib, an experimental therapy by Zentalis.
That’s according to data from the first part of the Phase 2 DENALI trial (NCT05128825), which is assessing the therapy’s safety and efficacy as a single treatment in women with PROC.
Zentalis is expected to start the second part of the trial, which will enroll about 130 women with cyclin E1+ PROC, in the first half of this year, with top-line data anticipated at the end of 2026. If successful, the trial may support a request for accelerated approval to the U.S. Food and Drug Administration.
“We are excited to outline a clear path for Zentalis to bring azenosertib to patients with Cyclin E1+ PROC,” Ingmar Bruns, MD, Zentalis’ chief medical officer, said in a press release. “In a patient population with a clear unmet medical need, the monotherapy data showed a meaningful and consistent improvement in responses as compared to historical data from current monotherapy chemo standard of care.”
Ovarian cancer develops within the ovaries, the female reproductive organs. The most common type is epithelial ovarian cancer, which impacts the cells lining the ovaries’ outer surface, high-grade serous carcinoma being the most prevalent form.
In 20% of patients with this cancer type, there is an over-expression of cyclin E1, a protein involved in regulating cell growth. Elevated cyclin E1 levels are frequently associated with resistance to platinum-based chemotherapy, which often complicates the treatment process.
“[A]pproximately 50% of patients with PROC are Cyclin E1+, and we believe that the therapeutic and commercial opportunity in this population, which tends to be especially treatment-refractory, is substantial,” Zentalis CEO Julie Eastland said.
Testing azenosertib in DENALI
Azenosertib is an oral small molecule that selectively targets WEE1, a protein involved in cell cycle regulation. By inhibiting WEE1, azenosertib promotes cell cycle progression even in the presence of significant DNA damage, leading to accumulation of DNA damage and eventual cancer cell death.
DENALI is a two-part trial testing azenosertib in patients with PROC as well as fallopian tube and primary peritoneal cancer. In Part 1b of the trial, 102 patients, half of whom were cyclin E1 positive and previously treated with up to five lines of treatment, received a 400 mg daily dose on a five days on, two days off weekly administration schedule.
As of the Dec. 2, 2024, data cutoff, about 35% of the 43 PROC patients with high cyclin E1 levels, who had at least one scan after receiving azenosertib, showed a response to therapy, defined as the time without disease progression. The median duration of treatment response was about 5.5 months.
“In addition, with over 350 patients treated at clinically active monotherapy doses … across our studies, we have observed a well-characterized safety profile and no new safety signals since our last report,” Bruns said.
The most reported treatment-related adverse events with azenosertib as a single therapy included gastrointestinal issues (decreased appetite, diarrhea, nausea, and vomiting), low levels of certain blood cells, and fatigue.
The second part of the trial consists of two separate stages. Part 2a will determine the optimal dosage for further investigation. In this stage, 60 patients will be randomly assigned to either 300 mg or 400 mg once daily. In Part 2b, about 70 patients will be treated with the dose selected in the previous stage. Dose selection and trial endpoints will be subjected to FDA feedback.
A Phase 3 confirmatory study in the same patient population will be conducted to compare the treatment’s efficacy to standard of care, pending FDA feedback.
“We are very pleased with the azenosertib results obtained to date and believe we have a clear path to advancing this product candidate to patients,” Eastland said.
The company is also conducting additional trials of azenosertib in patients with solid tumors, colorectal cancer, and other types of ovarian cancer.
