Early ctDNA Changes May Predict Benefit From Azenosertib in Recurrent Ovarian Cancer
By: Lisa Astor
Posted: Friday, November 6, 2026
Molecular response measured by circulating tumor DNA (ctDNA) within the first cycles of treatment tracked closely with clinical benefit in patients with recurrent high-grade serous ovarian cancer receiving the WEE1 inhibitor azenosertib, according to a retrospective analysis published in JCO Precision Oncology.
Molecular response captures early shifts in circulating biomarkers and has shown promise as a fast read on antitumor activity in lung and colorectal cancers. In high-grade serous ovarian cancer, evidence has come mainly from small studies using varied assays, leaving its performance unsettled. Because nearly all of these tumors carry TP53 mutations, the investigators used that gene as a tracking marker.
The study analyzed 123 patients with platinum-resistant recurrent disease enrolled across three open-label trials of single-agent azenosertib who received at least 300 mg daily on an intermittent 5-days-on, 2-days-off schedule. Plasma cell-free DNA was sequenced before treatment and again before cycle 2 or cycle 3. Molecular response was defined as a drop of more than 50% in the TP53 variant allele fraction at the first evaluable on-treatment draw. Those results were compared against imaging response by RECIST v1.1, time to progression, and CA-125 changes.
Patients with a molecular response had a higher objective response rate (odds ratio = 0.26, P = .012) and greater tumor shrinkage (P = 5.1e-5). Median time to progression was 5.49 months in molecular responders vs 2.69 months in nonresponders (hazard ratio [HR] = 0.43; P = 3.8e-5). The marker was also informative in the gray zone of stable disease: among patients whose first scan showed stable disease, molecular response identified those who went on to longer time to progression (HR = 0.44; P = 3.8e-3), and the molecular signal appeared several weeks ahead of the best overall response on imaging.
Compared with CA-125 at matched collection times, ctDNA was evaluable in more patients (88% vs 71%), while offering comparable prediction of time to progression (HR = 0.41 vs 0.45).
“Our findings support the validity and potential clinical utility of ctDNA-based [molecular response] as a minimally invasive, rapid, and reliable early surrogate endpoint in high-grade serous ovarian cancer,” concluded senior author Olivier Harismendy, PhD, of Zentalis Pharmaceuticals, San Diego, and colleagues.
Disclosure: The study was supported by Zentalis Pharmaceuticals, Inc. Several authors are employees of the company.
