According to the results of a retrospective analysis reported by Jeong et al in JCO Precision Oncology, early molecular response assessed using circulating tumor DNA (ctDNA) was associated with radiographic response and longer time to progression among patients with recurrent high-grade serous ovarian cancer treated with the investigational WEE1 inhibitor azenosertib. The findings suggest that changes in circulating TP53 variant allelic fraction during the first two treatment cycles may provide an early indicator of treatment efficacy.
Study Details
Investigators retrospectively analyzed patients with platinum-resistant recurrent high-grade serous ovarian cancer enrolled in three open-label studies of single-agent azenosertib. Patients received a pharmacologically active total daily dose of at least 300 mg on a 5-days-on, 2-days-off intermittent schedule. Radiographic tumor assessments were performed every 6 weeks according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Among 139 patients with successfully profiled longitudinal ctDNA , 123 (88.5%) had at least one pathogenic TP53 variant detectable at baseline and were evaluable for molecular response. Plasma cell-free DNA was assessed using next-generation sequencing at baseline and after the first and/or second treatment cycle. Molecular response was defined as a greater than 50% reduction in TP53 variant allelic fraction from baseline at the earliest evaluable on-treatment time point. Investigators compared molecular response with RECIST response, tumor-size changes, time to progression, and CA-125 dynamics.
Key Results
Of the 123 evaluable patients, 70 were classified as molecular responders and 53 as molecular nonresponders. The objective response rate was 29% among molecular responders vs 9% among nonresponders (P = .012). Progressive disease occurred in 13% vs 32%, respectively (P = .014). Molecular response was also significantly correlated with tumor-size change (P = 5.1 × 10–5); median tumor-size changes were –30.6%, –18.2%, –7.3%, and 5.7% among patients with molecular complete response, molecular partial response, molecular stable disease, and molecular progressive disease, respectively.
Molecular responders had a median time to progression of 5.49 months compared with 2.69 months for nonresponders (hazard ratio [HR] = 0.43, 95% confidence interval [CI] = 0.29–0.65; P = 3.8 × 10–5). Among 69 patients with stable disease at the first radiographic assessment, molecular responders also had longer median time to progression (6.14 vs 3.56 months; HR = 0.44, 95% CI = 0.25–0.78; P = .0038). Patients who achieved molecular complete response had a median time to progression of 6.47 months.
Molecular response also preceded subsequent RECIST outcomes. Among 24 molecular responders who initially had stable disease, 5 (21%) ultimately achieved a radiographic response; their molecular response occurred a median of 14 weeks before confirmation by RECIST. Conversely, among 28 molecular nonresponders with initial stable disease, 26 (93%) eventually experienced disease progression, with a lack of molecular response preceding progression by a median of approximately 8 weeks.
The investigators concluded: “Our findings support the validity and potential clinical utility of ctDNA-based [molecular response] as a minimally invasive, rapid, and reliable early surrogate end point in [high-grade serous ovarian cancer].”
Olivier Harismendy, PhD, of Department I of Zentalis Pharmaceuticals, Inc., San Diego, California, is the corresponding author for the JCO Precision Oncology article.
DISCLOSURE: The study was supported by Zentalis Pharmaceuticals, Inc. For full disclosures of the study authors, visit ascopubs.org.
