Molecular Response Assessment From Circulating Tumor DNA in Patients With Ovarian Cancer Treated With the WEE1 Inhibitor Azenosertib.

PURPOSE: Molecular response (MR) based on circulating tumor DNA (ctDNA) is emerging as a promising early biomarker of treatment efficacy in solid tumors; however, its clinical utility in high-grade serous ovarian cancer (HGSOC) remains to be established. This study evaluates the potential predictive value of ctDNA-based MR in with patients HGSOC treated with the WEE1 inhibitor azenosertib. METHODS: Plasma cell-free DNA was collected at baseline and after the first and/or second cycle of treatment from 123 patients with recurrent HGSOC enrolled in clinical trials of azenosertib (N = 123). Using the set samples evaluable by high throughput DNA sequencing, MR was defined as a reduction of TP53 variant allelic fraction >50% at the earliest evaluable on-treatment time point. MR was compared with radiographic response per Response Evaluation Criteria in Solid Tumors v1.1, time to progression (TTP), and CA-125 dynamics. RESULTS: Molecular responders showed a higher objective response rate (P = .012, odds ratio = 0.26), greater tumor shrinkage (P = 5.1e-5, Kruskal-Wallis), and a significantly longer TTP than nonresponders (TTP median 5.49 months v 2.69 months, P = 3.8e-5, hazard ratios [HR] = 0.43). MR was able to identify patients with prolonged survival among those having stable disease at the first radiographic assessment (P = 3.8e-3, HR = 0.44), and their MR preceded the best overall response by several weeks. Accounting for matching collection time points, MR was evaluable in more patients than CA-125, 88% (102 of 116) versus 71% (85 of 116), respectively, leading to similar predictive value (HR = 0.41 v 0.45, TTP evaluation). CONCLUSION: Our findings support the validity and potential clinical utility of ctDNA-based MR as a minimally invasive, rapid, and reliable early surrogate end point in HGSOC.