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

Abstract

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. 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 <i>TP53</i> 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. Molecular responders showed a higher objective response rate (<i>P</i> = .012, odds ratio = 0.26), greater tumor shrinkage (<i>P</i> = 5.1e-5, Kruskal-Wallis), and a significantly longer TTP than nonresponders (TTP median 5.49 months <i>v</i> 2.69 months, <i>P</i> = 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 (<i>P</i> = 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 <i>v</i> 0.45, TTP evaluation). 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.