Abstract 3254: Cell-free DNA molecular response predicts clinical efficacy in HGSOC patients treated with azenosertib

Abstract Background: Azenosertib is a novel selective WEE1 inhibitor showing promising activity in the treatment of gynecologic tumors, including high-grade serous ovarian cancer (HGSOC). The clinical development of azenosertib in HGSOC is conducted via several efficacy studies using Objective Response Rate (ORR) and progression free survival (PFS) as primary and secondary endpoints. Molecular response (MR), as measured by longitudinal changes of tumor DNA fraction in cell free DNA (cfDNA), can represent a cost-effective, and early efficacy endpoint, which needs further evaluation in HGSOC clinical studies. Method: Patients (N=139) enrolled in single-agent azenosertib studies (NCT04158336, NCT05128825, NCT05198804) were included in the analysis when 1) assigned to receive at least 300mg QD of azenosertib and 2) plasma cfDNA successfully profiled (Tempus xF+ Liquid Biopsy Assay) at baseline (C1D1) and at least one on-treatment timepoint (C2D1 or C3D1). Efficacy was extracted from an unlocked clinical database. MR positivity was defined as a decrease of TP53 variant allelic fraction greater than 50% between baseline and the earliest evaluable sample. Results: Most patients (123/139 88.5%) had detectable baseline TP53 mutations and were evaluable for MR of which 70/123 (57%) were MR+ including 28 with complete MR (mCR: 100% decrease). MR+ patients had a higher ORR (20/70 29% vs 4/53 8%, p=5.1e-3, Odds ratio=0.20). Stages of molecular response correlated with best tumor size change (Kruskal-Wallis p<2e-4) including 31% median tumor shrinkage in mCR patients. Consistently, MR predicted time to progression (TTP median 5.12 mo vs 2.69 mo, p=2.8e-4, HR=0.46) and a longer TTP was observed in mCR patients (median 5.68 mo). Remarkably, MR helped further stratify patients with stable disease at first assessment (SD1A patients), with MR+ patients showing a longer TTP (6.08 mo vs 3.42 mo, p=0.012, HR=0.45). In particular, 5/6 SD1A patients who eventually responded had positive MR identified at least 12 weeks (median 14w) prior to confirmation, while 24/39 SD1A patients who progressed had negative MR identified at least 2 weeks (median 7w) prior to progression. Of the 65 patients profiled at both C2D1 and C3D1, 38/65 (58%) had confirmed MR at C3D1. These confirmed MR were more likely to respond to the therapy (16/38 42% vs 4/27 15%, Odds ratio=0.24) and had a longer TTP (5.58 mo vs 3.25 mo, p=0.044, HR=0.52). Interestingly, confirmed MR patients were not more likely to have mCR at C2D1 (16/38 in confirmed vs 3/7 in unconfirmed MR) suggesting that the depth and duration of MR provide independent prognostic values. Conclusion: Molecular response by cfDNA is an early and reliable surrogate endpoint to measure clinical efficacy in HGSOC studies. Molecular response, duration, and depth were predictive of response or stable disease from azenosertib treatment, supporting its further clinical development. Citation Format: Jinkil Jeong, Jianhui Ma, Mona Abed, Heekyung Chung, Doris Kim, Nandini Molden, Divya Rajendran, Chang Shim, Danielle D. Jandial, Mark R. Lackner, Fiona Simpkins, Funda Meric-Bernstam, Leslie M. Randall, Olivier Harismendy. Cell-free DNA molecular response predicts clinical efficacy in HGSOC patients treated with azenosertib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3254.