Post-treatment ctDNA monitoring using a tumor-informed whole-genome sequencing-based assay in homologous recombination–proficient ovarian cancer.

5592 Background: Ovarian cancer (OC) has high mortality due to advanced stage at diagnosis and frequent, incurable recurrences. Homologous recombination–proficient (HRP) disease comprises approximately half of high-grade serous OC and is associated with limited benefit from platinum chemotherapy and PARP inhibitors, leading to poorer outcomes. Circulating tumor DNA (ctDNA) is a validated biomarker for molecular residual disease and early relapse; this study evaluates it’s ability to stratify HRP patients (pts) into clinically meaningful risk groups. Methods: We performed a retrospective analysis of clinically annotated residual samples from commercial ctDNA testing in pts diagnosed with OC. Signatera Genome assays (Natera, Inc.) were designed from the respective pts’ matched tumor and normal whole genome sequencing (WGS) data to detect and quantify ctDNA in serially collected post-operative plasma. Adjuvant chemotherapy (ACT) decisions and cadence of testing were at the provider’s discretion. HR status was determined using available clinical records and/or genomic data. Descriptive statistics were used to compare association of ctDNA across stages and at various timepoints post-surgery. Correlation between ctDNA status and progression-free survival (PFS) was assessed using Cox regression analysis. Results: Study cohort comprised 164 Stage I-IV OC pts, with 1,256 plasma samples for ctDNA testing (median: 7 tests/ pt, range 1–24). The median age at diagnosis was 66 (range 19–89) years. A total of 157 cases were HRP; among these, clinical outcome data was available for 44 pts with corresponding ctDNA timepoints for analysis. ctDNA-positivity within two weeks post-debulking surgery (before starting ACT) was associated with significantly worse PFS compared to ctDNA-negativity (N=20; HR: 14.01, 95%CI: 0.6–308.16; p=0.01). Furthermore, ctDNA-positivity post-ACT was also associated with worse PFS (N=26; HR: 6.6, 95%CI: 1.7–25.3; p=0.002) compared to ctDNA-negativity. Among ctDNA-positive pts, 50% (5/10) had progression <6 months post-ACT, whereas no events were observed <12 months post-ACT in ctDNA-negative pts (N=12). Clinical follow-up and additional analyses are ongoing. Conclusions: Tumor-informed ctDNA monitoring identifies pts with HRP OC who are at high risk for recurrence post-surgery including treatment refractory/resistant cases. Post-operative and post-adjuvant ctDNA positivity was strongly associated with inferior PFS. These findings support the use of ctDNA as a clinically important biomarker to inform post-surgical/treatment risk stratification, and consideration of alternative or escalated therapeutic strategies in this high-risk population. These results showcase the utility of ctDNA to further risk stratify HRP OC pts, which supports it’s integration into prospective clinical trials and clinical care.