Data from Identifying mechanisms of resistance by circulating tumour DNA in EVOLVE, a Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer at time of PARP Inhibitor Progression

• DOI: 10.1158/1078-0432.c.6779665.v3
• Publication Date: 2024-09-16T12:31:11Z
• Authors: Stephanie Lheureux; Stephenie D. Prok...; Leslie E. Oldfield; Eduardo Gonzalez-...; Jeff P. Bruce; Derek Wong; Arnavaz Danesh; Dax Torti; Jonathan Torchia; Alexander Fortuna; Sharanjit Singh; Matthew Irving; Kayla Marsh; Bernard Lam; Vanessa Speers; Aleksandra Yosifova; Ana Oaknin; Ainhoa Madariaga; Neesha C. Dhani; Valerie Bowering; Amit M. Oza; Trevor J. Pugh
• Keywords: Olaparib; PARP inhibitor

<div>Abstract<p>Purpose To evaluate the use of blood cell-free DNA (cfDNA) to identify emerging mechanisms resistance PARP inhibitors (PARPi) in high grade serous ovarian cancer (HGSOC). Patients and Methods We used targeted sequencing (TS) analyse 78 longitudinal cfDNA samples collected from 30 patients with HGSOC enrolled a phase II clinical trial evaluating cediranib (VEGF inhibitor) plus olaparib after progression on PARPi alone. was at baseline, before treatment cycle 2, end treatment. These were compared whole exome (WES) baseline tumour tissues. Results At (time initial progression), fractions 0.2-67% (median 3.25%) ctDNA levels (>15%) had higher burden (sum target lesions; p = 0.043). Across all timepoints, detected known WES 74.4% sensitivity, 3 5 expected BRCA1/2 reversion mutations. In addition, identified 10 novel mutations not by WES, including 7 TP53 annotated as pathogenic ClinVar. fragmentation analysis attributed these clonal hematopoiesis indeterminate potential (CHIP). significant differences mutant fragment size distribution shorter time (p 0.001). Conclusions Longitudinal testing TS provides non-invasive tool for detection tumour-derived that may aid directing appropriate therapeutic strategies. With analyses, CHIP several warrants further investigation.</p></div>