Abstract B026: Detection and characterization of DDR reversion alterations in baseline tissue and plasma samples from patients enrolled in the TRESR and ATTACC Phase I clinical trials
Authors: Silverman Ian M. , Schonhoft Joseph D. , Jain Esha , Ulanet Danielle , Yang Julia , Kim Insil , Fei Kezhen , Lagow Errin , Yablonovitch Arielle , Cecchini Michael , Rosen Ezra , Lee Elizabeth , Lheureux Stephanie , Yap Timothy A. , Fontana Elisa , Koehler Maria , Rimkunas Victoria 
Published: January 2024

Abstract
Reversions in DNA damage repair (DDR) genes are an established mechanism of acquired resistance in patients (pts) treated with poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum-based therapies. Despite the clinical development of novel DDR targets in this population, baseline detection and characterization of reversions is not widely reported. We report our experience with baseline DDR reversions in the Phase I trials TRESR (NCT04497116) and ATTACC (NCT04972110), which evaluated safety and efficacy of the ataxia telangiectasia and Rad3-related inhibitor (ATRi) camonsertib as monotherapy or in combination with a PARPi or gemcitabine. Pts ≥18 years, ECOG PS 0-1, with advanced solid tumors and deleterious DDR alterations were enrolled, including 119 with homologous recombination deficiency (HRD)-related tumors (breast, ovarian, prostate, pancreas) previously treated with PARPi or platinum harboring revertible primary alterations (excluding complex alterations) in HRD-related genes previously known to revert (BRCA1, BRCA2, PALB2, RAD51C or RAD51D) as of June 2023. Reversions were identified through automated and manual curation of local genomics, central targeted sequencing (SyNthetic lethal Interactions for Precision Diagnostics [SNiPDx]), whole-genome sequencing and circulating tumor (ct)DNA analysis. Reversions were detected at baseline in 33% (39/119) of pts; including breast (38%; 11/29), ovarian (23%; 13/57), pancreatic (40%; 8/20) and prostate (54%; 7/13) cancers; and tumors with BRCA1 (24%; 14/59), BRCA2 (41%; 18/44), PALB2 (54%; 6/11) and RAD51C (25%; 1/4) primary alterations. Eighty-six unique reversions were detected in liquid (86%; n=74), tissue (12%; n=10) or both (2%; n=2). Most were deletions, including 1 nucleotide (nt; 12%; n=10), short (&gt;1nt & &lt;50nt, 29%; n=25), large (≥50 nt, 24%; n=21) and InDels (20%; n=17). Short insertions (3%; n=3) and single nucleotide variants (12%; n=10) were also detected. Mechanistically, most reversions had near-complete restoration of the coding sequence (69%; n=60); other larger-scale reversions affected whole exons by either deletion (10%; n=9) or splice-site disruption (21%; n=18). In addition, 2 pts with ovarian cancer enrolled with large deletions in BRCA1/2 later determined to be reversions of smaller, unreported primary alterations. Three pts had reversions in genes not previously reported to revert, 1 in NBN (pancreatic) and 2 in ATM (breast and colorectal). In pts treated with camonsertib and PARPi and uniformly profiled with Guardant Infinity (42/119), overall response was significantly higher in pts without (43%; 9/21) vs. with baseline reversions (10%; 2/21; p=0.03, Fisher’s exact test). These data highlight the genomic complexity and current diagnostic challenges to detect and characterize baseline reversion alterations in heavily pre-treated, DDR-selected patients. Interrogation of ctDNA or tumor biopsies with better diagnostic tools that include broad intron coverage and enhanced reversion calling will aid in interpretation of efficacy data for next-generation DDR agents.
Citation Format: Ian M. Silverman, Joseph D. Schonhoft, Esha Jain, Danielle Ulanet, Julia Yang, Insil Kim, Kezhen Fei, Errin Lagow, Arielle Yablonovitch, Michael Cecchini, Ezra Rosen, Elizabeth Lee, Stephanie Lheureux, Timothy A. Yap, Elisa Fontana, Maria Koehler, Victoria Rimkunas. Detection and characterization of DDR reversion alterations in baseline tissue and plasma samples from patients enrolled in the TRESR and ATTACC Phase I clinical trials [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B026.