Comprehensive baseline ctDNA characterization in two biomarker-selected Phase 1/2 studies using genomic and methylation profiling

The development of DNA damage response (DDR)-directed therapies is a major area of clinical investigation, yet to date Poly (ADP-ribose) polymerase (PARP) inhibitors remain the only approved therapy in this space. Major challenges to DDR-targeted therapies in the post-PARPi era are the context dependency of DDR alterations and the presence of pre-existing resistance in this heavily pre-treated population. To that end, we used a contemporary platform to analyze pre-treatment circulating tumor DNA (ctDNA) samples from 173 patients enrolled onto two Phase 1/2 trials harboring pathogenic variants (PVs) in DDR genes. Baseline ctDNA analysis revealed a wealth of insights, including circulating tumor fraction estimation, impact of clonal hematopoiesis, PV allelic status, homologous recombination deficiency (HRD) signatures and presence of pre-existing resistance. HRD reversions were detected in 44% of evaluable patients and included large genomic rearrangements leading to deletion of whole or partial exons. We also discovered reversion of ATM in two patients previously treated with platinum chemotherapy, which has not previously been described. This study showcases the genomic complexity of DDR-altered tumors, revealed through baseline ctDNA profiling, an understanding of which is crucial for the future clinical development of novel DDR-directed therapies and combinations.