Beyond HRD Status: Unraveling Genetic Variants Impacting PARP Inhibitor Sensitivity in Advanced Ovarian Cancer.

Abstract: The management of advanced epithelial ovarian cancer (AOC) has undergone significant advancements with the emergence of molecular diagnostics, particularly in predicting responses to PARP inhibitors (PARPi) based on homologous recombination deficiency (HRD) status. However, understanding sensitivity and resistance beyond HRD status remains elusive. This study aims to explore molecular factors that may elucidate why HRD status does not consistently predict PARPi sensitivity. Therefore, we conducted a post hoc translational analysis of formalin-fixed paraffin-embedded tumor samples from the ENGOT-ov24/NSGO-AVANOVA part 1 and 2 trial (NCT02354131), focusing on alterations pertaining radiologic response and progression-free survival (PFS). DNA sequencing was performed using the TruSight Oncology 500 HT gene panel, with variants classified according to recent guidelines. HRD status had been assessed by Myriad MyChoice CDx. We identified, among 92 patients in the ENGOT-ov24/NSGO-AVANOVA part 1 and 2 trial, 151 pathogenic or likely pathogenic variants across 81 samples. PARPi-sensitizing variants were found in two out of 10 HRD-negative samples from patients with clinical benefit (PFS ≥12 months), whereas three out of 10 HRD-positive samples from patients having no benefit (PFS ≤6 months) harbored variants associated with PARPi resistance. Additionally, analysis of BRCA1 variants revealed that truncating variants in exon 11 correlated with clinical benefit when niraparib was combined with bevacizumab. Conclusively, our findings highlight the complexity of PARPi response in AOC and underscore the importance of exploring somatic variants beyond HRD status. Further investigation into exon 11 variants of BRCA1 and the potential of combination treatment is warranted.

Significance: The irregular response to PARPi in HRD-positive and -negative tumors highlights the need for identifying additional biomarkers. This study explores the mutational landscape beyond HRD status in AOC, ultimately advancing precision oncology in future clinical practice.