Choosing wisely: Selecting PARP inhibitor combinations to promote anti-tumor immune responses beyond BRCA mutations

PARP inhibitors have transformed the management of advanced high-grade serous ovarian cancer. Despite the overwhelming success of PARP inhibition, particularly in BRCA-mutated ovarian cancer, several limitations and unanswered questions remain. With PARP inhibitors now being used in earlier treatment settings, the issue of both de novo and acquired resistance mechanisms and appropriate post-PARP management are pressing concerns. In addition, the population appropriate to target with PARP inhibitors and their use in patients without BRCA mutations is controversial and evolving. In this review we will discuss exciting PARP combinations and biologic rationale for the development and selection of PARP inhibitor combinations. •PARP inhibitors (PARPi) have transformed the management of advanced ovarian cancer.•With increased PARPi use, the resistance to PARPi will become a increasing clinical concern.•Combinatorial approaches can overcome de novo and acquired resistance to PARPi by exploiting DDR mechanisms.•PARPi combinations can induce “BRCAness”, inhibit DNA repair, promote replication stress, or enhance immunomodulation.•Selection of the appropriate combination for the clinical context could overcome, or prevent, PARPi resistance.