Poly-ADP-ribose polymerase inhibitors (PARPis) are the most active and interesting therapies approved for the treatment of epithelial ovarian cancer. They have changed the clinical management of a disease characterized, in almost half of cases, by extreme genetic complexity and alteration of DNA damage repair pathways, particularly homologous recombination (HR) deficiency. In this review, we provide an updated overview of the available results of recent clinical trials on the three Food and Drug Administration and European Medicines Agency approved PARPis in ovarian cancer: olaparib, niraparib, and rucaparib. Furthermore, we anticipate the future perspective of combination regimens with antiangiogenic, immunocheckpoint inhibitors, and other biological agents as strategies to overcome resistance mechanisms, potentiate the therapeutic efficacy, and expand their clinical use in non-HR deficient tumors. Mechanism of action of PARPs and PARPs inhibitors PARPs are a family of 17 nucleoproteins characterized by a common catalytic site that transfers an ADP-ribose group on a specific acceptor protein using NAD + as cofactor. Interestingly, most PARP members are able to transfer only a mono-ADP ribose group to their target proteins, whereas PARP1, PARP2, PARP3, PARP5a, PARP5b characteristically add repeated ADP-ribose units, thus generating long poly(ADP-ribose) (PAR) chains [5]. This post-translational protein modification is named PARylation and allows PARPs involvement in different cellular activities. In this regard, PARP1 is the best characterized PARP. PARP1 modulates chromatine structure via PARylation of core histone proteins resulting in chromatine relaxation, thus enabling replication, repair, and transcription processes [6]. As to transcription, PARP1 plays a pivotal role in its regulation by both serving as a transcriptional cofactor and by hindering methylation of specific sequences, like those of housekeeping genes (Fig. 1a/b). To date, activation of PARP-1, dependent on CCCTC binding factor (CTCF), appears to affect DNA
