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

ObjectiveTo report our 15-year institutional experience of fertility-sparing treatment in young patients with early endometrial cancer (EC) treated by combined hysteroscopic resection and progestin therapy.MethodsTwenty-eight patients (stage IA, G1 and 2 endometrioid EC) wishing to preserve their fertility were enrolled into this prospective study. Hysteroscopic resection was used to resect the tumor, endometrium adjacent to the tumor and myometrium underlying the tumor. Adjuvant hormonal therapy consisted of oral megestrol acetate or levonorgestrel intrauterine device for 6 months or more.ResultsAfter 3 months from the progestin start date, 25 patients (89.3%) showed a complete regression (median time to complete regression, 3 months [range, 3-9 months]), two (7.1%) showed persistent disease, while one patient (3.6%) presented with progressive disease and underwent definitive surgery (stage IA, G3 endometrioid). At 6 months, one of the two patients with persistent disease underwent definitive surgery (stage IA, G1 endometrioid), while the other one was successfully re-treated. Two recurrences were observed (7.7%) both involving the endometrium and synchronous ovarian cancer. The median duration of complete response was 94.5 months (range, 8-175 months). More than half of the responders (57.7%) attempted to conceive with 93.3% and 86.6% pregnancy and live birth rates, respectively.ConclusionThe addition of a standardized three-step resectoscopy to progestin would seem to improve the efficacy of progestin alone. High pregnancy and live birth rates were observed in women attempting to conceive.

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Olaparib as maintenance therapy in patients with BRCA 1-2 mutated recurrent platinum sensitive ovarian cancer. A real world experience from the MITO group.