The introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) into the management of ovarian cancer has transformed the treatment landscape for patients affected by this malignancy. However, as the use of PARPi expands into both frontline maintenance and recurrence settings, the emergence of drug resistance has become a significant clinical challenge in the treatment of these patients. Although platinum-based chemotherapy (PBC) and PARPi act through different mechanisms—PBC causes DNA damage while PARPi blocks its repair—both depend on the integrity of DNA damage repair (DDR) pathways, leading to overlapping mechanisms of resistance. Here, we review the key resistance mechanisms shared by PARPi and PBC, and then we discuss their clinical implications in the management of patients with ovarian cancer. We also examine clinical rationale supporting the hypothesis that prior PARPi exposure may reduce the efficacy of subsequent PBC in patients experiencing a disease recurrence. Furthermore, we review preliminary clinical data assessing the potential role of PARPi retreatment in patients who have previously progressed on PARPis.

Current immunotherapies have proven effective in strengthening antitumor immune responses, but constant opposing signals from tumor cells and the surrounding microenvironment eventually lead to immune escape. We hypothesized that in situ release of antigens and regulation of both the innate and adaptive arms of the immune system would provide a robust and long-term antitumor effect by creating immunologic memory against tumors. To achieve this, we developed CARG-2020, a genetically modified virus-like vesicle (VLV) that is a self-amplifying RNA with oncolytic capacity and encodes immune regulatory genes. CARG-2020 carries three immune modulators: (i) the pleiotropic antitumor cytokine IL12, in which the subunits (p35 and p40) are tethered together; (ii) the extracellular domain (ECD) of the protumor IL17RA, which serves as a dominant-negative antagonist; and (iii) a shRNA targeting PD-L1. Using a mouse model of ovarian cancer, we demonstrated the oncolytic effect and immune-modulatory capacities of CARG-2020. By enhancing IL12 and blocking IL17 and PD-L1, CARG-2020 successfully reactivated immune surveillance by promoting M1, instead of M2, macrophage differentiation, inhibiting MDSC expansion and establishing a potent CD8+ T cell–mediated antitumoral response. Furthermore, we demonstrated that this therapeutic approach provided tumor-specific and long-term protection against the establishment of new tumors. Our results provide a rationale for the further development of this platform as a therapeutic modality for ovarian cancer patients to enhance antitumor responses and prevent a recurrence.

We read with interest the recent publication by Guo et al