PARP Inhibitor Rechallenge Could be an Effective Strategy in Platinum-Sensitive Ovarian Cancer: A Retrospective Study

Background: The poly ADP-ribose polymerase inhibitors (PARPi) are widely used for treating ovarian cancer. However, there is a need for additional clinical evaluation to determine the mechanisms underlying resistance and the potential benefits of PARPi re-challenge. Therefore, this study evaluated the potential therapeutic advantages of PARPi as a maintenance therapy for women with ovarian cancer who have acquired resistance to front-line PARP inhibitors. Methods: The clinical data of 479 epithelial ovarian cancer (EOC) patients were retrospectively reviewed from the database of Chongqing University Cancer Hospital, China. A cohort of patients diagnosed with platinum-sensitive recurrent ovarian cancer (PSOC) who had previously received PARPi maintenance therapy underwent a comprehensive analysis and 39 patients were selected for subsequent exploration. Among them, 16 patients received PARPi as second-line maintenance therapy after chemotherapy (Group A) and 23 did not receive any maintenance therapy (Group B). Disease response and safety profiles were recorded. Tumor tissues from a patient exhibiting resistance to fluzoparib were collected for next generation sequencing (NGS) analysis using the BGISEQ-500 (BGI, Beijing Genomics Institute) platform provided by BGI Inc. in Shenzhen, China. Results: Out of the total patients, 37 (94.9%) had received pretreatment with a maximum of two prior lines of chemotherapy. Twelve patients underwent optimal debulking cytoreductive surgeries. The clinical characteristics of the two groups, including age, federation international of gynecology and obstetrics (FIGO) stage, breast cancer susceptibility (BRCA) gene mutation status, and the condition of first-line PARPi, were well-matched. There was a statistically significant difference in progression free survival (PFS) between the two regimens. The mean PFS was 20 months (95% confidence interval (CI): 14-not available (NA)) in group A and 8 months (95% CI: 5-14) in group B, indicating superior clinical benefits with the rechallenge regimen. A difference was observed in PFS concerning re-cytoreductive surgery (RCRS) when considering a one-sided p < 0.1 as significant (p = 0.077). The tolerability of adverse events was acceptable. Genomic profiling showed that one patient had amplified radiation sensitive 52 (RAD52), myelocytomatosis oncogene (MYC), and fibroblast growth factor 6 (FGF6) genes after PARPi, which might be associated with resistance to fluzoparib. Conclusion: The rechallenge of PARPi is effective in the treatment of patients with <= 2 lines of PSOC who have previously demonstrated resistance to a front-line PARP inhibitor. Additionally, optimal cytoreductive surgery performed before PARP inhibitor rechallenge may be associated with improved progression-free survival in these patients.