Adrian Kohut

PARP Inhibitors in Ovarian Cancer: Resistance Mechanisms, Clinical Evidence, and Evolving Strategies

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.

Evaluating the Role of Hyperthermic Intraperitoneal Chemotherapy in Cytoreductive Surgery for Advanced-Stage Ovarian Cancer

Hyperthermic intraperitoneal chemotherapy (HIPEC) is used to eliminate minimal residual disease in patients with peritoneal surface malignancies, including advanced epithelial ovarian cancer (EOC). While some trials suggest potential benefits, the role of HIPEC during cytoreductive surgery (CRS) in EOC remains uncertain. This study aimed to evaluate outcomes for patients undergoing HIPEC during CRS for advanced-stage EOC in the United States (US). This multicenter, retrospective cohort study included women with stage III-IV EOC who underwent CRS with or without HIPEC between 2006 and 2021 at Commission on Cancer-accredited US facilities. Propensity score matching was used to create a control group of patients who underwent CRS only. Overall survival (OS) was analyzed using the Kaplan-Meier log-rank method and adjusted for confounding factors with Cox proportional hazards regression. Among 1400 patients identified, 700 underwent CRS with HIPEC and 700 underwent CRS only. Of these 1400 patients, 932 underwent interval CRS and 468 underwent primary CRS. No significant difference in median OS was observed between the overall CRS+HIPEC and CRS-only groups (57.6 vs. 47.6 months; p = 0.105). However, interval CRS+HIPEC was associated with significantly improved median OS compared with interval CRS-only (57.6 vs. 45.7 months; p = 0.003). After adjustment, HIPEC remained significantly associated with improved survival (hazard ratio 0.77, 95% confidence interval 0.64-0.92; p = 0.004). HIPEC is associated with improved OS in patients undergoing interval CRS for advanced-stage EOC. Further research should explore the selective use of HIPEC during interval CRS.