The PROOV Study: Exploiting the Synergistic Effect of PARP Inhibition With Cisplatin and Hyperthermia During Interval Cytoreductive Surgery and HIPEC in Ovarian Cancer

Peritoneal recurrence is common in patients with advanced epithelial ovarian cancer (EOC) despite cytoreductive surgery (CRS) and platinum-based chemotherapy. Novel therapeutic strategies have emerged, such as Hyperthermic Intra PEritoneal Chemotherapy (HIPEC) added to interval CRS and maintenance therapy with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors (PARPi). While these treatment strategies effectively delay recurrences, long-term survival for patients with advanced EOC remains poor. It has been demonstrated that PARP inhibition synergizes with platinum compounds, but concurrent treatment with systemically administered platinum is considered too (myelo-)toxic. On the other hand, hyperthermia induces a transient state of homologous recombination deficiency (HRD) that is required for a therapeutic effect of PARP inhibition. Hence, we hypothesize that administering HIPEC when PARP is inhibited could optimally exploit the synergistic effect of local cisplatin and hyperthermia at the peritoneal surface without adding systemic toxicity. The study population will consist of min. 40 to max. 55 patients with histologically proven FIGO stage III and operable stage IV high-grade serous ovarian cancer, peritoneal cancer, or fallopian tube carcinoma eligible for interval CRS with HIPEC, meaning that only patients with a response or stable disease after neo-adjuvant chemotherapy (NACT) will be eligible. The study participants enrolled in the PROOV will receive seven days of PARPi (olaparib, Lynparza®) twice a day. The dosage will be either 100mg, 150mg or 300mg, depending on the phase of the trial. The treatment with olaparib will start 7 days before the scheduled CRS, with the final dose administered in the morning prior to the surgery. Following achievement of optimal or complete interval CRS, HIPEC will be performed by administering cisplatin intraperitoneally (either 100 mg/m2 with a maximum of 220 mg, or 40 mg/L) and sodium thiosulphate intravenously. Blood samples and peritoneal tissue samples (before and after HIPEC) will be collected for the translational analyses. Whenever possible, tissue at recurrence will also be collected.