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.

Inclusion criteria

• In order to be eligible to participate in this study, a subject must meet all of the following criteria:

• Signed and written informed consent
• At least 18 years of age and able to understand patients' information
• FIGO stage III primary high-grade serous ovarian, fallopian tube, or extra-ovarian cancer.
• FIGO stage IV is allowed in the following situations:

• Resectable stage IV desease, such as local bowel involvement, iatrogenic abdominal wall metastases or umbilical lesions
• Stage IV based on cardiophrenic lymph nodes <1cm
• The diagnosis should be confirmed with either histology or cytology. If the diagnosis of ovarian carcinoma is based on cytology only, immunohistochemistry, including keratin 7, keratin 20, p53, PAX8 should be considered for confirmation of the diagnosis (at the discretion of the pathologist)
• Eligible and planned for interval cytoreductive surgery with HIPEC

• Neo-adjuvant chemotherapy consists of at least 3 courses of carboplatin/paclitaxel
• Patients should have response or stable disease after NACT; no progression should occur
• Operability has been evaluated in a multidisciplinary team (MDT) meeting via CT scan, MRI or diagnostic laparoscopy and an optimal or complete interval CRS is deemed feasible
• Fit for major surgery, WHO performance status 0-2
• Adequate bone marrow function (hemoglobin level >5.5 mmol/L, leukocytes >3 x10^9/L, platelets > 100 x10^9/L)
• Adequate hepatic function (ALT, AST, and bilirubin < 2.5 times the upper limit of normal)
• Adequate renal function (creatinine clearance ≥ 60 ml/min using Cockcroft-Gault formula or 24-hour measurement or ml/min/1,73 m2 using MDRD or CKD-EPI)

Exclusion criteria

• A potential subject who meets any of the following criteria will be excluded from participation in this study:

• History of previous malignancy treated with chemotherapy
• Opting for fertility-sparing surgery
• Concurrent use of potent inducers or inhibitors of CYP3A4 as assessed with the KNMP "G-standaard" that cannot be stopped temporarily