A randomized, open-label phase II non-inferiority study of niraparib maintenance after 3 versus 6 cycles of platinum-based chemotherapy in patients with completely debulked advanced HRD-positive high-grade ovarian cancer in first-line therapy (N-PLUS/NOGGO-ov53/ENGOT-ov62)

Abstract Background Standard therapy for advanced ovarian cancer consists of primary surgical debulking followed by 6 cycles of platinum-based chemotherapy and maintenance therapy with bevacizumab and/or poly-ADP ribose polymerase (PARP) inhibitors (PARPi). While homologous recombination deficiency (HRD)-positive patients derive meaningful benefit from PARPi maintenance; HRD-negative patients derive limited benefit, and the toxicity associated with 6 cycles of chemotherapy may negatively affect patients' quality of life, raising the question whether reducing chemotherapy cycles could decrease morbidity without compromising efficacy. Primary Objective To compare recurrence-free survival and overall survival in patients with International Federation of Gynecology and Obstetrics stage III to IV, HRD-positive ovarian cancer who achieve complete debulking, treated with either 3 or 6 cycles of platinum-based chemotherapy, both followed by maintenance therapy with the PARP inhibitor niraparib. Study Hypothesis We hypothesize that recurrence-free survival in patients receiving 3 cycles of chemotherapy followed by niraparib is non-inferior (defined as a hazard ratio [HR] ≤1.3) to 6 cycles of chemotherapy followed by niraparib, as assessed by a multi-variable Cox regression model. Trial Design This is a multicenter, randomized, open-label Phase II non-inferiority study. Participants will be randomized 1:1 to either 3 (Arm A) or 6 (Arm B) cycles of platinum-based chemotherapy, both followed by niraparib maintenance for 3 years, at a starting dose of 200 mg once daily or 300 mg once daily depending on patient factors (eg, body weight, platelet count), after complete surgical debulking. The study is currently open for recruitment in all participating countries in Europe, further details can be found under at Clinicaltrials.gov ID: NCT05460000. Major Inclusion/Exclusion Criteria Eligible patients include women with International Federation of Gynecology and Obstetrics stage III to IV high-grade ovarian cancer, confirmed HRD positivity (including pathogenic BRCA mutations) after centralized testing, and no residual disease following primary tumor debulking. The HRD test will be conducted centrally using the validated North-Eastern-German Society of Gynaecologic Oncology-Genomic Instability Score Assay. Primary Endpoint The primary endpoint is recurrence-free survival. Main Secondary Endpoints Overall survival, Quality of life, Toxicity, detailed list under "outcomes." Sample Size 640 patients. Estimated Dates for Completing Accrual and Presenting Results Accrual completion is expected in 2032, with results presentation anticipated in 2033. Trial Registration NCT05460000. Conclusions This trial aims to provide high-quality evidence on whether a reduced number of chemotherapy cycles in the era of niraparib maintenance for 3 years can safely maintain efficacy while minimizing treatment-related toxicity and improving patients' quality of life.