Article Text
Abstract
Introduction PARP inhibitors have been widely used as maintenance therapy in ovarian cancer management. However, their potential as neoadjuvant therapy remains unclear. Here, we report the activity and safety of neoadjuvant niraparib (NANT) monotherapy in homologous recombination deficiency (HRD)-positive high-grade serous ovarian cancer (HGSOC), and investigate cell clusters that associate with response to niraparib.
Methods Key eligibility: patients with newly diagnosed FIGO III/IV HRD-positive HGSOC and low likelihood of optimal cytoreduction or poor surgical candidates. Enrolled patients received daily oral niraparib (200 or 300 mg) for two 28-day cycles. The co-primary endpoints were objective response rate (ORR) and R0 resection rate. Cell clusters were profiled by scRNA-seq and mIHC.
Results Between January 18, 2021 and July 18, 2023, 67 patients received NANT monotherapy, 48 patients completed response evaluations, and 40 patients underwent interval debulking surgery. The ORR was 62.5% (30 PRs; table 1). The R0 resection rate was 80.0% (n=32). The GCIG CA125 response rate was 79.2% (n=38). The prevalence of CRS 3, 2, and 1 was 17.9%, 51.3%, and 30.8%, respectively. No new safety signal was observed. Grade ≥3 treatment-related adverse events occurred in 61.2% (n=41) of patients. Post-treatment eTreg cell proportion was positively correlated with CA125 concentrations and targeting eTreg cells using anti-CCR8 antibody (ZL-1218) potentiated niraparib in preclinical models (figure 1).
Conclusion/Implications NANT monotherapy achieved encouraging clinical activity and tolerable toxicities in HRD-positive HGSOC, offering an alternative option for patients unwilling to receive or unable to tolerate neoadjuvant chemotherapy (NANT study/NCT04507841). Niraparib plus anti-CCR8 antibodies is a promising combination strategy for HRD-positive HGSOC.