Efficacy, safety, and biomarkers of neoadjuvant niraparib monotherapy in homologous recombination deficiency (HRD) advanced ovarian cancer: A prospective, multicenter, phase II, single-arm NANT study.

5549 Background: The efficacy of PARP inhibitors as neoadjuvant therapy and its clear association with tumor microenvironment (TME) status remain enigmatic. Here, for the first time, we reported the efficacy and safety of niraparib monotherapy, an oral low-toxicity PARP inhibitor, as the neoadjuvant therapy in patients (pts) with HRD high-grade serous ovarian cancer (HGSOC), and directly linked pre-treatment TME components with response using cutting-edge technologies. Methods: Treatment-naïve pts with newly diagnosed advanced unresectable HGSOC and those who could not endure primary debulking surgery were enrolled to receive laparoscopic biopsies. TME landscape was profiled by single-cell RNA sequencing and multiplex immunohistochemistry. Pts with HRD ( BRCA1/2 mutations and/or genomic instability score ≥ 42) HGSOC received daily oral niraparib for two 28-day cycles. Pts with complete response, partial response (PR), or stable disease (SD) received interval debulking surgery (IDS). The co-primary endpoints were objective response rate (ORR) and R0 resection rate. Results: Between January 18, 2021 and July 18, 2023, 127 pts from six centers were screened for eligibility. Totally, 67 HRD pts received neoadjuvant niraparib monotherapy, 48 pts completed response evaluations, and 40 pts underwent IDS. Thirty pts achieved PR and 12 pts reached SD, resulting in an ORR of 62.5% and a disease control rate (DCR) of 87.5%. BRCAm pts exhibited improved responses with increased ORR (77.3%) and DCR (100.0%). For surgical outcomes, 80.0% of pts achieved R0 resection and 95.0% of pts accomplished optimal debulking. Treatment-related adverse events (TRAEs) of grade ≥3 were observed in 61.2% of pts and hematological toxicities were the most common. No fatal TRAEs were reported. Co-enrichment of MRC1 + macrophages, effector regulatory T cells, and myofibroblastic cancer-associated fibroblasts were associated with lack of response. Conclusions: Neoadjuvant niraparib monotherapy regimen achieved encouraging ORR and R0 resection rate with tolerable toxicities in pts with HRD unresectable HGSOC, offering an alternative option for those pts unwilling to receive or unable to tolerate neoadjuvant chemotherapy. Pre-treatment TME factors were correlated with clinical response to PARP inhibitors. Clinical trial information: NCT04507841 . Table: see text