Effectiveness and Safety of Niraparib as Neoadjuvant Therapy in Advanced Ovarian Cancer With Homologous Recombination Deficiency (NANT): Study Protocol for a Prospective, Multicenter, Exploratory, Phase 2, Single-Arm Study

Abstract

BackgroundOvarian cancer (OC) is a heterogeneous gynecological malignancy with a poor prognosis as the majority of patients are diagnosed at an advanced stage. Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is recommended for patients who cannot achieve optimal cytoreduction or cannot endure primary debulking surgery (PDS). As there is an increased risk of chemoresistance for platinum-based NACT, it is important to investigate an alternative option. A Poly (ADP-ribose) polymerase inhibitor (PARPi), niraparib, has shown high anti-tumor activity, especially in homologous recombination deficiency (HRD) positive patients with OC. Thus, niraparib as a neoadjuvant treatment agent may help improve surgery accessibility and create survival benefits.MethodsThis multicenter, prospective, single-arm, open-label, phase II study plans to recruit 53 patients (aged 18-75 years) with newly diagnosed HRD positive, unresectable (Fagotti score ≥ 8 or upper abdominal computed tomography [CT] score ≥ 3) International Federation of Gynecology and Obstetrics (FIGO) stage III-IV OC. The HRD status was detected by next-generation sequencing and HRD positive patients will be counseled for study participation. Enrolled patients will receive niraparib capsules QD (200mg or 300mg per day) for two cycles (4 weeks/cycle). After neoadjuvant niraparib treatment, patients exhibiting complete response (CR), partial response (PR), or stable disease (SD) will undergo tumor reduction surgery and subsequent standard carboplatin/paclitaxel-based chemotherapy. The primary objectives include the objective response rate (ORR) and R0 resection rate. The rate of treatment interruption/termination and progression-free survival (PFS) will be secondary objectives. The study uses Simon’s optimal two-stage design (24 and 21 patients for the first and second stage respectively). The data manager will record all adverse events (AEs).DiscussionThis is the first prospective study to evaluate the effectiveness and safety of niraparib in neoadjuvant treatment for advanced OC. The result of this study will provide a solid base for further expanding the clinical applications of the PAPRi and exploring more therapeutic possibilities for patients with HRD positive advanced OC. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT04507841.

Targeted therapy and immunotherapy: Diamonds in the rough in the treatment of epithelial ovarian cancer

“…Thrombocytopenia was the predominant TEAE, occurring in parallel with the decline in CA125. The above data provide preliminary evidence that niraparib single-agent neoadjuvant therapy is effective and has a good safety profile (Zhou et al, 2022). Expanding the trial sample size, increasing the number of patients included, and including a control group could make the findings of similar future studies more convincing.…”

“…The use of alternative platinum-based NACT regimens can help avoid platinum resistance without compromising the role of subsequent platinum-based agents in adjuvant therapy. NANT pioneered the exploration of niraparib monotherapy as an alternative to platinum as neoadjuvant therapy in patients with advanced non-R0 resectable BRCAm/HRD-positive OC (Zhou et al, 2022). According to the latest data presented at SGO 2022, CA125 decreased from week 2 of dosing, with a median lower baseline concentration of 88.5% (26.8%-99.3%) after two cycles (8 weeks in total) of treatment and an ORR of up to 75%.…”

MAD2L2, a key regulator in ovarian cancer and promoting tumor progression

“…PARP inhibitors showed a significant effect in OVCA treatment. However, a previous study indicated that the loss of MAD2L2 renders PARP inhibitors ineffective in BRCA1-deficient tumors, suggesting a new possible mechanism of MAD2L2 for the acquisition of resistance to PARP inhibitors in OVCA patients 7 , which makes the underlying mechanisms of MAD2L2 in OVCA worth to get a deep insight. Moreover, MAD2L2 was reported to be overexpressed in multiple cancers, such as glioma, breast cancer, and epithelial OVCA 8 , 9 .…”

CT-based radiomics nomogram analysis for assessing BRCA mutation status in patients with high-grade serous ovarian cancer

“…Decision-making on whether to perform NAC after confirming the BRCA gene status can bring more benefits. In addition, the preliminary results from an ongoing study showed that niraparib, a PARP inhibitor used as a neoadjuvant therapy, was an effective strategy for BRCA-mutant patients with advanced ovarian cancer (12). Therefore, preoperatively using targeted drugs may be an expected direction for the precise treatment of BRCA-mutant ovarian cancer in the future.…”