An In-Depth Review of Niraparib in Ovarian Cancer: Mechanism of Action, Clinical Efficacy and Future Directions

Abstract

Niraparib is an oral, potent, highly selective poly-ADP ribose polymerase 1 (PARP1) and PARP2 inhibitor. In most developed countries, it is approved as a maintenance treatment for epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients with complete or partial response to platinum-based therapy. These approvals are based on results of randomised, double-blind, placebo-controlled trials, particularly the NOVA trial and more recently the PRIMA trial. In this comprehensive review, we delve into the scientific basis of PARP inhibition, discussing both preclinical and clinical data which have led to the current approval status of niraparib. We also discuss ongoing trials and biological rationale of combination treatments involving niraparib, with particular focus on antiangiogenic drugs, immune checkpoint inhibitors and cyclic GMP-AMP synthase stimulator of interferon genes (cGAS/STING) pathway. In addition, we reflect on potential strategies and challenges of utilising current biomarkers for treatment selection of patients to ensure maximal benefit.

Keywords: Combined therapy; Niraparib; Ovarian Cancer; PARP inhibitors; Pharmacokinetics.

Fig. 1

Mechanism of action of PARP inhibitors. In the presence of base excision repair and homologous recombination deficiency, double-strand break accumulation occurs which eventually leads to cell death. BER base excision repair, HRD homologous recombination deficiency, SSB single-strand break, DSB double-strand break

Fig. 2

NOVA study design. CR complete response, PR partial response, PFS progression-free survival, RECIST Response Evaluation Criteria in Solid Tumours, gBRCAmut = germline BRCA mutation, non-gBRCAmut = No germline BRCA mutation

Fig. 3

PRIMA study design. CR complete response, PR partial response, PFS progression-free survival, RECIST Response Evaluation Criteria in Solid Tumours, OD once daily, Plt platelets

Fig. 4

QUADRA trial profile and overall response rates by HRD and platinum status. Platinum Res/Ref platinum chemotherapy-resistant or -refractory, PARPi PARP inhibitor

Fig. 5

Key dates for the FDA, EMA and NICE approvals for niraparib. FDA Food and Drug Administration, EMA European Medicines Agency, NICE National Institute for Health and Care Excellence

Fig. 6

Schematic depicting activation of cGAS/STING pathway by PARP inhibition, leading to downstream type 1 interferon production resulting in a direct immunosuppressive effect by the cancer cell, as well as increased natural killer (NK) cell and CD8 cytotoxic T cell activity causing direct anti-tumour killing. IFN interferon, TBK-1 tank-binding kinase 1, interferon regulatory factor 3, APC antigen-presenting cell