A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models

Abstract

Niraparib is an orally bioavailable and selective poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of both BRCA mutant (mut) and BRCA wildtype (wt) adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers who have demonstrated a complete or partial response to platinum-based chemotherapy. In patients without germline BRCA mutations (non-gBRCAmut), niraparib improved progression-free survival (PFS) by 5.4 months, whereas another PARP inhibitor (PARPi) olaparib supplied only 1.9 months of improvement in a similar patient population. Previous studies revealed higher cell membrane permeability and volume of distribution (VD) as unique features of niraparib in comparison to other PARPi including olaparib. Here, we explore the potential correlation of these pharmacokinetic properties to preclinical antitumor effects in BRCAwt tumors. Our results show that at steady state, tumor exposure to niraparib is 3.3 times greater than plasma exposure in tumor xenograft mouse models. In comparison, the tumor exposure to olaparib is less than observed in plasma. In addition, niraparib crosses the blood-brain barrier and shows good sustainability in the brain, whereas sustained brain exposure to olaparib is not observed in the same models. Consistent with its favorable tumor and brain distribution, niraparib achieves more potent tumor growth inhibition than olaparib in BRCAwt models and an intracranial tumor model at maximum tolerated doses (MTD). These findings demonstrate favorable pharmacokinetic profiles and potent antitumor effects of niraparib in BRCAwt tumors, consistent with its broader clinical effect in patients with both BRCAmut and BRCAwt tumors.

Niraparib as maintenance therapy in a patient with ovarian cancer and brain metastases

“…The SOLO2, NOVA and ARIEL3 studies revealed that the PARP inhibitors are beneficial in terms of progression free survival (PFS) following second-line or subsequent chemotherapy, especially in patients with BRCA gene mutation (see table 1). 13–15 Preclinical tumour models have demonstrated that niraparib crosses the blood–brain barrier, which was not seen with olaparib 16…”

The Genomic Landscape of Prostate Cancer Brain Metastases

“…Moreover, HRD signatures have been reported to be enriched in breast cancer brain metastases compared with primary tumors 43 , and the occurrence of brain metastases is relatively frequent event in BRCA1/2 mutated cancers 44,45 . In a pancreatic xenograft model, niraparib has shown higher intracranial activity compared with olaparib 41 . Rucaparib 46 and talazoparib 47 seem to have a more restricted blood-brain barrier penetrance.…”

“…Testing for these alterations in advanced PCa is already being recommended by several guideline groups 36 . PARP inhibitors, such as olaparib 37,38 or niraparib 39,40 , have shown to be active on brain metastases in patients with homologous recombination deficient (HRD) breast cancer and in murine models of brain metastases 41,42 . Moreover, HRD signatures have been reported to be enriched in breast cancer brain metastases compared with primary tumors 43 , and the occurrence of brain metastases is relatively frequent event in BRCA1/2 mutated cancers 44,45 .…”

Rapid and temporary improvement of depression and anxiety observed following niraparib administration: a case report

“…Brain penetration and retention for many PARP inhibitors is poor and is a deterrent to treating brain cancers [22]. In contrast, niraparib crosses the blood brain barrier and accumulates in brain tissue [23]. Finally, niraparib likely contributed to the development of thrombocytopenia and neutropenia in this patient.…”