OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded 
encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the 
optimal treatment setting remains unknown. We assessed the effect of niraparib 
on HGSOC patient-derived xenograft (PDX) models as well as the relationship 
between certain markers of homologous recombination (HR) status, including 
BRCA1/2 mutations and formation of RAD51 foci after DNA damage, and response of 
these PDXs to niraparib in vivo.
METHODS: Massively parallel sequencing was performed on HGSOCs to identify 
mutations contributing to HR deficiency. HR pathway integrity was assessed using 
fluorescence microscopy-based RAD51 focus formation assays. Effects of niraparib 
(MK-4827) on treatment-naïve PDX tumor growth as monotherapy, in combination 
with carboplatin/paclitaxel, and as maintenance therapy were assessed by 
transabdominal ultrasound. Niraparib responses were correlated with changes in 
levels of poly(ADP-ribose), PARP1, and repair proteins by western blotting.
RESULTS: Five PDX models were evaluated in vivo. Tumor regressions were induced 
by single-agent niraparib in one of two PDX models with deleterious BRCA2 
mutations and in a PDX with RAD51C promoter methylation. Diminished formation of 
RAD51 foci failed to predict response, but Artemis loss was associated with 
resistance. Niraparib generally failed to enhance responses to 
carboplatin/paclitaxel chemotherapy, but maintenance niraparib therapy delayed 
progression in a BRCA2-deficient PDX.
CONCLUSIONS: Mutations in HR genes are neither necessary nor sufficient to 
predict response to niraparib. Assessment of repair status through multiple 
complementary assays is needed to guide PARP inhibitor therapy, design future 
clinical trials and identify ovarian cancer patients most likely to benefit from 
PARP inhibition.