BACKGROUND: Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and 
transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 
and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour 
models with loss of BRCA and PTEN function. We investigated the safety, 
tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic 
profiles, and preliminary antitumour activity of niraparib.
METHODS: In a phase 1 dose-escalation study, we enrolled patients with advanced 
solid tumours at one site in the UK and two sites in the USA. Eligible patients 
were aged at least 18 years; had a life expectancy of at least 12 weeks; had an 
Eastern Cooperative Oncology Group performance status of 2 or less; had 
assessable disease; were not suitable to receive any established treatments; had 
adequate organ function; and had discontinued any previous anticancer treatments 
at least 4 weeks previously. In part A, cohorts of three to six patients, 
enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten 
escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum 
tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 
patients to confirm tolerability. In part B, we further investigated the maximum 
tolerated dose in patients with sporadic platinum-resistant high-grade serous 
ovarian cancer and sporadic prostate cancer. We obtained blood, circulating 
tumour cells, and optional paired tumour biopsies for pharmacokinetic and 
pharmacodynamic assessments. Toxic effects were assessed by common toxicity 
criteria and tumour responses ascribed by Response Evaluation Criteria in Solid 
Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate 
patients were analysed for exploratory putative predictive biomarkers, such as 
loss of PTEN expression and ETS rearrangements. This trial is registered with 
ClinicalTrials.gov, NCT00749502.
FINDINGS: Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 
in part A and 40 in part B. 300 mg/day was established as the maximum tolerated 
dose. Dose-limiting toxic effects reported in the first cycle were grade 3 
fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 
mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common 
treatment-related toxic effects were anaemia (48 patients [48%]), nausea (42 
[42%]), fatigue (42 [42%]), thrombocytopenia (35 [35%]), anorexia (26 [26%]), 
neutropenia (24 [24%]), constipation (23 [23%]), and vomiting (20 [20%]), and 
were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the 
mean terminal elimination half-life was 36·4 h (range 32·8-46·0). 
Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater 
than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. 
Eight (40% [95% CI 19-64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian 
cancer had RECIST partial responses, as did two (50% [7-93]) of four mutation 
carriers with breast cancer. Antitumour activity was also reported in sporadic 
high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate 
cancer. We recorded no correlation between loss of PTEN expression or ETS 
rearrangements and measures of antitumour activity in patients with prostate 
cancer.
INTERPRETATION: A recommended phase 2 dose of 300 mg/day niraparib is well 
tolerated. Niraparib should be further assessed in inherited and sporadic 
cancers with homologous recombination DNA repair defects and to target 
PARP-mediated transcription in cancer.
FUNDING: Merck Sharp and Dohme.