BackgroundNiraparib is a selective oral poly(ADP-ribose) polymerase 1/2 inhibitor (PARPi) approved as maintenance treatment of recurrent ovarian cancer. Previous studies revealed unique pharmacological properties of niraparib, including a large volume of distribution, suggesting higher tissue penetration of this drug. Preclinical studies have consistently demonstrated that niraparib tumor exposure is higher than plasma exposure, whereas another PARPi, olaparib, has demonstrated lower tumor exposure than plasma exposure in tumor xenograft models. In a clinical study, tumor concentrations of olaparib were on average 41% of plasma concentrations in patients with breast cancer (BC)1. Here we report for the first time the intra-tumoral concentration of niraparib in clinical samples. MethodsTumor biopsies and plasma samples were collected from patients enrolled in a pilot study (NCT03329937) evaluating the antitumor activity and safety of niraparib as neoadjuvant treatment for HER2-negative, BRCA-mutated localized BC. Patients (N=9) received oral niraparib 200mg once daily over two 28-day cycles; 2 patients in the analysis had dose reduction to 100mg. Biopsies and plasma were obtained at the end of Cycle 2. Additional plasma samples were collected on Cycle 2/Day 1 at 0, 2, and 4hours post dose to determine steady-state maximum concentration (Cmax). Niraparib concentrations in plasma and tumor samples for each patient were quantified using a qualified liquid chromatography–tandem mass spectrometry method. ResultsNiraparib concentrations in plasma from patients with BC (N=5) were within the reference range previously reported for solid tumors (steady state Cmax 3160+/-2799nM, Ctrough 1753+/-1707nM). In the same cohort of BC patients, niraparib concentrations in tumors ranged from approximately 4–131-fold higher than those in corresponding plasma samples after 2 months of niraparib treatment. Data for all patients will be presented at the meeting. ConclusionsThese results provide the first clinical data of at least 4-fold higher intra-tumor concentration of niraparib compared with plasma concentration in patients with BC. Reference: Bundred N et al. Invest New Drugs 2013; 31: 949-58. Clinical trial identificationNCT03329937. Legal entity responsible for the studyTesaro: A Gsk Company. FundingTesaro: A Gsk Company. DisclosureM. Shan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Tesaro: A GSK Company. E. Hamilton: Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Genzyme; Travel / Accommodation / Expenses: Helsinn Therapeutics; Travel / Accommodation / Expenses: HERON; Travel / Accommodation / Expenses: Lexicon; Travel / Accommodation / Expenses: Medivation; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Sysmex; Travel / Accommodation / Expenses: Guardant Health; Travel / Accommodation / Expenses: Foundation Medicine. C. Santa-Maria: Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Medimmune. S. Isakoff: Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: PharmaMar; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck; Research grant / Funding (institution): OncoPep; Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar. D.B. Page: Honoraria (self): Novartis; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Syndax; Advisory / Consultancy: Nektar; Research grant / Funding (self): NanoString Technologies; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Puma Biotechnology; Speaker Bureau / Expert testimony: Genentech/Roche; Research grant / Funding (institution), Travel / Accommodation / Expenses: MedImmune; Research grant / Funding (institution): Merck; Speaker Bureau / Expert testimony: Philips Healthcare. P. Pan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Tesaro: A GSK Company. K. Sun: Shareholder / Stockholder / Stock options, Full / Part-time employment: Tesaro: A GSK Company. J.R. Graham: Shareholder / Stockholder / Stock options, Full / Part-time employment: Tesaro: A GSK Company. H.S. Han: Research grant / Funding (institution): Tesaro, Inc.; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Prescient; Research grant / Funding (institution): Horizon; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): TapImmune; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Department of Defense. All other authors have declared no conflicts of interest.