Abstract 4128: Niraparib shows superior tissue distribution and efficacy in a prostate bone metastasis model compared with other PARP inhibitors

Abstract

Abstract Patients whose prostate tumors bear deleterious mutations in genes that cause DNA repair defects (DRD), such as breast cancer (BRCA)2, respond to inhibitors of poly (ADP-ribose) [PAR] polymerase (PARP)-1 and PARP-2. Several PARP inhibitors, including niraparib, are in clinical development for the treatment of late stage prostate cancer. Prostate cancer typically metastasizes to bone marrow, and it is possible that efficacy of PARP inhibitors could differ based on their ability to penetrate and inhibit tumor growth in bone. Nonclinical studies were conducted to evaluate activity of PARP inhibitors in vitro, and to compare tissue exposure and efficacy in mice bearing PC-3-luc-C6 prostate tumors grown either subcutaneously (SC) or in bone. PC-3-luc-C6 cells do not have identifiable mutations in DRD genes, but they were >10-fold more sensitive in vitro to PARP inhibition than other prostate tumor lines. Treatment with niraparib induced a pattern of γ-H2AX and RAD51 staining that indicated the cells are deficient in DNA repair. Niraparib and olaparib exhibited similar potency in a biochemical PARP trapping assay, but in vitro cellular cytotoxicity studies of PC-3-luc-C6 cells demonstrated that niraparib was ~8-fold more potent than olaparib. A steady state PK study in mice bearing PC-3-luc-C6 SC prostate tumors demonstrated distinct patterns of tissue exposure of PARP inhibitors. For example, niraparib was detected for 12 or 24 hours in all tissues tested, including in plasma, tumor, and bone marrow. In contrast, olaparib was detected for up to 12-24 hours in plasma and tumor, but only transient exposure was observed in bone marrow. Mean AUC24 ratio estimates showed that niraparib had several-fold higher distribution to tumor and bone marrow as compared with olaparib. Efficacy studies were performed in the PC-3-luc-C6 tumor model, implanted either SC or by intracardiac injection to seed bone metastases. In the soft tissue SC tumor model, efficacy of the PARP inhibitors was similar, increasing lifespan by up to ~30%. However, the PARP inhibitors were differentiated by efficacy in the bone metastasis model. Niraparib significantly inhibited bone tumor growth and prolonged survival by ~30% over control mice, while olaparib did not prolong survival. This result is consistent with the hypothesis that niraparib's superior bone marrow exposure results in greater inhibition of tumor growth in bone. It further suggests that prostate cancer patients may derive greater benefit from PARP inhibitors that can penetrate the bone marrow. Citation Format: Linda A. Snyder, Rajendra N. Damle, Shefali Patel, Jared Bohrer, Jenny Driscoll, Rebecca Hawkins, Christopher F. Stratton, Carol Manning, Kanaka Tatikola, Volha Tryputsen, Kathryn Packman, Rao Mamidi. Niraparib shows superior tissue distribution and efficacy in a prostate bone metastasis model compared with other PARP inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4128.