Abstract
Prostate cancer patients whose tumors bear deleterious mutations in DNA-repair pathways often respond to poly (ADP-ribose) polymerase (PARP) inhibitors. Studies were conducted to compare the activity of several PARP inhibitors in vitro, and their tissue exposure and in vivo efficacy in mice bearing PC-3M-luc-C6 prostate tumors grown subcutaneously (SC) or in bone. Niraparib, olaparib, rucaparib, and talazoparib were compared in proliferation assays, using several prostate tumor cell lines, and in a cell-free PARP trapping assay. PC-3M-luc-C6 cells were ~12-20-fold more sensitive to PARP inhibition than other prostate tumor lines, suggesting these cells bear a DNA damage repair defect. The tissue exposure and efficacy of these PARP inhibitors were evaluated in vivo in PC-3M-luc-C6 SC and bone metastasis tumor models. A steady-state pharmacokinetic study in PC-3M-luc-C6 tumor-bearing mice demonstrated that all of the PARP inhibitors had favorable SC tumor exposure, but niraparib was differentiated by superior bone marrow exposure compared with the other drugs. In a PC-3M-luc-C6 SC tumor efficacy study, niraparib, olaparib, and talazoparib inhibited tumor growth and increased survival to a similar degree. In contrast, in the PC-3M-luc-C6 bone metastasis model, niraparib showed the most potent inhibition of bone tumor growth compared to the other therapies (67% vs 40-45% on Day 17), and the best survival improvement over vehicle control (hazard ratio [HR] 0.28 vs HR 0.46-0.59) and over other therapies (HR 1.68-2.16). These results demonstrate that niraparib has superior bone marrow exposure and greater inhibition of tumor growth in bone, compared with olaparib, rucaparib, and talazoparib.
