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.
Molecular cancer therapeutics. 2022 May 02 [Epub ahead of print]
Linda A Snyder, Rajendra Damle, Shefali Patel, Jared Bohrer, Anna Fiorella, Jenny Driscoll, Rebecca Hawkins, Christopher F Stratton, Carol D Manning, Kanaka Tatikola, Volha Tryputsen, Kathryn Packman, Rao N V S Mamidi
Janssen Research and Development, Spring House, PA, United States., Janssen Research and Development, United States., Janssen Research and Development, Springhouse, PA, United States., Janssen Research and Development, Spring House, Pennsylvania, United States., Janssen Research and Development, PA, United States., Janssen Research and Development, raritan, NJ, United States., Janssen Research & Development, LLC, Newton, MA, United States., Janssen Research and Development, Raritan, NJ, United States.