Differences in Durability of PARP Inhibition by Clinically Approved PARP Inhibitors: Implications for Combinations and Scheduling

SIMPLE SUMMARY: PARPi are approved as monotherapy agents and under advanced clinical investigation as a combination therapy for the treatment of cancer. We demonstrate for the first time that five of the approved PARPi vary in their ability to suppress cellular PARP activity after drug removal. Rucaparib caused the most durable PARP inhibition, and olaparib and niraparib the least. Rucaparib enhanced ATR inhibitor cytotoxicity in sequential and co-exposures, whereas olaparib and niraparib were only active in co-exposure settings. These data have implications for the scheduling of PARPi clinically, particularly in combination with other drugs. ABSTRACT: Six PARP inhibitors (PARPi) are approved for cancer therapy as monotherapy agents in daily or twice-daily continuous dosing schedules to maintain the necessary continuous suppression of PARP activity. Continuous PARP inhibition is required for single-agent anticancer activity. To investigate if such intense schedules are necessary, we determined the durability of PARP inhibition up to 72 h after a 1 h pulse of 1 µM of five of the approved PARPi, rucaparib, olaparib, niraparib, talazoparib and pamiparib, in IGROV-1 and ES-2 (human ovarian cancer) cells. Rucaparib caused the most persistent inhibition of PARP activity when maintained at ≥75% at 72 h after drug withdrawal in both IGROV-1 and ES-2 cells, but inhibition was more rapidly lost with the other PARPi. PARPi are also under clinical investigation with ATR inhibitors, and thus, we evaluated the implications for scheduling with an ATR inhibitor (VE-821). Rucaparib enhanced VE-821 cytotoxicity in co-exposure, sequential and delayed (24 h drug-free) schedules in IGROV-1 and ES-2 cells. Olaparib and niraparib enhanced VE-821 cytotoxicity only in co-exposed cells and not in sequential exposures. These data have clinical implications for the scheduling of PARPi as a monotherapy and in combination with ATR inhibitors and other cytotoxic drugs.