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

Area of Science:

• Oncology
• Pharmacology
• Cancer Biology

Background:

• Six poly(ADP-ribose) polymerase inhibitors (PARPi) are approved for cancer therapy using continuous dosing schedules.
• Continuous PARP inhibition is considered essential for single-agent anticancer activity.
• The necessity of such intense dosing schedules for PARPi requires further investigation.

Purpose of the Study:

• To determine the durability of PARP inhibition by five approved PARPi after a short drug exposure.
• To evaluate the impact of PARPi scheduling on cytotoxicity when combined with an ATR inhibitor.

Main Methods:

• Assessed PARP inhibition durability up to 72 hours post-drug withdrawal in ovarian cancer cells (IGROV-1, ES-2) after a 1-hour pulse of five PARPi.
• Evaluated the cytotoxic effects of combining rucaparib, olaparib, or niraparib with an ATR inhibitor (VE-821) in various schedules (co-exposure, sequential, delayed).

Main Results:

• Rucaparib demonstrated the most persistent PARP inhibition, with activity maintained at ≥75% at 72 hours post-withdrawal in both cell lines.
• Olaparib, niraparib, talazoparib, and pamiparib showed less durable PARP inhibition compared to rucaparib.
• Rucaparib enhanced ATR inhibitor cytotoxicity in all tested schedules, while olaparib and niraparib only enhanced it in co-exposure.

Conclusions:

• Rucaparib exhibits superior durability of PARP inhibition compared to other tested PARPi.
• The scheduling of PARPi can significantly influence their efficacy, particularly in combination therapies with ATR inhibitors.
• These findings suggest potential for optimized, less frequent dosing schedules for PARPi in cancer treatment.