A Very Long-Acting PARP Inhibitor Suppresses Cancer Cell Growth in DNA Repair-Deficient Tumor Models.

Abstract

PARP inhibitors are approved for treatment of cancers with <i>BRCA1</i> or <i>BRCA2</i> defects. In this study, we prepared and characterized a very long-acting PARP inhibitor. Synthesis of a macromolecular prodrug of talazoparib (TLZ) was achieved by covalent conjugation to a PEG_40kDa carrier via a β-eliminative releasable linker. A single injection of the PEG∼TLZ conjugate was as effective as ∼30 daily oral doses of TLZ in growth suppression of homologous recombination-defective tumors in mouse xenografts. These included the KT-10 Wilms' tumor with a <i>PALB2</i> mutation, the <i>BRCA1</i>-deficient MX-1 triple-negative breast cancer, and the <i>BRCA2</i>-deficient DLD-1 colon cancer; the prodrug did not inhibit an isogenic DLD-1 tumor with wild-type <i>BRCA2</i>. Although the half-life of PEG∼TLZ and released TLZ in the mouse was only ∼1 day, the exposure of released TLZ from a single safe, effective dose of the prodrug exceeded that of oral TLZ given daily over one month. μPET/CT imaging showed high uptake and prolonged retention of an 89Zr-labeled surrogate of PEG∼TLZ in the MX-1 <i>BRCA1</i>-deficient tumor. These data suggest that the long-lasting antitumor effect of the prodrug is due to a combination of its long <i>t</i> _1/2, the high exposure of TLZ released from the prodrug, increased tumor sensitivity upon continued exposure, and tumor accumulation. Using pharmacokinetic parameters of TLZ in humans, we designed a long-acting PEG∼TLZ for humans that may be superior in efficacy to daily oral TLZ and would be useful for treatment of PARP inhibitor-sensitive cancers in which oral medications are not tolerated. SIGNIFICANCE: These findings demonstrate that a single injection of a long-acting prodrug of the PARP inhibitor talazoparib in murine xenografts provides tumor suppression equivalent to a month of daily dosing of talazoparib.