ABSTRACT
Poly (ADP ribose) polymerase (PARP) inhibitors are a class of systemic anticancer therapies which target the impaired DNA repair mechanisms found in some cancer cells. Cells normally utilise two main methods of DNA repair: homologous recombination of double-strand breaks involving BRCA1 and BRCA2 proteins, and single-strand break repair via PARP. PARP inhibitors trap PARP at sites of DNA damage. The resulting accumulation of unrepaired DNA single-strand breaks causes replication fork collapse during DNA replication and double-strand breaks. Impairment of one DNA repair pathway alone is not lethal and can be compensated for by the other pathway, allowing cell survival. PARP inhibitors were designed specifically to exploit the homologous recombination DNA repair deficiency associated with a constitutional pathogenic mutation in the BRCA1 and BRCA 2 genes; in this setting, PARP inhibition causes synthetic lethality and cell death. The OlympiA study aimed to investigate the efficacy of the PARP inhibitor olaparib in the adjuvant treatment of early breast cancer patients with confirmed germline BRCA1 or BRCA2 pathogenic mutations.
