What is the percentage of the DNA repair defects found in patients with progressing to advanced prostate cancer?
Germline alterations in DNA repair genes have been found to occur in roughly 12% of men progressing to advanced prostate cancer, while somatic alterations are found in upwards of a quarter of all CRCPCs. Mutations in genes involved in homologous recombination (HR) such as BRCA1/2, PALB2, and ATM are frequently deleteriously mutated in CRPC. These mutations in DNA repair have critical clinical consequences such as those seen in patients harboring deleterious germline BRCA2 mutations being at increased prostate cancer risk. Cancers possessing defects in HR repair represents an attractive target in the treatment of metastatic castration-resistant prostate cancer. One such drug to come out of this is olaparib, which, in a trial in 2015 was shown to demonstrate anti-tumor activity in patients with both somatic and germline aberrations in BRCA and other genes involved in HR DNA repair through its role as a poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor. The led to the FDA in January 2016 supporting the accelerated approval of olaparib for monotherapy treatment of BRCA1/2 or ATM mutations in mCRPC.
Olaparib is a potent PARP inhibitor that induces synthetic lethality in BRCA1 and BRCA2 deficient tumor cells. When DNA damage occurs and is limited to a single strand, PARP enzymes assist in coordinating base excision repair. PARP is a zinc-finger DNA binding protein that detects single strand breaks in DNA where it catalyzes the transfer of the ADP-ribose moiety from an NAD+ substrate to several protein acceptors involved in DNA metabolism and activating base excision repair to repair SSB. Inhibition of PARP enzymes would stop initiation of base-excision repair, leading to the accumulation of DNA damage. In non-cancer cells, PARP inhibition would not be significant due to the presence of efficient double-stranded break repair mechanisms. However, in prostate cancer cells such as those harboring BRCA mutations which as a result have deficient HR, PARP inhibition would be lethal. The would result in PARP inhibitors killing tumor cells selectively, with healthy cells with normal gene functions suffering minimal effects.