PARP Inhibition — DNA Damage Response

Poly(ADP-ribose) polymerase (PARP) enzymes, principally PARP1 and PARP2, are nuclear DNA damage sensors that recognise single-strand DNA breaks (SSBs) and catalyse poly-ADP-ribosylation of nearby proteins, recruiting the base excision repair (BER) machinery. PARP also plays roles in replication fork protection and regulation of transcription. In cells with intact homologous recombination (HR) — the high-fidelity repair pathway for double-strand breaks (DSBs) — PARP inhibition is tolerated because SSBs can be alternatively repaired. However, in cells deficient in HR (due to BRCA1 or BRCA2 mutations, or other HR deficiency-causing alterations), PARP inhibition results in SSBs persisting to become DSBs at replication forks, which cannot be repaired — causing replication fork collapse and cell death. This cancer-selective vulnerability is termed synthetic lethality.

BRCA1 and BRCA2 are tumour suppressor genes whose germline mutations confer markedly elevated lifetime risks of breast, ovarian, pancreatic, and prostate cancers. BRCA-mutant tumours rely on PARP-mediated SSB repair due to their underlying HR deficiency, creating exquisite sensitivity to PARP inhibitors. Beyond germline BRCA mutations, somatic BRCA mutations and other HR pathway alterations (PALB2, RAD51C/D, CDK12 mutations) collectively constitute the broader biomarker of homologous recombination deficiency (HRD), which extends the PARP inhibitor-sensitive population. Validated HRD testing platforms (e.g., Myriad myChoice CDx) assess genomic instability scars (LOH, TAI, LST) as surrogates for cumulative HR pathway dysfunction.

PARP inhibitors (olaparib, niraparib, rucaparib, talazoparib) differ in their potency of PARP trapping — physically trapping the PARP-DNA complex at damaged sites, preventing repair complex recruitment — and their selectivity across PARP family members. PARP trapping potency correlates with both anti-tumour activity and haematological toxicity. Olaparib and niraparib are approved for maintenance therapy in platinum-sensitive relapsed ovarian cancer and in first-line maintenance in BRCA-mutated or HRD-positive ovarian cancer. Olaparib is approved in BRCA-mutated metastatic breast cancer, pancreatic cancer (germline BRCA), and metastatic castration-resistant prostate cancer (BRCA1/2, ATM mutations). Acquired PARP inhibitor resistance via BRCA reversion mutations or restoration of fork protection mechanisms is an area of active translational research.