How PARP Inhibitors Work: Synthetic Lethality and Trapping

What PARP Normally Does

PARP1 detects single-strand DNA breaks and base damage, binds the lesion, and uses NAD+ to add poly(ADP-ribose) chains to itself and nearby proteins. This recruits repair factors and then releases PARP so repair can finish. It is a core part of single-strand break and base excision repair.

If single-strand breaks are not repaired, they are converted to double-strand breaks when a replication fork runs into them.

The Synthetic-Lethal Idea

A cell that has also lost homologous recombination — for example through BRCA1 or BRCA2 loss — cannot accurately repair those replication-associated double-strand breaks. It must use error-prone routes, and the accumulating damage becomes lethal.

Neither defect alone is fatal: normal cells tolerate PARP inhibition, and homologous-recombination-deficient cells survive with intact PARP. It is the combination that kills, which is what 'synthetic lethality' means.

PARP Trapping Adds Cytotoxicity

Beyond blocking PARP's enzymatic activity, most PARP inhibitors also stabilise PARP on the DNA — they 'trap' it. A trapped PARP-DNA complex is itself a barrier to replication and transcription and is more toxic than simply removing PARP function.

Trapping potency differs between drugs: talazoparib is the strongest trapper, olaparib and rucaparib are intermediate, and this partly explains their different potencies and haematological toxicity.

Beyond BRCA, and Resistance

Activity extends to other homologous-recombination gene defects (PALB2, RAD51C/D) and to tumours that are 'HRD-positive' by genomic-scar testing, though the predictive strength varies by cancer type and assay. ATM and CHEK2 alterations are less reliably predictive.

Resistance mechanisms include restoration of homologous recombination (BRCA reversion mutations, loss of 53BP1), stabilisation of the replication fork, reduced drug uptake, and loss of PARP1 itself.

Dosing, Toxicity and the Leukaemia Question

All are oral and continued until progression or unacceptable toxicity, most often as maintenance after platinum-based chemotherapy. The dominant early toxicity is myelosuppression — anaemia with olaparib, rucaparib and talazoparib, thrombocytopenia with niraparib — managed by dose interruption, reduction and transfusion, with blood counts checked weekly at first and then monthly. Nausea and fatigue are common, and niraparib can raise blood pressure and heart rate.

A small excess of myelodysplastic syndrome and acute myeloid leukaemia has been reported with prolonged use, generally in heavily pre-treated patients. Persistent unexplained low counts prompt a bone-marrow assessment, and this risk is weighed against the progression-free and, in some settings, overall survival benefit.

Key Takeaways

• ·PARP inhibitors block single-strand break repair; in HR-deficient cells the resulting damage is lethal.
• ·They also trap PARP on DNA, and trapping strength differs between drugs.
• ·BRCA reversion mutations are a well-documented route to resistance.