More about PARPi

 

Alternate therapeutic pathways for PARP inhibitors and potential mechanisms of resistance

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         PARP inhibitors (PARPi) have the potential to revolutionise the treatment of ovarian cancers. These drugs are the first clinical application of a concept called synthetic lethality; this is a combination of 2 or more gene expression alterations leading to cell death.

         PARPi act on two separate pathways; firstly they inhibit DNA repair via the PARP1 enzyme and second they protect the cell from homologous recombination deficiency (HRD), which causes DNA instability.

         Many clinical trials have demonstrated the efficacy of 4 different PARPi drugs either alone or in combination. Initially the trials showed survival advantages for patients with germ-line or somatic mutations, recent evidence shows the advantages are more widespread with benefits to patients outside these groups.

         Unfortunately drug resistance to PARPi is becoming commonplace. It seems that the most likely cause is mutation to normal HR status. The high cost of these drugs will be a barrier to approval for routine first-line therapy.