Niraparib (Zejula), A Small Molecule, PARP1/2 Inhibitor for Treating Breast, Ovarian, and Pancreatic Cancers

Poly(ADP-ribose) polymerases (PARPs) are a family of 17 proteins involved in posttranslational modification of proteins. Although PARP1 was first discovered in 1966, it took another 50 years before a PARP inhibitor was shown to be the first cancer drug to exploit synthetic lethality. PARP1 and PARP2 are nuclear proteins that contain both a DNA binding domain and a catalytic domain. A hallmark of high grade serous ovarian cancer is a defective DNA damage response, of which PARP inhibitors can exploit through synthetic lethality. Interestingly, talazoparib has the highest PARP trapping potency, followed by niraparib, rucaparib, olaparib, and veliparib. Niraparib and other PARPi represent a new class of oncology drugs that exploit synthetic lethality. As the third US Food and Drug Administration-approved PARP inhibitor, niraparib was a significant improvement over olaparib and rucaparib since it was approved for patients without a germline or somatic BRCA mutation with single daily dosing.