The HRD Decision - Which PARP Inhibitor to Use for Whom and When

Abstract

Rucaparib, a polyADPribose polymerase inhibitor (PARPi), was approved recently for use in women with high-grade serous ovarian cancer (HGSOC). It is now one of three approved PARPi for use in recurrent ovarian cancer, a family of agents that has changed the HGSOC treatment landscape and outcome. Clin Cancer Res; 23(23); 7155-7. ©2017 AACRSee related article by Balasubramaniam et al., p. 7165.

Figure 1. PARP inhibitor application and pathway events as a function of homologous recombination capacity

HGSOC subtypes are designated as germline deleterious (gBRCA) or somatic (sBRCA) mutation of BRCA1/2, or HRD, homologous recombination deficient, as determined by HRD testing, or wild type. DNA DSBs occur directly or as a result of stalled replication fork degeneration. Inability to repair due to loss of HR capacity in g/sBRCA and HRD play out using different mechanisms. s/gBRCA have HR dysfunction caused by the inability to recruit and load RAD51 at DNA DSBs as occurs in wild type HR. Absent HR, PARP is recruited and PARylation of DNA ends occurs followed by activation of nonhomologous end-joining (NHEJ) or alternative end-joining (altEJ), both low fidelity repair mechanisms ultimately leading to cell injury, apoptosis, or mitotic arrest or catastrophe. HRD may also occur in the absence of defined mutations; in such cases, the causative event may not be known, hence the “black box”. In HRD without known mutation, recruitment of BRCA1/2 and downstream partners may occur but normal HR repair does not; similar to g/sBRCA, low fidelity repair occurs and PARP susceptibility is observed. PARP inhibitor susceptibility is a function of HR capacity and of platinum-sensitivity as shown. Current FDA approvals are outlined.