PARP inhibitors: Clinical utility and possibilities of overcoming resistance

Abstract

PARP inhibitors represent a major breakthrough in ovarian cancer care. Almost half of all ovarian cancers have deficiencies in the homologous recombination (HR) DNA repair pathway, namely BRCA1/2 mutations. Given the limited therapeutic options for recurrent ovarian cancer patients there has been a significant effort to develop novel therapies to exploit DNA repair deficiencies. In 2005 and 2006, inhibiting PARP enzymes was first observed to be highly effective against cancers with HR deficiencies. PARP inhibitors are being utilized in the clinic to manage recurrent ovarian cancers that display defects in the HR repair pathway. However, PARP inhibitors also show significant clinical benefit in patients without HR deficiencies. There are currently three FDA-approved PARP inhibitors for recurrent ovarian cancer and an additional two PARP inhibitors being evaluated in late stage clinical trials. Given the expanding clinical use of PARP inhibitors and the high likelihood of acquired resistance, there is a significant need for clinical strategies to manage PARP inhibitor resistant disease. This review will examine PARP inhibitors in the context of: indications and toxicities, novel biomarkers to predict response, targeted-therapy resistance, and potential approaches to manage resistant disease.

Keywords: BRCA1/2 mutation; Ovarian cancer; PARP inhibitors; Therapy resistance.

Figure 1. PARP inhibitors that are FDA-approved or in clinical development

Figure 2. Proposed treatment regimen for platinum-sensitive, BRCA1/2-mutated or HRD positive recurrent ovarian cancer

There are now several clinical options of PARPi. As PARPi are more widely utilized there is significant need to delineate, prioritize, and standardize treatment strategies. Depicted is a hypothetical treatment plan for an ovarian cancer patient.

Figure 3. PARPi resistance is mediated through a variety of targetable pathways

The FDA has approved three PARPi for ovarian cancer and as PARPi are commonly prescribed there will be an increase in acquired resistance. Currently, several targetable pathways (HR restoration, PI3K/AKT, miRNA) have been attributed to resistance.