INVITED COMMENTARY Biomarkers of PARP inhibitor sensitivity

The PARP inhibitors represent one of the most exciting recent developments in cancer therapy. Substantial efficacy has been shown with PARP inhibitors in the treatment of hereditary BRCA1/2 related Breast and Ovarian cancer as single agents [1–3] and in combination with temozolomide [4]. Similarly, encouraging activity has been shown in sporadic ovarian cancer with a PARP inhibitor as a single agent [5], and in sporadic triple negative breast cancer in combination with gemcitabine/carboplatin chemotherapy [6]. Yet the picture is not universally positive. Negative studies have been reported in heavily pre-treated sporadic triple negative cancer, with PARP inhibitor as a single agent [5] and no evidence of activity in combination with temozolomide [4]. To understand the reasons some studies have succeeded, and others failed, the development of biomarkers that will predict the sensitivity, or resistance, to PARP inhibitors is required. There are two conceptually independent ways in which PARP inhibitors are thought to act as anti-cancer agents. First, PARP inhibitors work as single agents targeting homologous recombination (HR) deficient cancers through synthetic lethality. Second, PARP inhibitors also act as chemotherapy or radiotherapy sensitizers in the absence of single agent activity. For example, PARP inhibitors substantially increase the potency of temozolomide in vitro. Whether this translates to an increased therapeutic window in cancers with normal DNA repair in unclear; substantial bone marrow toxicity has been demonstrated with PARP inhibitor and chemotherapy combinations. In reality many PARP inhibitors are being developed assuming a combination of these two strategies, on the assumption that a combination of a PARP inhibitor with chemotherapy may target HR deficient cancers more effectively than PARP inhibitor alone.