For some time we have understood that there was a genetic component to breast and ovarian cancers because some families appear to have higher incidences. This phenomenon has become known as hereditary breast-ovarian cancer (HBOC) syndrome and multiple genes have been implicated, the most famous of which being the BRCA mutations. BRCA1 and BRCA2 are involved in double strand repair of DNA. There are several mechanisms for repairing single-strand DNA break but at the front of these pathways lays a gatekeeper known as poly (ADP-ribose) polymerase (PARP). BRCA deficient cells are highly sensitive to PARP inhibitors. Olaparib, one of the PARP inhibitor showed high response rate (RR) against HBOC patients even though who had been heavily pretreated.
A phase III trial of iniparib, one of the PARP inhibitor, failed to demonstrate a significant improvement in survival for women with metastatic triple-negative breast cancer (TNBC). In the previous randomized phase II study, the addition of iniparib to gemcitabine/carboplatin therapy significantly improved RR, progression-free survival (PFS), and overall survival (OS) with metastatic TNBC. The phase III study randomly assigned 519 women with stage IV TNBC to gemcitabine/carboplatin or to gemcitabine/carboplatin/iniparib. In the intent-to-treat population, median PFS was 5.1 months in the gemcitabine/carboplatin/ iniparib arm versus 4.1 months with gemcitabine/carboplatin (P = 0.027), which was a 21% reduction in risk that did not meet the pre-specified alpha (P = 0.01). Median OS was 11.8 versus 11.1 months, for a 12% risk reduction (P = 0.28). Iniparib-containing triplet given second- or third-line to 43% of patients reduced mortality risk by 35%, with a median overall survival of 10.8 months, up from 8.1 months with gemcitabine/carboplatin. Median PFS was 4.2 versus 2.9 months, a 33% risk reduction. The exploratory analysis suggests there is a potential efficacy benefit among second- and third-line patients. Iniparib may work in some molecular subtypes of triple-negative breast cancer but not others. Triple-negative breast cancer is highly heterogeneous on intrinsic subtype. Specific biomarkers are needed to evaluate patient populations in TNBC that would be sensitive to iniparib.