Combining PI3K and PARP inhibitors for breast and ovarian cancer treatment

PARP inhibitors have shown antitumor activity in phase II trials, nevertheless, the magnitude of benefit in the metastatic setting is modest and there is therefore a need to combine with other compounds [1, 2]. Matulonis et al. [3] report the toxicity and efficacy of a combination between BKM120, a non-selective PI3K inhibitor, and olaparib, a PARP inhibitor, in patients with breast and ovarian cancers. The rationale for this trial came from two studies reported in 2012 [4, 5]. The first showed that PI3K inhibition decreases BRCA1/2 expression and leads to homologous recombination deficiency. The authors then showed that the combination of PI3K and PARP inhibitors exhibits antitumor activity in triple negative breast cancer with wild type BRCA1. The second study showed that, in a model of BRCA1-mutated TNBC, BKM120 increased antitumor effects of PARP inhibitors. This second paper focused on BRCA1, and the synergism was not investigated in BRCA2-mediated cancers.

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