Emerging therapeutic modalities of PARP inhibitors in breast cancer

Abstract

Inhibition of Poly (ADP-ribose) polymerase (PARP) has shown marked benefit for breast cancer with homologous recombination deficiency, whether driven by defects in BRCA1, BRCA2, or other pathway components. Since the initial approval of olaparib, a mostly investigated PARP inhibitor (PARPi), the clinical development of PARPi in breast cancer treatment has been a major emphasis. Researches in investigating platinum-PARPi combination use compared with platinum monotherapy demonstrated promising benefit in metastatic BRCA mutated breast cancer or TNBC, while no such superiority was observed in the neoadjuvant setting of TNBC. Moreover, the utility of PARP inhibition in BRCA1/2 mutated breast cancer with different platinum-free interval was investigated. There was a clear association between clinical benefit with PARPi and platinum sensitivity, whereas partial efficacy of PARPi still occurs in platinum-resistant patients. In addition, proof-of-principle studies of immunotherapy combined with PARPi in breast cancer have obtained promising results, indicating the potential benefit of the combination therapy in patients with breast cancer. These efforts, contributing to maximize the utility of PARPi, may drive a new era of this agent after its first routine use. In this review, we summarized the utility of combining platinum-PARPi in BRCA mutated breast cancer or TNBC compared with platinum monotherapy and provided promising prospects of PARPi as maintenance therapy in breast cancer, as well as providing a strong rationale for testing immunotherapy combined with PARPi in breast cancer to expand the clinical utility of PARPi.

Keywords: BRCA mutation; Breast cancer; Maintenance; PARPi; Platinum.