Combining poly(ADP-ribose) polymerase inhibitors and immune checkpoint inhibitors in breast cancer: rationale and preliminary clinical results

Purpose of review: Recently, both immune checkpoint inhibitors and poly(ADP-ribose) polymerase inhibitors have demonstrated clinical benefit in some subsets of HER2-negative breast cancer patients. A biological rationale exists supporting a potential synergism between these compounds, which may further increase their antitumor activity in the clinic.

Recent findings: PARP inhibitors were shown to activate type I interferon pathway, thus eliciting local and general immune response, while inducing programmed cell death-ligand 1 (PD-L1) up-regulation. In addition, the DNA damages created by PARP inhibition may increase tumor mutational burden and neo-antigens, thereby favoring efficacy of immune checkpoint inhibitors. Accordingly, clinical trials combining PARP inhibitors and agents targeting the PD-1/PD-L1 axis have been initiated in breast cancer in both advanced and early stages, enrolling patients with germline BRCA1/2 mutation, homologous recombination deficiency and/or with triple negative phenotype. Preliminary safety and efficacy results are encouraging, but it is still unclear whether the combination adds benefit compared with each therapeutic administered as single agent.

Summary: Although a strong rationale exists to support the combination of PARP inhibitors with immune checkpoint inhibitors, future clinical trials will have to demonstrate whether it improves outcome and to identify which patients are the most likely to benefit from.