**14.1 Immune checkpoint inhibitors in combination with PARP inhibitors**

Breast cancer patients with germline BRCA1 or BRCA2 mutations account for around 5% of all cases. While TNBC is the most common cancer with the mutation in BRCA1 gene, cancers linked to the BRCA2 mutation can turn up in any subtype of breast cancer with the same frequency as sporadic subtypes. Breast cancers with BRCA1/2 mutations have a deficiency in homologous recombination repair, a DNA double-strand break repair mechanism, the defect which has a lethal synergy with single-strand DNA repair inhibition [87]. The poly(ADPribose) polymerase (PARP) is involved in single-strand DNA repair, and PARP inhibitors have shown antitumor activity in patients with HER2-negative metastatic breast cancer who have BRCA1/2 germline mutations. The use of immune checkpoint inhibitors in combination with PARPi in TNBC patients has the ability to cause a powerful immune response against tumors due to the infiltrating T cell activation followed by tumor antigen release via PARPi-induced cell death. Moreover, PARPi has been shown to increase the expression of PD-L1 in cell lines, supplying additional support for combining treatment with checkpoint inhibitors [88].

The TOPACIO (NCT02657889) trail found that a combination of pembrolizumab with the PARPi niraparib resulted in an ORR of 29% in mTNBC patients [89]. The ORR was higher than what has been identified in similar patient populations for anti-PD1 monotherapy [64]. In addition, various clinical trials evaluating the PD-L1 inhibition combination with PARP inhibitors in mTNBC have been planned, two phase II studies included the combination of the PARPi olaparib with durvalumab (NCT03167619 and NCT03801369) and a phase II trial of atezolizumab in combination with olaparib (NCT02849496). In addition, triplet PD-L1 inhibition therapies with PARPi and VEGF inhibitors are currently being developed. A phase I/II analysis (NCT02484404) in case of progressive or recurring solid tumor is looking at the combination of durvalumab in conjunction with olaparib and cediranib the VEGFR inhibitor. According to preliminary findings, the recommended dosage was bearable and resulted in clinical benefit rate of 67% in 9 women having recurring solid tumors, TNBC was one of them (**Table 5**) [90].


#### **Table 5.**

*Combinations of PD1/PD-L1 antibody-targeted therapy in TNBC.*
