Editors' ChoiceCancer

PARP inhibitors unleash the antitumor immune response

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Science Translational Medicine  02 Sep 2020:
Vol. 12, Issue 559, eabe4434
DOI: 10.1126/scitranslmed.abe4434


Combination of a PARP inhibitor with immune checkpoint blockade showed promising antitumor activity without additional toxicity.

Cells are exposed to genotoxic agents, such as ultraviolet (UV) light or ionizing radiation, that can damage the genome. This can compromise correct transmission of DNA to daughter cells during replication and can lead to the development of cancer. To respond to this damage, cells have adapted by developing several DNA damage response (DDR) pathways. Patients with deleterious mutations in genes involved in DDR, including the breast cancer risk genes BRCA1 and BRCA2, often respond to poly-(ADP-ribose)-polymerase (PARP) inhibitors, which block an additional pathway involved in DDR. PARP inhibition in patients with germline BRCA1 or BRCA2 mutations can lead to further tumor DNA damage and genomic instability. This instability can increase tumor immunogenicity and lead to enhanced antitumor immunity in combination with immune checkpoint inhibitors. Antibodies against programmed death-1 (PD-1) and its ligand (PD-L1) are immune checkpoint inhibitors that have transformed treatment for many tumor types. Durvalumab is an anti-PD-L1 antibody approved for treatment of urothelial cancer and both non-small cell and small cell lung carcinoma.

Domchek et al. report the results of a cohort of breast cancer patients treated with the PARP inhibitor olaparib and followed by durvalumab from the multicenter, open-label, phase 1/2, basket MEDIOLA trial. Eligible patients carried deleterious germline BRCA1 or BRCA2 mutations and had progressive, locally advanced, or metastatic HER2-negative breast cancer. Patients with hormone-receptor positive or negative tumors were eligible for the study. The results of this study demonstrate that the combination of olaparib and durvalumab is safe and tolerable without additional toxicity compared to monotherapy. Promising antitumor activity of the combination of olaparib and durvalumab was observed, with an objective response rate of 63% and with disease control at 12 weeks in 80% of patients. The sample size of this study was small, at only 34 patients. However, these results highlight the importance of randomized studies evaluating the combination of PARP and immune checkpoint inhibitors in patients with BRCA1 or BRCA2 mutated breast cancer.

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