The novel ATR inhibitor BAY 1895344 is efficacious as monotherapy and combined with DNA damage-inducing or repair-compromising therapies in preclinical cancer models.

The DNA damage response (DDR) secures the integrity of the genome of eukaryotic cells. DDR deficiencies can promote tumorigenesis but concurrently may increase dependence on alternative repair pathways. The ataxia telangiectasia and Rad3-related (ATR) kinase plays a central role in the DDR by activating essential signaling pathways of DNA damage repair. Here, we studied the effect of the novel selective ATR kinase inhibitor BAY 1895344 on tumor cell growth and viability. Potent anti-proliferative activity was demonstrated in a broad spectrum of human tumor cell lines. BAY 1895344 exhibited strong monotherapy efficacy in cancer xenograft models that carry DNA damage repair deficiencies. The combination of BAY 1895344 with DNA damage-inducing chemotherapy or external beam radiation therapy (EBRT) showed synergistic anti-tumor activity. Combination treatment with BAY 1895344 and DDR inhibitors achieved strong synergistic anti-proliferative activity in vitro, and combined inhibition of ATR and poly (ADP-ribose) polymerase (PARP) signaling using olaparib demonstrated synergistic anti-tumor activity in vivo. Furthermore, the combination of BAY 1895344 with the novel, non-steroidal androgen receptor antagonist darolutamide resulted in significantly improved anti-tumor efficacy compared to respective single agent treatments in hormone-dependent prostate cancer, and addition of EBRT resulted in even further enhanced anti-tumor efficacy. Thus, the ATR inhibitor BAY 1895344 may provide new therapeutic options for the treatment of cancers with certain DDR deficiencies in monotherapy and in combination with DNA damage-inducing or DNA repair-compromising cancer therapies by improving their efficacy.