Efficacy of ATR kinase inhibitor elimusertib monotherapy or combination in tumors with DNA damage response pathway and other genomic alterations.

Abstract

The ataxia telangiectasia and RAD3-related (ATR) kinase functions with ataxia telangiectasia mutated (ATM) kinase as a modulator of DNA damage response (DDR). We assessed the antitumor effects of the ATR inhibitor elimusertib (BAY 1895344) in patient-derived xenograft (PDX) models with DDR alterations. Antitumor activity was assessed by change in tumor volume (TV) from baseline. Responses were categorized as follows: partial response (PR): >30% decrease in TV; >20% increase in TV: progressive disease (PD); and non-PR/PD: stable disease (SD). Event-free survival was defined as time for tumor doubling (EFS-2). Of 21 PDX models tested, 11 had significant prolongation of EFS-2 with elimusertib monotherapy. Four models had a PR and 4 had SD. PR/SD was observed in 2 of 5 models with ATM loss on IHC and in models with a variety of alterations in DDR genes, including BRCA1/2 and ATM. Elimusertib prolonged EFS-2 in three of 5 models with known PARP inhibitor resistance. Pharmacodynamic studies conducted in 4 PDX models showed an increase in DNA damage markers. PI3K/mTOR pathway signaling increased in 2 of 4 models. The combination of the PI3K inhibitor copanlisib with elimusertib enhanced EFS-2 compared to monotherapy in 3 of 11 models tested. The combination of elimusertib with the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib enhanced antitumor activity compared to single agents in PARP-resistant PDX models. Our study shows that ATR inhibition has antitumor activity, including in models with both intrinsic and acquired PARP inhibitor resistance. Further work is needed to better refine patient selection for ATR-based therapies.