Efficacy of ATR kinase inhibitor elimusertib monotherapy or combination in tumors with DNA damage response pathway and other genomic alterations
Introduction:The ataxia telangiectasia and RAD3-related (ATR) kinase is a key component of DNA damage response (DDR) that functions in conjunction with ataxia telangiectasia mutated (ATM) kinase as a modulator in response to DNA single and double strand breaks and stalled replication forks. ATM deficiency can increase reliance on ATR signaling for DDR. ATR inhibition has demonstrated synthetic lethality with ATM loss in preclinical studies. We sought to test the antitumor effects of the potent ATR inhibitor elimusertib (BAY 1895344) in tumors with DDR alterations including ATM loss.Methods:Patient- derived xenograft (PDX) models with varying DDR pathway alterations were established into immunodeficient mice and then treated with elimusertib monotherapy and combination therapy. Monotherapy treatment was performed at 20 mg/kg and 40 mg/kg twice a day 3 days on/4 days off. Efficacy was assessed by change in tumor volume from baseline (and by event-free survival, defined as time for tumor volume to double in size (EFS-2). Responses at 21 days were categorized as follows: average of >30% decrease in tumor volume was defined as partial response (PR); >20% increase in tumor volume was defined as progressive disease (PRD) and any non-PR/PD was defined as stable disease (SD). Pharmacodynamic changes were assessed 10 days after treatment initiation using immunohistochemistry (IHC) and Reverse Phase Proteomics Array (RPPA).Results:Of 21 PDX models tested, 11 had a statistically 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 immunohistochemistry and in models with a variety of genomic alterations in DDR genes, including BRCA1/2 and ATM. Three of 5 models with known PARP inhibitor resistance had statistically significant prolongation of EFS-2 with elimusertib. Pharmacodynamic studies conducted in 4 PDX models with varying sensitivity to elimusertib showed an increase in DNA damage markers. PI3K/mTOR pathway signaling increased in 2 of 4 models (both in a responder and a resistant model) . 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 activity in PDX models with known PARP inhibitor resistance.Conclusion:ATR inhibition has monotherapy activity in molecularly-selected PDXs, including models with both intrinsic and acquired PARPi resistance. Rational combinations of ATR inhibition with PI3K or PARP inhibition are promising strategies and are in clinical trials.Clinical Significance:ATR inhibitors are in active clinical trial development for patients with a range of solid tumors. By performing a broad examination of PDX models across multiple cancer types, we evaluated putative predictive biomarkers of sensitivity and resistance and have preclinically tested rational combinations currently in clinical trials.