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; and non-PR/progressive disease, 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 four had SD. PR/SD was observed in two of five 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 five models with known PARP inhibitor resistance. Pharmacodynamic studies conducted in four PDX models showed an increase in DNA damage markers. PI3K/mTOR pathway signaling increased in two of four models. The combination of the PI3K inhibitor copanlisib with elimusertib enhanced EFS-2 compared with monotherapy in three of 11 models tested. The combination of elimusertib with the PARP inhibitor niraparib enhanced antitumor activity compared with 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.

This content is only available via PDF.
©2025 The Authors; Published by the American Association for Cancer Research
2025
American Association for Cancer Research
This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License .
Attribution-NonCommercial-NoDerivatives

Article PDF first page preview

First page of Efficacy of ATR Kinase Inhibitor Elimusertib Monotherapy or Combination in Tumors with DNA Damage Response Pathway and Other Genomic Alterations<alt-title alt-title-type="short">ATR Inhibitor Elimusertib in Tumors with DDR Alterations</alt-title>

Supplementary data

Supplementary Figure 1

Supplementary Figure 1: Comparison of response to elimusertib 40 mg/kg vs 20 mg/kg.

- pdf file
Supplementary Figure 2

Supplementary Figure 2. Tumor volume growth curve and waterfall plots for models shown in Figure 1. Waterfall plot represent day 20 or the last day of control group measurement.

- pdf file
Supplementary Figure 3

Supplementary Figure 3. Change in body weight of mice bearing 10 different patient derived xenografts treated with elimusertib 40 mg/kg.

- pdf file
Supplementary Figure 4

Supplementary Figure 4. ATM IHC and genomics of PDXs treated with elimusertib 40 mg/kg.

- pdf file
Supplementary Figure 5

Supplementary Figure 5: Tolerability of 40 mg/kg elimusertib

- pdf file
Supplementary Figure 6

Supplementary Figure 6: In vivo response to elimusertib from pre-treatment biopsy PDX models.

- pdf file
Supplementary Figure 7

Supplementary Figure 7: PARPi resistant models with response to ATR inhibition.

- pdf file
Supplementary Figure 8

Supplementary Figure 8: PARPi resistant models with response to ATR inhibition.

- pdf file
Supplementary Figure 9

Supplementary Figure 9: Additional IHC and RPPA results from pharmacodynamic experiments.

- pdf file
Supplementary Figure 10

Supplementary Figure 10: Additional IHC and RPPA results from pharmacodynamic experiments.

- pdf file
Supplementary Table 1

Supplementary Table 1: Characteristics and treatment histories of PDXs.

- pdf file
Supplementary Table 2

Supplementary Table 2: Characteristics and treatment histories of PDXs.

- pdf file
Supplementary Table 3

Supplementary Table 3: All actionable alteration found in PDXs.

- pdf file
Supplementary Table 4

Supplementary Table 4: Clinical elimusertib response of coclinical PDXs.

- pdf file