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. 2025 Sep 2;24(9):1402-1414.
doi: 10.1158/1535-7163.MCT-24-0884.

Efficacy of ATR Kinase Inhibitor Elimusertib Monotherapy or Combination in Tumors with DNA Damage Response Pathway and Other Genomic Alterations

Kaushik Varadarajan  1 , Christian X Cruz Pico  1 , Kurt W Evans  2 , Maria Gabriela Raso  3 , Yasmeen Qamar Rizvi  2 , Xiaofeng Zheng  4 , Dhruv Chachad  2 , Timothy P DiPeri  1 , Bailiang Wang  2 , Stephen M Scott  2 , Ming Zhao  2 , Argun Akcakanat  2 , Antje M Wengner  5 , Timothy A Yap  2 , Funda Meric-Bernstam  1   2
Affiliations

Efficacy of ATR Kinase Inhibitor Elimusertib Monotherapy or Combination in Tumors with DNA Damage Response Pathway and Other Genomic Alterations

Kaushik Varadarajan et al. Mol Cancer Ther. .

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; 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.

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Conflict of interest statement

K.W. Evans reports grants from Bayer during the conduct of the study. A.M. Wengner reports employment with Bayer AG at the time of data generation. T.A. Yap reports other support from University of Texas MD Anderson Cancer Center (VP, Head of Clinical Development in the Therapeutics Discovery Division, which has a commercial interest in drug discovery and development), personal fees from AbbVie, Acrivon, Adagene, Aeneid Therapeutics, Almac, Alterome Therapeutics Inc., Audro, Amgen Inc., Amphista, Astex, Atavistik, Athena, Atrin, Avenzo, Avoro, Axiom, Baptist Health Systems, Bicycle, BioCity Pharma, Bluestar Bio, Boxer, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research Horizons, Cancer Research UK, Carrick Therapeuitcs, Circle Pharma, Clasp, Cybrexa, Daiichi Sankyo, DAiNA, Dark Blue Therapeutics, Dawn Manco, Debiopharm, Diffusion, Duke Street Bio, EcoR1 Capital, Eikon, Ellipses Pharma, Entos, Flagship Pioneering, Forbion, FoRx Therapeutics, Genesis Therapeutics, Genmab, Glenmark, GLG, Globe Life Sciences, Grey Wolf Therapeutics, GSK, Guardant, Guidepoint, Idience, Ignyta, I-Mab, Impact Therapeutics, Institut Gustave Roussy, Intellisphere, Janssen, Jazz Pharma, Joint Scientific Committee for Phase I Trials in Hong Kong, Kyn, Kyowa Kirin, Lumanity, MEI pharma, Mereo, Merit, Monte Rosa Therapeutics, Natera, Nested Therapeutics, Nexus Pharmaceuticals, Nimbus, Novocure, Odyssey Therapeutics, OHSU, OncoSec, Ono Pharma, Onxeo, PanAngium Therapeutics, Pegascy, PER, Pfizer, Piper-Sandler, Pliant Therapeutics, Plexium Inc., Prelude Therapeutics, Prolynx, Protai Bio, PSIM, Radiopharma Theranostics, Repare, resTORbio, Roche, Ryvu Therapeutics, SAKK, Sanofi, Schrodinger, Servier, Stablix, Synnovation, Synthis Therapeutics, Tango, TCG Crossover, TD2, Techspert.io, Terremoto Biosciences, Tessellate Bio, Theragnostics, Terns Pharmaceuticals, Thryv Therapeutics, Tolremo, Tome Biosciences, Trevarx Biomedical, Varian, Veeva, Versant, Vibliome Therapeutics, Vivace, Voronoi Inc., Xinthera, and Zai Labs, grants and personal fees from Artios, AstraZeneca, Bayer, BeiGene, Blueprint, BridGene Biosciences, Clovis, 858 Therapeutics, EMD Serono, F-Star, Ideaya Biosciences, ImmuneSensor, and Merck, and grants from Accent, Aprea Therapeutics, BioNTech, Bristol Myers Squibb, Boundless Bio, Circle Pharma, Constellation, CPRIT, Cyteir, Department of Defense, Eisbach Bio, Eli Lilly and Company, Exelixis, Forbius, Gilead Sciences, GlaxoSmithKline, Genetech, Golfers Against Cancer, Haihe, Insilico Medicine, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Loxo Oncology, Mirati, Novartis, NIH/NCI, Pfizer, Pliant, Prelude, Ribon Therapeutics, Regeneron, Repare, Roche, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Springworks, Synnovation, Tango, Tesaro, V Foundation, Zenith, Vivace, and Zentalis outside the submitted work. F. Meric-Bernstam reports grants and personal fees from AstraZeneca, Daiichi Sankyo, Debiopharm, eFFECTOR Therapeutics, Zymeworks, and Guardant Health, personal fees from Becton Dickinson, Calibr (a division of Scripps Research), Dava Oncology, EcoR1 Capital, Elevation Oncology, Exelixis, GT Aperion, Incyte, Jazz Pharmaceuticals, LegoChem Biosciences, Lengo Therapeutics, Menarini Group, Molecular Templates, Protai Bio, Ribometrix, Tallac Therapeutics, Tempus, Cybrexa, FogPharma, GO Therapeutics, Harbinger Health, Karyopharm Therapeutics, Kivu Biosciences, LOXO Oncology, Mersana Therapeutics, OnCusp Therapeutics, Sanofi, Seagan, Theratechnologies, and Zentalis Pharmaceuticals, grants from Jazz Pharmaceuticals, Aileron Therapeutics, Bayer Healthcare, Calithera Biosciences, Inc., Curis, Inc., CytomX Therapeutics, Genentech, Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology, Inc., and Taiho Pharmaceutical, personal fees and other support from Dava Oncology, and other support from European Organisation for Research and Treatment of Cancer, European Society for Medical Oncology, and Cholangiocarcinoma Foundation outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Response of PDXs with known actionable alterations to elimusertib. Waterfall plot of response of all models to elimusertib 40 mg/kg (twice a day, 3 days on/4 days off) at day 21/22 or earlier time point (BCX.011 and BCX.010). Best % change in tumor volume from baseline is shown for PDX models with any decrease in tumor volume whereas the T/C ratio is shown for models without tumor regression. Percentage nuclear expression of ATM by IHC is shown below the waterfall plot. Also shown are tumor type by histology and treatment response at day 21 designated as PR/CR (30% decrease or more in tumor volume), PD (20% increase or in tumor volume), or SD (neither progressive or partial response), and ATM IHC score. Genomic heatmap of alterations of DDR and PIK3 pathways and other selected genes are shown below. AA, amino acid; Amp, amplification; CR, complete response; Del, deletion; Mut, mutation.
Figure 2.
Figure 2.
Response of PDXs with varying levels of ATM expression and differing talazoparib sensitivities to elimusertib. A, Tumor volume growth curve, waterfall plot, and Kaplan–Meier curve for BCX.017. B, Tumor volume growth curve, waterfall plot, and Kaplan–Meier curve for PDX.003.233. C, Tumor volume growth curve, waterfall plot, and Kaplan–Meier curve for BCX.006. D, Tumor volume growth curve, waterfall plot, and Kaplan–Meier curve for BCX.024. Growth curves shown as shown as mean ± SEM. E, Representative ATM IHC images at 40× magnification with H score. F, T/C ratios comparing elimusertib monotherapy vs. talazoparib monotherapy. Ctrl, control; Eli, elimusertib.
Figure 3.
Figure 3.
Elimusertib response and baseline proteomics. A, Volcano plot of protein states differing between models with SD or PR models and models with PD. B, RPPA heatmap of PI3K/AKT/mTOR pathway protein expression at baseline in all PDX models tested. * indicates the co-clinical trial model.
Figure 4.
Figure 4.
Pharmacodynamic change results for treatment with elimusertib. A, Characteristics of models that underwent short course 10-day treatment (3 days on, 4 days off and 3 days on) with ATR inhibition for the pharmacodynamic study. B, Study design for the pharmacodynamic experiment. C, Heatmap of differential protein expression in BCX.017, the most sensitive model. D, RPPA results for DNA damage confirmatory markers. E, RPPA results for AKT/mTOR pathway markers. Model that has SD or PR when treated with 40 mg/kg elimusertib are marked. All others had PD. F, IHC for DNA damage markers. G, Representative IHC images for selected DNA damage response markers. Images are at 20× magnification. Eli, elimusertib. (B, Created with BioRender.com)
Figure 5.
Figure 5.
Efficacy of the combination of elimusertib and copanlisib in PDXs. A, Composite summary of T/C ratios of models tested with elimusertib plus copanlisib sorted by best sensitivity to combination therapy. B, Tumor volume growth curves, waterfall plots, Kaplan–Meier curves for the three models that had synergistic response to combination therapy and improved EFS. C, Summary of the three models with synergistic response to combination therapy. CCA, cholangiocarcinoma; Eli, elimusertib.
Figure 6.
Figure 6.
Efficacy of the combination of elimusertib and niraparib in PDXs. A, Tumor volume growth curves, waterfall plots, and Kaplan–Meier curves for BCX.017 treated with elimusertib + niraparib on intermittent dose schedules. B, Tumor volume growth curves, waterfall plots, and Kaplan–Meier curves for BCX.017 with treated elimusertib + niraparib at continuous dose schedule. C, Tumor volume growth curves, waterfall plots, and Kaplan–Meier curves for PDX.003.348 treated with elimusertib in combination with niraparib. D, Summary of the two models. Eli, elimusertib; Mut, mutation.
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