ceralasertib (AZD6738) / AstraZeneca - LARVOL DELTA

Targeting ATR offers multifaceted treatment strategies involving RAD51-mediated compensatory DNA repair in bladder cancer. (PubMed, J Exp Clin Cancer Res) - No abstract available

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • RAD51

Role of DNA damage sensing and TP53 function as modulators of sensitivity to calicheamicin-based antibody-drug conjugates (ADCs) for acute leukemia (ASH 2025) - "Better survival of some patients with the CD33 ADC, gemtuzumab ozogamicin (GO), and the CD22 ADC, inotuzumab ozogamicin (InO), validate these efforts, but these ADCs are ineffective in many others...CLM-induced cytotoxicity was assessed in vitro in the presence/absence of a Mouse Double Minute 2 homolog (MDM2) inhibitor (idasanutlin), Ataxia-Telangiectasia Mutated (ATM) inhibitor (AZD1390, lartesertib), Ataxia Telangiectasia and Rad3-related (ATR) inhibitor (ceralasertib), Checkpoint Kinase 1 and Checkpoint Kinase 1 (Chk1/Chk2) inhibitors (prexasertib, BML-277), and poly(ADP-ribose) polymerase (PARP) inhibitor (veliparib)... Our studies identify ATM, MDM2, and TP53 as key modulators of CLM-induced cytotoxicity in acute leukemia cells. These results support further evaluation of combination therapies with corresponding small molecule inhibitors (currently pursued in patients with other cancers) toward possible clinical testing as novel strategies to increase the efficacy..."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Ataxia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Immunology • Leukemia • Movement Disorders • Primary Immunodeficiency • CD22 • CD33 • CDKN1A • FBXW7 • TP53

Methylation-based ctDNA Dynamics as a Biomarker for Treatment Response and Prognosis in Patients on the plasmaMATCH trial (SABCS 2025) - "Cohorts A-D were analyzed together (ER-positive breast cancer on targeted therapy), with cohort E analysed separately (TNBC on olaparib PARP and ceralasertib ATR inhibitor combination).We analysed C1D1/C2D1 matched samples from 74 patients for ctDNA methylation (30 from cohorts A-D and 44 from cohort E). Using a tumour agnostic breast cancer ctDNA methylation assay, we show that on treatment ctDNA methylation dynamics are predictive of response to targeted therapy. There was no association between BRCA1 methylation in ctDNA and outcomes, suggesting the sensitivity to PARP and ATR inhibition combination of cohort E was not mediated by BRCA1 methylation.Subject to further independent validation, ctDNA methylation dynamics may present a simple way to identify early patients who are responding to novel therapy combinations."

Biomarker • Circulating tumor DNA • Clinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Triple Negative Breast Cancer • BRCA1 • ER

A Study to Evaluate the Safety and Pharmacokinetics of Ceralasertib in Combination With Durvalumab in Chinese Patients With Advanced Solid Tumours (clinicaltrials.gov) - P1 | N=14 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Oct 2025 ➔ Mar 2026

Trial completion date • Solid Tumor

Safety Run-In Phase of the ATRiBRAVE trial: a Phase II Study Evaluating Ceralasertib Priming Followed by Durvalumab/Nab-Paclitaxel to Restore Immunotherapy Sensitivity in Advanced Triple Negative Breast Cancer (TNBC) (SABCS 2025) - "Ceralasertib priming at a 160 mg BID for 7 days, followed by durvalumab and nab-paclitaxel, is feasible and well tolerated. Nine additional patients have already been enrolled in the phase II portion of the trial (total enrolment: 18 patients) and patient enrolment is currently ongoing.Updated safety data for patients who completed treatment in the study will be presented at the meeting.This study was funded by Fondazione AIRC under 5 per mille 2019 (ID. 22759 program—group leader VG and SM)."

Clinical • Metastases • P2 data • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • STING

Ceralasertib, an ATR kinase inhibitor, as monotherapy in Japanese patients with advanced solid malignancies: Results from a phase 1 study. (PubMed, Invest New Drugs) - P1 | "Ceralasertib monotherapy was generally well tolerated in Japanese patients with advanced solid tumors. The small number of patients enrolled prevents definitive conclusions on the efficacy of ceralasertib monotherapy to be made."

Journal • Monotherapy • P1 data • Oncology • Solid Tumor • ATR

LATIFY: A Phase III Study of Ceralasertib Plus Durvalumab Versus Docetaxel in Patients With Non Small Cell Lung Cancer (NSCLC) Whose Disease Progressed On or After Prior Anti PD (L)1 Therapy And Platinum Based Chemotherapy (clinicaltrials.gov) - P3 | N=594 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Oct 2025 ➔ Oct 2026

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR

Differential Response to ATR/Chk1 Inhibition in Preleukemia and Transformed Leukemia in an MLL-ENL Model of Leukemogenesis Reflects Enrichment for Myc-Transcriptional Program (ASH 2024) - "We hypothesize that in preleukemia, ATR/Chk1 DNA damage response (DDR) checkpoint activation serves as part of intrinsic anti-cancer barrier, while in leukemia, ATR-dependent signaling is essential for leukemia cell proliferation and survival.We tested the consequences of ATR/Chk1 inhibition during Mll-ENL leukemogenesis, using ceralasertib (ATRi1, p.o. 25 mg/kg), elimusertib (ATRi2, p.o. 50 mg/kg) and AZD-7762 (Chk1i, i.v. 25 mg/kg), 3-5 times weekly, 1-6 months, using the preleukemic mice...In vitro, MEER cells showed high sensitivity to JAK2i ruxolitinib (RX, IC50 24 nM), higher than to the tested FLT3i...In preleukemia, attenuation of ATR/Chk1 checkpoint promotes the development of leukemia from preleukemia. Combinatory targeting of DDR components and activated oncogenic signaling to induce synthetic lethality in preleukemia stage of MLL remains to be fully elucidated."

Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • AMBRA1 • CHEK2 • FLT3

Unraveling Novel Mechanisms for Targeting the Intra-S-Phase Checkpoint in p53-Mutated Acute Myeloid Leukemia (ASH 2023) - "When used sequentially with LBS-007, hydroxyurea provided a robust response yielding GI50's between 1 and 3 nM for LBS-007, effectively blocking DNA replication origins (LBS-007) and inducing fork stalls (HU)...Most impressively, the combination of LBS-007 and venetoclax was exponentially enhanced when used in conjunction with ceralasertib (4.8 pM)...Our results identify a unique and potentially efficacious strategy to treat one of the most difficult to treat subtypes of AML. These findings will provide the rationale for potential clinical trials using CDC7 inhibition in p53 mutated or R/R AML."

IO biomarker • P53mut • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CDC7 • MCM2 • TP53

Identification of Epigenetic Modifiers Essential for Growth and Survival of AML1/ETO-Positive Leukemia (ASH 2023) - "Materials and methodsIn the customized shRNA library screen, 2009 shRNAs developed to target 671 genes were pool-cloned into a retroviral vector allowing doxycycline-inducible expression to generate a plasmid shRNA library (Antonova et al...We validated, genetically and pharmacologically, DNMT1 and ATR using several AML1/ETO-positive (SKNO-1, Kasumi-1) and AML1/ETO-negative cell lines (OCI-AML3, HL60) with median IC50 for decitabine 74 nM (range 44-219), azacytidine 146 nM (range 14-267), berzosertib 219 nM (range 16-460) and ceralasertib 85 nM (range 42-328)...Some of these epigenetic regulators, such as DNMT1 and ATR, are susceptible to pharmacological inhibition by small molecules showing promising preclinical and clinical efficacy, and confirmation studies (Baeten et al. , ASH meeting 2022) appear warranted."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BRD4 • HDAC8 • KMT5A • PARP2 • RUNX1 • RUNX1T1 • SETD1A • SMARCA4 • SMYD2

Decitabine Synergizes with Replication Checkpoint Inhibitors in TP53-Mutated Acute Myeloid Leukemia (ASH 2024) - "Prior reports suggest that DNA methyltransferase inhibitors (DNMTi), such as decitabine and azacitidine, form covalent DNA-DNMT1 adducts and invoke a DNA damage response (DDR) characterized by activation of the ATR-CHK1 pathway, including in TP53MT AML samples...Similar results were obtained from decitabine (EC50 = 300 ± 100 nM) and ceralasertib (CI 0.54), adavosertib (CI 0.67), MK-8776 (CI 0.52), and prexasertib (CI 0.81) in annexin V assays.These combinations were further evaluated (SubG1 assays) in an isogenic pair of Molm13 and Molm13 TP53-/- cell lines...Combination treatment was antagonistic with ceralasertib (CI 2.2), additive with prexasertib (CI 1.0), and synergistic with adavosertib (CI 0.88).ConclusionsIn multiple cell lines and diverse primary AML samples, decitabine activated the ATR-CHK1 DDR pathway and synergized with ATRi, CHK1/2i, and WEE1i. Amongst these, only the combination of decitabine plus adavosertib exhibited synergy across all three models,..."

Checkpoint inhibition • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • DNMT1

O6-Guanine Targeting Novel DNA Cross-Linker and ATR Inhibitor Combination for MGMT-Silenced IDH1/2 Mutant Acute Myeloid Leukemia (ASH 2024) - P1 | "Interestingly, temozolomide (TMZ), which is an FDA-approved MGMT-dependent methylating agent, and our novel first-in-class fluoro-ethylating agent KL50 emerged as top hits imparting the maximum therapeutic index.Previous MGMT-biomarker based clinical trials in AML using temozolomide (TMZ) highlighted a moderate correlation of MGMT promoter hypermethylation with overall treatment response...Blocking the ATR-mediated DNA repair axis with AZD6738, an ATR inhibitor (ATRi) currently in clinical trials for myeloid leukemia (NCT03770429) profoundly synergizes with the low doses of KL50 in MGMT-isogenic in vitro and in vivo preclinical AML models. We are now investigating the synergistic efficacy of this novel combination on MGMT-silenced patient-derived xenografts (PDXs) in humanized MISTRG mice models. This clinically translatable study holds tremendous potential for identifying a new class of combinatorial therapy that could target both de novo and refractory/relapsed..."

Acute Myelogenous Leukemia • Anemia • Aplastic Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CEBPA • IDH1 • IDH2 • MGMT • RUNX1

Clinical Activity and Safety of the Oral ATR Inhibitor Ceralasertib (AZD6738) in Patients with MDS or CMML after Prior HMA Therapy (ASH 2024) - P1 | "The schedule of 160mg BID 7on/7off had similar response rates, OS, and PFS compared to a 14on/14off schedule, with a lower rate of severe thrombocytopenia, and this schedule merits further evaluation. At the time of progression, RUNX1 mutations were enriched; future efforts are ongoing to evaluate the mechanisms of response to ATRi in MDS and CMML."

Clinical • Anemia • Chronic Myelomonocytic Leukemia • Febrile Neutropenia • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Leukopenia • Myelodysplastic Syndrome • Neutropenia • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Septic Shock • Thrombocytopenia • RUNX1 • SF3B1 • SRSF2 • U2AF1 • ZRSR2

ATR Inhibition and Replication Stress Converge on a BCL6-Mediated Reversal of the Dark Zone Signature in DLBCL (ASH 2024) - "Gemcitabine is a routinely used chemotherapeutic for second-line treatment of DLBCL, and neither it nor AZD6738 shows lymphodepletion in humans. As DLBCL with DZ-like signatures show poor outcomes on standard chemo-immunotherapy, our finding that ATR inhibition with gemcitabine reverses DZ signatures suggests the possibility of this being a non-lymphodepleting genotoxic backbone for combinations with T-cell engaging bispecific antibodies."

IO biomarker • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL6 • CHEK1 • PARP1

PTEN protein and lipid phosphatase deficiency confers sensitivity to ATR inhibitor-based treatment in high-grade serous ovarian cancer (AACR-NCI-EORTC 2025) - "Importantly, we have further assessed PTEN as a potential biomarker via biopsy samples from platinum-sensitive HGSOC patients treated with the ATR inhibitor ceralasertib and the PARP inhibitor olaparib. In summary, we demonstrate PTEN as an important biomarker for prediction of clinical benefit to ATR inhibitor-based treatment. As ATR inhibition continues to move forward as a high-priority strategy in ovarian cancer, our work may ultimately contribute to optimal patient selection where there is high unmet medical need."

High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • CHEK1 • MCM2 • PTEN • RAD51

Phase I, dose-escalation study evaluating safety & efficacy of trastuzumab deruxtecan (T-DXd) in combination with ATR inhibitor (AZD6738, ceralasertib) in advanced solid tumors with HER2 expression (DASH) (ESMO 2025) - P1 | "Table: 939P Dose Level 1 (N = 6) 2 (N = 6) 3 (N = 6) 4 (N = 4) Total HER2 IHC 1/2+ (N = 15) 1/6 (17) 1/4 (25) 2/3 (67) 0/2 (0) 4/15 (27) 3+ (N = 7) - 1/2 (50) 2/3 (67) 1/2 (50) 4/7 (57) Total (N = 22) 1/6 (17) 2/6 (33) 4/6 (67) 1/4 (25) 8/22 (36) Table shows investigator-assessed objective response rate (%) per RECISTv1.1 Conclusions Preliminary evidence in this study showed that AZD6738 at 120 mg/d plus T-DXd at 5.4mg/kg was well-tolerated and yielded promising antitumor activity in heavily pretreated pts with high and low HER2-expressing advanced solid tumors. Expansion (colorectal and gastric-esophageal cancers) is ongoing and experience in other solid tumors is warranted."

Clinical • Combination therapy • Metastases • Esophageal Cancer • Gastric Cancer • Oncology • Solid Tumor • HER-2

Resistance to trastuzumab deruxtecan acquired through multifaceted pathway alterations in preclinical models (AACR-NCI-EORTC 2025) - "These preclinical studies demonstrate that T-DXd resistance in HER2-expressing cell lines emerges via multifaceted mechanisms, including reduced HER2 expression, altered ADC trafficking/internalization, increased efflux, and changes in payload sensitivity."

Preclinical • Oncology • ABCC1 • ABCG2 • TOP2A

Chemo-immunotherapy followed by durvalumab and ceralasertib in treatment naïve patients with extensive-stage small cell lung cancer (ESMO 2025) - P2 | "Methods A multicenter single arm phase II study was conducted to evaluate the efficacy of adding ceralasertib to maintenance durvalumab (CD) after induction with platinum-etoposide and durvalumab (PED) in patients with treatment naïve ES-SCLC. Fourteen patients (46.7%) developed serious adverse events, of which seven (50%) were treatment related. Conclusions The combination of chemo-immunotherapy followed by ceralasertib and durvalumab has shown promising efficacy with higher rates of 12- and 24-month survival over that expected for durvalumab maintenance alone, and did not show any new safety signal."

Clinical • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

The Prognostic and Predictive Impact of Circulating Tumour DNA Levels in Patients with Advanced Breast Cancer Enrolled on the plasmaMATCH Trial. (PubMed, Clin Cancer Res) - "Baseline low ctDNA levels predict response to targeted therapy, potentially suggesting shared mechanisms between high ctDNA release and resistance to therapy. Both baseline ctDNA levels and on-treatment dynamics are a promising surrogate endpoint for drug development, with clearance of ctDNA being a robust cross-therapy surrogate for outcome."

Circulating tumor DNA • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • PALB2

EFFORT2: COMBINATION CERALASERTIB (ATRI) PLUS OLAPARIB (PARPI) IN WOMEN WITH PLATINUM SENSITIVE HOMOLOGOUS RECOMBINATION DEFICIENT (HRD) OVARIAN CANCER WITH PRIOR PARPI EXPOSURE (IGCS 2025) - "Of 16 enrolled patients, 15 were evaluable. 9 (60%) had BRCA mutations and 6 (40%) were HRD positive. All evaluable patients (100%) experienced clinical benefit: 4 (27%) patients had an objective response (all partial response) while 11 (73%) patients had stable disease >4 cycles."

Clinical • Platinum sensitive • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • BRCA • HRD

S2409: Using Biomarker Tests to Select and Test New, Personalized Treatments for Extensive Stage Small Cell Lung Cancer, PRISM Study (clinicaltrials.gov) - P2 | N=900 | Recruiting | Sponsor: SWOG Cancer Research Network | Not yet recruiting ➔ Recruiting

Biomarker • Enrollment open • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • SLFN11

Combination ATR and PARP Inhibitor (CAPRI) Trial With AZD6738 and Olaparib in Recurrent Ovarian Cancer (clinicaltrials.gov) - P2 | N=123 | Completed | Sponsor: University of Pennsylvania | Active, not recruiting ➔ Completed | Trial completion date: Dec 2025 ➔ Jul 2025 | Trial primary completion date: Dec 2025 ➔ Jul 2025

Platinum resistant • Platinum sensitive • Trial completion • Trial completion date • Trial primary completion date • Oncology • Ovarian Cancer • Solid Tumor • BRCA • HRD • MUC16

THE ROLE AND MECHANISM OF THE HOST RESTRICTION FACTOR SLFN5 IN HEPATITIS B VIRUS TRANSCRIPTION AND REPLICATION (AASLD 2025) - "SLFN5 knockdown increased ATR phosphorylation, and this effect was reversed by the ATR inhibitor AZD6738... This study shows that SLFN5 is significantly upregulated in HBV-infected cells following interferon treatment, potentially acting as a host restriction factor to inhibit HBV replication. SLFN5 overexpression suppresses HBV transcriptional replication. Specifically, SLFN5 restricts HBV replication through its C-terminal domain and by regulating the ATR/CHK1 signaling pathway."

Hepatitis B • Hepatology • Herpes Simplex • Human Immunodeficiency Virus • Infectious Disease • Inflammation • IFNA1 • SLFN

AZD6738 for Patients With Progressive MDS or CMML (clinicaltrials.gov) - P1 | N=52 | Active, not recruiting | Sponsor: Massachusetts General Hospital | Recruiting ➔ Active, not recruiting | Trial completion date: May 2025 ➔ May 2026 | Trial primary completion date: May 2024 ➔ Apr 2025

Enrollment closed • Trial completion date • Trial primary completion date • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • SF3B1 • SRSF2 • U2AF1 • ZRSR2

LOTOS: A Study to Investigate Efficacy and Safety of Ceralasertib Plus Durvalumab in Participants Aged ≥ 18 Years With Advanced or Metastatic Non-small Cell Lung Cancer Whose Disease Progressed on or After Prior Anti-PD-(L)1 Therapy and Platinum-based Chemotherapy (clinicaltrials.gov) - P2 | N=39 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Jul 2025 ➔ Jan 2027

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR