ceralasertib (AZD6738) / AstraZeneca - LARVOL DELTA

Single-Cell Transcriptional Analysis Reveals the Mechanism of AZD6738 in HCC Immunotherapy via EZH2 Targeting. (PubMed, Drug Des Devel Ther) - "Animal experiments revealed that AZD6738 can enhance the immune microenvironment in liver cancer; specifically, AZD6738 not only promotes the proliferation of CD8+ T cells but also enhances their differentiation into effector memory T cells, indicating that the drug can potentiate anti-tumor immune responses. This study reveals that AZD6738 demonstrates significant therapeutic efficacy by targeting the key molecule EZH2, thereby modulating the tumor microenvironment and enhancing anti-tumor immunity."

IO biomarker • Journal • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • CCNB1 • CD8 • EZH2 • PRKDC • SLC6A3

Evaluation of antitumor effects of plogosertib, PLK1 inhibitor in biliary tract cancer with BUBR1 as a potential biomarker (AACR 2025) - "We used plogosertib (PLK1 inhibitor), ceralasertib (ATR inhibitor) and panobinostat (HDAC2/3 inhibitor). BTC cells with high BUBR1 expression are sensitive to the PLK1 inhibitor plogosertib, which shows synergistic effects when combined with an ATR inhibitor. In contrast, BTC cells with low BUBR1 expression which are relatively insensitive to plogosertib, HDAC2/3 inhibition increases the sensitivity to plogosertib. These findings suggest that targeting PLK1 could be an effective strategy for BTC treatment, especially with BUBR1 expression as a potential biomarker to inform optimal combination therapies."

Biomarker • Biliary Cancer • Biliary Tract Cancer • Oncology • Solid Tumor • ANXA5 • AURKA • BUB1B • HDAC2

Unveiling markers of response to ATR inhibitor and TMZ combinations in rare tumor PDXs (AACR 2025) - "The combination of ATR inhibitors with temozolomide (TMZ) [ATRi+TMZ] enhances the cytotoxic effects of TMZ by targeting DNA damage response pathways, particularly in cancer cells with impaired DNA repair mechanisms, offering a promising therapeutic strategy for tumors resistant to conventional treatments. This study utilized gene expression profiling of 38 rare tumor patient-derived xenograft (PDX) models available in the NCI Patient-Derived Models Repository (PDMR) (https://pdmr.cancer.gov) to identify potential biomarkers that predict responses to TMZ combined with either of two ATR inhibitors, i.e., AZD6738 (Ceralasertib) and BAY1895344 (Elimusertib)...Our findings revealed distinct expression signatures associated with favorable responses to two ATR inhibitors when individually combined with TMZ, highlighting candidate markers that could guide treatment decisions. Additional validation in a larger study would establish the potential utility of these candidate genes..."

Biomarker • Oncology • MCM2 • MGMT

Potential novel interventions of oncohistones, epigenetic modifications, and RNA processing machinery in betel-nuts related HNSCC in Taiwan (AACR 2025) - "PI3K/AKT/mTOR interventions, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, AT2AR inhibitor, Mcl-1 inhibitor, MEK1/2 inhibitor, JAK2 inhibitor, CXCR4 inhibitor, FAK inhibitor, p53 reactivator, MDM2 inhibitor, SHP2 inhibitor, PARP7 inhibitor, IAP inhibitor, GLS1 inhibitor, eribulin, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and modulation of stemness & PD1/PDL1 pathway...Disrupting NSD1 in HNSCC cell lines led to CpG hypomethylation & enhanced cisplatin sensitivity. TW2.6 used to test (1)in vitro drug sensitivity to (a)Chemical Modulators of Splicing; (b)PRMT5 inhibitor; (c)CDK9 inhibitor, EZH2i, DNMT3i, BRD/BET4i, and HDACi; (d)NSD1/SETD2 inhibitor; (e)METTL3 inhibitor; (2)synergistic effects with other therapies by MTT assay, colony..."

IO biomarker • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • AKT1 • ALK • ARID1B • ATM • AXL • BRD4 • CCND3 • CDK12 • CXCR4 • DDR2 • EPHB1 • FAT1 • FGF10 • FGFR • FLCN • HRAS • KDM5A • KDR • METTL3 • MITF • NSD1 • PDGFRB • PIK3CA • RICTOR • RPS6KB1 • SDHA • SETD2 • SOX9 • STK11 • TERT • TIPARP • TMB • TNFAIP3

PERK as a biomarker to optimize therapy of GRP78 inhibitor, BOLD-100, in gastric cancer (AACR 2025) - "BOLD-100 (GRP78 inhibitor), TUDCA (Tauroursodeoxycholic acid; ER stress inhibitor), and AZD6738 (ATR inhibitor) were used. The expression of PERK determines sensitivity to GRP78 inhibition by BOLD-100 in GC. PERK-high GC cells are sensitive to BOLD-100 and show efficacy as monotherapy. In PERK-low GC cells, the combination of BOLD-100 and ATR inhibitor is an optimal therapeutic option for GC treatment."

Biomarker • Gastric Cancer • Oncology • Solid Tumor • ANXA5 • CHEK1 • EIF2A • EIF2S1 • HSPA5

Targeting histone H3K27 demethylase for anti-tumor activity: Monotherapy and combination with ceralasertib in non-small cell lung carcinoma (AACR 2025) - "Targeting KDM6A alone emerges as a promising therapeutic strategy for NSCLC. Furthermore, combining KDM6A depletion with ceralasertib significantly enhances anti-tumor activity by disrupting the ATR-CHK1 checkpoint signaling pathway, leading to an enhanced anti-tumor activity."

Monotherapy • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KDM6A

CDK2 activation mediates response of acute myeloid leukemia to CHK1, ATR and WEE1 inhibitors (AACR 2025) - "Here we have comprehensively characterized the processes that occur between the interruption of replication checkpoints and leukemic cell death in these sensitive cells versus cells selected for RCM resistance. Using the CHK1 inhibitors MK8776 and prexasertib, ATR inhibitors berzosertib and ceralasertib, and WEE1 inhibitor adavosertib as paradigm drugs, we examined signaling in two AML cell lines, U937 and THP.1, that were selected for CHK1 inhibitor resistance, examined cross-resistance patterns, and assessed the biochemical basis for leukemic cell death. Our findings reveals critical new insights into the factors that influence the response to CHK1 inhibitors in AML. Importantly, we found no evidence of cross-resistance to inhibitors of other replication checkpoint proteins, enabling alternative options."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • CDC25A • CDK2 • CHEK1 • GNRP • TNFA • TP53

Inhibition of ATR enhances the anticancer activity of ciclopirox in triple-negative breast cancer (AACR 2025) - "The results indicate that inhibition of ATR with AZD6738 can potentiate the anticancer activity of CPX in TNBC cells in vitro and in vivo. Our finding suggests that combination of CPX and AZD6738 may represent a novel therapeutic approach for TNBC."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CASP3

Decitabine (DAC) induces a DNA damage response (DDR) and synergizes with replication checkpoint inhibitors in acute myeloid leukemia (AML) (AACR 2025) - "(nM)Molm13 (TP53WT)Molm13 (TP53-/-)U937 (TP53G187fs*/-)KG1a (TP53V225fs*/-)Primary AML (TP53WT orTP53MT)UnitsDecitabineDNMT16.25 – 20025 ± 11350 ± 260310 ± 1806.1 ± 1.6NDEC50, nM (mean, SD)CeralasertibATR250 – 5000.93 (0.66 – 1.24)0.90 (0.84 – 0.96)0.15 (0.08 – 0.21)0.74 (0.63 – 1.02)0.66 (0.43 – 2.43)CI with decitabine (median, IQR) CamonsertibATR10 – 1000.27 (0.19 – 0.59)0.24 (0.22 – 0.34)0.34 (0.21 – 0.39)NDNDPrexasertibCHK1/21.0 – 6.00.89 (0.82 – 1.06)0.78 (0.68 – 0.90)0.95 (0.93 – 1.08)ND0.88 (0.29 – 1.28)MK-8776CHK1250 – 1,0000.57 (0.48 – 0.80)0.76 (0.73 – 1.19)0.89 (0.57 – 1.39)NDNDRabusertibCHK1600 – 1,000NDNDND0.51 (0.48 – 0.56)NDAdavosertibWEE1100 – 4000.70 (0.63 – 1.11)0.99 (0.78 – 1.14)0.67 (0.60 – 0.74)0.67 (0.37 – 0.93)0.65 (0.43 – 0.88)Table 1. U937 data were replicated using annexin V. Prexasertib showed no activity in KG1a cells (suggesting drug efflux) requiring the use of the alternate CHK1 inhibitor, rabusertib. Abbreviations: ATR,..."

Checkpoint inhibition • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • ANXA5 • ATR • DNMT1

A Study to Evaluate the Effect of Ceralasertib on Drug X, Drug Y and Drug Z (clinicaltrials.gov) - P1 | N=20 | Not yet recruiting | Sponsor: AstraZeneca

New P1 trial • Solid Tumor

NCI-2018-01648: Ceralasertib (AZD6738) Alone and in Combination With Olaparib or Durvalumab in Patients With Solid Tumors (clinicaltrials.gov) - P2 | N=89 | Recruiting | Sponsor: Rahul Aggarwal | Trial completion date: Sep 2027 ➔ Mar 2028 | Trial primary completion date: Sep 2027 ➔ Mar 2028

Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Clear Cell Renal Cell Carcinoma • Endometrial Cancer • Genito-urinary Cancer • Hepatology • Oncology • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer • ARID1A • ATM • MSI • UGT1A1

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 | Not yet recruiting | Sponsor: SWOG Cancer Research Network | Initiation date: Mar 2025 ➔ Sep 2025

Trial initiation date • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • SLFN11

CONCORDE: A Platform Study of Novel Agents in Combination With Radiotherapy in NSCLC (clinicaltrials.gov) - P1 | N=200 | Recruiting | Sponsor: University of Leeds | Trial primary completion date: Apr 2025 ➔ Mar 2026

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

Testing the Addition of AZD6738 (Ceralasertib) to Immunotherapy to Increase Time Without Cancer for Patients With Non-Small Cell Lung Cancer (clinicaltrials.gov) - P3 | N=630 | Not yet recruiting | Sponsor: National Cancer Institute (NCI) | Initiation date: Mar 2025 ➔ Jun 2025

Trial initiation date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

D5330C00004: Ascending Doses of Ceralasertib in Combination With Chemotherapy and/or Novel Anti Cancer Agents (clinicaltrials.gov) - P1/2 | N=357 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Mar 2025 ➔ Dec 2025 | Recruiting ➔ Active, not recruiting

Enrollment closed • Trial completion date • Breast Cancer • Colorectal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Head and Neck Cancer • HER2 Breast Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • ATM • BRCA • HER-2 • HRD • RAD51C • RAD51D

An Update on the CONCORDE study: A Phase Ib Platform Study of DNA Damage Repair Inhibitors (DDRis) in Combination With Conventional Radiotherapy in NSCLC (BTOG 2025) - P1 | "In 2 study arms, participants also receive consolidation durvalumab ±DDRi for up to 12 months...The primary objective is to assess safety and to determine the recommended phase II dose of each DDRi. Since 17/03/21, 4 arms have opened: A (olaparib, PARPi), B (AZD1390, ATMi), C (ceralasertib, ATRi) and E (saruparib, PARP-1i)... CONCORDE continues to recruit patients to three study arms (A,C,E). The platform demonstrated excellent capability in identifying excess toxicity in DDRi-RT combinations, leading to Arm–B closure. Analysis of patient-reported outcomes and efficacy are ongoing."

Combination therapy • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • PARP1

An update on the CONCORDE study: A phase Ib platform study of DNA damage repair inhibitors (DDRIs) in combination with conventional radiotherapy in NSCLC (ELCC 2025) - P1 | "Recruitment update: Since 17/03/21, 4 arms have opened: A (olaparib, PARPi), B (AZD1390, ATMi), C (ceralasertib, ATRi) and E (saruparib, PARP-1i)...DDRIs have been successfully escalated to dose level 2 (C + E) or 3 (A) with integration of consolidation durvalumab in 2 arms (C + E)...Analysis of patient-reported outcomes and efficacy are ongoing. A multimodality translational program to identify toxicity biomarkers is in development."

Combination therapy • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PARP1

Olaparib in Combination With Either Durvalumab, Selumetinib, or Capivasertib or Ceralasertib Alone in Treating Patients With Metastatic Triple Negative Breast Cancer (clinicaltrials.gov) - P2 | N=27 | Active, not recruiting | Sponsor: OHSU Knight Cancer Institute | Recruiting ➔ Active, not recruiting | N=132 ➔ 27 | Trial completion date: Dec 2027 ➔ Nov 2025 | Trial primary completion date: Dec 2025 ➔ Oct 2024

Enrollment change • Enrollment closed • Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • ER • HER-2 • PGR

Targeting Resistant Prostate Cancer With ATR and PARP Inhibition (TRAP Trial) (clinicaltrials.gov) - P2 | N=49 | Active, not recruiting | Sponsor: University of Michigan Rogel Cancer Center | Trial completion date: Jan 2027 ➔ Aug 2028

Trial completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • BRCA1 • BRCA2

NCI-2019-04148: Olaparib With Cediranib or AZD6738 for the Treatment of Advanced or Metastatic Germline BRCA Mutated Breast Cancer (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Mar 2025 ➔ Dec 2027 | Trial primary completion date: Mar 2025 ➔ Dec 2027

Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA • ER • HER-2

Testing Olaparib and AZD6738 in IDH1 and IDH2 Mutant Tumors (clinicaltrials.gov) - P2 | N=50 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Mar 2025 ➔ Mar 2026 | Trial primary completion date: Mar 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • IDH1 • IDH2

VIOLETTE: To Assess Safety and Efficacy of Agents Targeting DNA Damage Repair With Olaparib Versus Olaparib Monotherapy. (clinicaltrials.gov) - P2 | N=273 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Dec 2024 ➔ Dec 2025

Monotherapy • Trial completion date • Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

Olaparib with Ceralasertib in Recurrent Osteosarcoma (clinicaltrials.gov) - P2 | N=63 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Recruiting ➔ Active, not recruiting

Enrollment closed • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

Discovery of the Clinical Candidate YY2201 as a Highly Potent and Selective ATR Inhibitor. (PubMed, J Med Chem) - "YY2201 shows superior in vivo anticancer efficacy and a better therapeutic index compared to AZD6738 in a lung cancer xenograft model. YY2201 also exhibits potent cancer suppression effects in combination with chemotherapy in vivo. Currently, the investigational new drug application of YY2201 has been approved by the FDA for further clinical investigation."

Journal • Lung Cancer • Oncology • Solid Tumor

Combination of S-1 and the oral ATR inhibitor ceralasertib is effective against pancreatic cancer (JSMO 2025) - No abstract available

Oncology • Pancreatic Cancer • Solid Tumor