ceralasertib (AZD6738) / AstraZeneca - LARVOL DELTA

Evaluation of pleural mesothelioma sensitivity to targeted DNA damage response inhibitors (EACR 2025) - "Long-term cell proliferation assays lasting 7 to 15 days were conducted using various concentrations of the following DDR inhibitors: berzosertib and ceralasertib (ATR inhibitors), AZD0156 (an ATM inhibitor), olaparib (a PARP inhibitor), adavosertib (a WEE1 inhibitor), and rabusertib (a CHEK1 inhibitor). These results represent a preclinical rationale for designing clinical trials with DDR for MPM patients."

Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Sarcoma • Solid Tumor • BAP1 • RAD51

Testing Olaparib and AZD6738 in IDH1 and IDH2 Mutant Tumors (clinicaltrials.gov) - P2 | N=24 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=50 ➔ 24 | Trial completion date: Mar 2026 ➔ Jul 2026 | Trial primary completion date: Mar 2026 ➔ Mar 2025

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

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) - No abstract available

Clinical • Combination therapy • Metastases • Oncology • Solid Tumor • HER-2

KEAP1 and STK11/LKB1 alterations enhance vulnerability to ATR inhibition in KRAS mutant non-small cell lung cancer. (PubMed, Cancer Cell) - "ATRi shows enhanced anti-tumor activity in LKB1 and/or KEAP1-deficient non-small cell lung cancer (NSCLC) models and synergizes with gemcitabine. In the HUDSON trial, LKB1/KEAP1-deficient NSCLC patients demonstrate enhanced benefits to the ATRi ceralasertib plus durvalumab. These findings suggest that alterations in the KEAP1-NRF2 pathway and/or LKB1 are associated with enhanced sensitivity to ATRi and could serve as biomarkers for predicting response to ATRi combination regimens."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KEAP1 • KRAS • STK11

Chemo-immunotherapy followed by Durvalumab and Ceralasertib in treatment naïve patients with extensive-stage small cell lung cancer (ESMO 2025) - No abstract available

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

Comprehensive machine learning analysis of PANoptosis signatures in multiple myeloma identifies prognostic and immunotherapy biomarkers. (PubMed, Sci Rep) - "Drug sensitivity analysis revealed heightened sensitivity to cyclophosphamide, Sinularin, Wee1 inhibitor, osimertinib, JQ1, VE-822, and AZD6738 in high-risk patients. Furthermore, CCK-8 assays and Wright-Giemsa staining confirmed the crucial role of PARP1 in regulating MM cell viability. This PANoptosis-based prognostic model provides a valuable tool for predicting MM prognosis and guiding personalized treatment."

Biomarker • IO biomarker • Journal • Tumor mutational burden • Hematological Malignancies • Multiple Myeloma • Oncology • CASP3 • IGF2BP1 • LY96 • PARP1 • TMB • ZBP1

Targeting the DNA damage response prevents regrowth of colorectal peritoneal metastasis-derived organoids following treatment with mitomycin C. (EACR 2025) - "We tested whether inhibitors of the DNA damage response (DDR) could prevent recurrence in an in vitro HIPEC model.Material and Peritoneal metastasis-derived organoids (PMDOs; n=10) were treated with inhibitors of ATR (berzosertib, ceralasertib, elimusertib), CHK1 (rabusertib), and WEE1 (adavosertib) alone, and in combination with MMC, oxaliplatin, or irinotecan. PMDOs can be completely eradicated if MMC treatment is followed by inhibition of ATR or other DDR kinases. DDR inhibitors may, therefore, have value in the adjuvant treatment of peritoneal metastases following CRS-HIPEC."

Colorectal Cancer • Oncology • Solid Tumor • CHEK1

L-Ascorbic acid preferentially kills KRAS mutant pancreatic cancer cells through DNA damage. (PubMed, Sci Rep) - "We also showed that AA synergizes with the DNA-damaging agent AZD6738 in PC cells and AA induces an enhanced DNA damage response in BRCA mutant PC cells, as confirmed in PC PDCs having with KRAS G12D or BRCA1/2 mutation. This study showed the antitumor activity of AA in PC cells and PDCs, indicating that KRAS G12D identifies an attractive subset of PC cells for treatment using AA and novel agents targeting key molecules involved the DNA damaging pathway. In addition, DNA damage response (DDR)-defective cell subsets, including germline BRCA1/2 mutants, may be potential candidates for this novel approach, which provides new insights for future clinical development."

IO biomarker • Journal • Oncology • Pancreatic Cancer • Solid Tumor • BRCA • BRCA1 • BRCA2 • GAPDH • KRAS

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 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting | Initiation date: Jun 2025 ➔ Mar 2026

Checkpoint inhibition • Enrollment open • Trial initiation date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Combinatorial assessment of DXd-based antibody drug conjugates with DNA damage response inhibitors in ovarian and endometrial cancers (EACR 2025) - "Our findings indicate that combining Dato-DXd and T-DXd with specific DDR inhibitors potentially enhances anti-tumour activity in ovarian and endometrial cancer models, which offers potential pathways for clinical translation. These combinations, particularly those involving ATM and ATR inhibitors, support the need for further investigation in clinical settings."

Endometrial Cancer • Oncology • Ovarian Cancer • Solid Tumor • HER-2 • TACSTD2

EXPLOITING REPLICATION STRESS AS A NOVEL THERAPEUTIC TARGET IN CIC REARRANGED SARCOMAS. (EACR 2025) - "Cerelasertib (AZD6738) is an ATP competitive, commercially avalable ATR inhibitor (ATRi) that blocks phosphorylation of CHK1 proteins disrupting DNA replication, inducing DNA damage, and preventing DNA repair, finally leading to cell death... CIC::DUX4 oncogenic fusion induce transcription of genes involved in replication stress. To the best of our knowledge, this is the first study showing a cytotoxic effect of ATR inhibition in CIC::DUX4 sarcoma in vitro, particularly in three tumoroid models. Moreover, non cytotoxic concentration of ATRi showed a significant radiosensitization effect in both monolayer and tumoroid models."

Ataxia • Ewing Sarcoma • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Sarcoma • Solid Tumor • CHEK1 • DUX4

Targeting immune signaling to overcome radioresistance by increasing DNA damage in breast cancer cells (EACR 2025) - "Cellular survival after irradiation (IR) and ATR inhibition (ATRi) by AZD6738 was assessed by colony formation assay... These results show that immune signaling was enhanced by DNA damage-induced activation of cGAS/STING signaling after combined treatment of IR and ATRi in radioresistant, BRCA1-mutated BC cells. This consequently led to a radiosensitizing effect, which may open up new avenues for the treatment of patients that developed a resistance to RT."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • BRCA1 • CHEK1 • CXCL10 • IFIT1 • IFNB1 • STAT1

Exploring the Efficacy of AZD6738 in Corneal Neovascularization: Autophagy Enhancement and Angiogenesis Inhibition. (PubMed, J Ocul Pharmacol Ther) - " AZD6738 showed potential in preventing CNV. Its ability to enhance autophagy and inhibit PI3K-AKT-VEGF pathways in angiogenesis suggests that AZD6738 could be an effective treatment strategy for CNV."

Journal • Ataxia • Fibrosis • Immunology • Movement Disorders • Primary Immunodeficiency • AMPK • ATR • BECN1 • KDR

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 | Terminated | Sponsor: Gordon Mills, MD, PhD | Trial completion date: Nov 2025 ➔ Dec 2024 | Active, not recruiting ➔ Terminated; loss of funding

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

Therapeutic potential of BOLD-100, a GRP78 inhibitor, enhanced by ATR inhibition in pancreatic ductal adenocarcinoma. (PubMed, Cell Commun Signal) - "BOLD-100 synergizes with AZD6738, an ATR inhibitor, to enhance anti-tumor efficacy compared to either agent alone in both in vitro and in vivo models. These findings suggest that BOLD-100, especially in combination with an ATR inhibitor, represents a promising therapeutic option for patients with PDAC."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CHEK1 • HSPA5

Novel ATR/PARP1 Dual Inhibitors Demonstrate Synergistic Antitumor Efficacy in Triple-Negative Breast Cancer Models. (PubMed, Adv Sci (Weinh)) - "A novel series of ATR/PARP1 dual inhibitors is developed through the pharmacophore fusion of AZD6738 and Olaparib. B8 also enhanced γH2AX expression in tumor tissues. These findings confirm the synergistic effects of ATR/PARP1 co-inhibition and highlight the potential of this novel inhibitor class for TNBC therapy."

Journal • Preclinical • Ataxia • Breast Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Triple Negative Breast Cancer

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: Apr 2025 ➔ Oct 2025

Trial completion date • Solid Tumor

Results of a phase II trial of olaparib in combination with ceralasertib in patients with recurrent and unresectable osteosarcoma. (ASCO 2025) - P2 | "The observed response to cisplatin in osteosarcoma, in vitro susceptibility of osteosarcoma cell lines to ATR and PARP inhibitors, and the presence of mutations in genes involved in DDR served as the basis for the development of this trial. The study did not meet the predetermined threshold for efficacy for Cohort 1; however, a subset of patients may be benefit from this combination treatment. Results of Cohort 2 (resectable osteosarcoma limited to the lung parenchyma) will be reported separately. Assessment of potential biomarkers of response is underway."

Clinical • Combination therapy • P2 data • Anemia • Hematological Disorders • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

A phase 2 study of the olaparib and AZD6738, an ATM/ATR inhibitor, in isocitrate dehydrogenase (IDH) mutant solid tumors. (ASCO 2025) - P2 | "Olaparib with AZD6738 did not demonstrate activity in IDH mutant solid tumors. However, the stability seen in the patient with low-grade tumors could suggest that the effect is restricted to lower-grade tumors, still dependent on IDH mutations. Further evaluation of the correlative data is required to elucidate why pre-clinical evidence suggesting potential efficacy did not translate into clinical benefit in IDH mutant solid tumors."

P2 data • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • Glioma • Oncology • Sarcoma • Solid Tumor • HRD • IDH1 • IDH2

Ceralasertib (cerala) + olaparib (ola) in patients (pts) with homologous recombination repair (HRR)-deficient platinum-sensitive relapsed ovarian cancer (OC) after progression on prior PARP inhibitor (PARPi) treatment (tx). (ASCO 2025) - P1/2 | "In this setting of high unmet need, cerala + ola had acceptable safety, a low discontinuation rate, and clinical activity in both BRCAm/HRRm and HRD+/non-BRCAm pts after progression on a prior PARPi. Exploratory analyses highlighted emerging PARPi resistance mechanisms; ongoing assessments of PARPi resistance to inform pt selection and novel combination strategies in post-PARPi settings will be presented."

Clinical • Platinum sensitive • Anemia • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • BRCA • HRD • PALB2 • RAD51 • RAD51C • RAD51D • TP53BP1

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

Enrollment open • Solid Tumor

National Lung Matrix Trial: Multi-drug Phase II Trial in Non-Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=423 | Active, not recruiting | Sponsor: University of Birmingham | Trial completion date: Sep 2024 ➔ Sep 2025 | Trial primary completion date: Sep 2024 ➔ Sep 2025

IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • NKX2-1 • TP63

Sequential ATR and PARP inhibition overcomes acquired DNA damaging agent resistance in pancreatic ductal adenocarcinoma. (PubMed, Br J Cancer) - "We provide in vitro evidence of a novel therapeutic strategy to overcome acquired resistance to PARP inhibitor and platinum in PDAC, using sequential exposure to ceralasertib and olaparib. A sequential regimen should be investigated clinically to circumvent dose limiting toxicity seen in concurrent combinations."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Disruption of ATR Signaling by Epstein-Barr Virus Latent Membrane Protein 1 Sensitizes Nasopharyngeal Carcinoma Cells to Cisplatin. (PubMed, J Med Virol) - "Inhibition of ATR (VE821 or AZD6738), but not ATM (KU55933 or AZD0156), phenocopied the G1 arrest and hypersensitivity. Publicly available RNA-sequencing data from microdissected NPC tumors showed that LMP1 expression in the primary tumors was the lowest in cisplatin-treated patients that experienced recurrence. These findings could have clinical significance in stratifying NPC patients such that tumors with limited or variable LMP1 expression might benefit from ATR inhibitor therapy."

Journal • Epstein-Barr Virus Infections • Immunology • Infectious Disease • Nasopharyngeal Carcinoma • Oncology • Solid Tumor

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