peposertib (M3814) / EMD Serono - LARVOL DELTA

Efficacy Enhancement of PSMA-Targeted a- and ß --TRT by DNA-PK Inhibition Enables Dose De-Escalation (ASTRO 2026) - "Although [Lu-177]Lu- and [Ac-225]Ac-PSMA-617 demonstrate promising results in metastatic castration-resistant prostate cancer, 20-30% of patients exhibit primary or acquired TRT-resistance despite adequate target expression...For proof-of-concept combination study, PSMA-TRT was paired with Nedisertib®, a second-generation DNA-PK inhibitor targeting the non-homologous end-joining DNA repair pathway... DNA-PK inhibition significantly enhances the therapeutic response to PSMA-TRT and enables dose de-escalation. The response even in PSMA-negative PC-3 cells highlights the potential of Ac-225-based combination strategies for overcoming radioresistance. These findings support further mechanistic studies and in vivo validation of PSMA-TRT/DNA-PK inhibitor combinations."

Clinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Phase I Trial with Expansion Cohort of DNA-PK Inhibitor Peposertib and Intensity Modulated Radiation Treatment (IMRT) in Cisplatin-Ineligible Patients with Stage 3-4 Local-Regionally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC) (ASTRO 2026) - "The MTD of peposertib with IMRT in cisplatin-ineligible patients with local-regionally advanced HNSCC was established at 50 mg/d. Using NRG HN004 results as a reference, peposertib at 50 mg demonstrated comparable incidence of grade =3 toxicity to other non-platinum radio-sensitizing agents concurrent with IMRT in the treatment of HNSCC."

Clinical • Metastases • P1 data • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Phase I trial of M3814 (Peposertib) in combination with lutetium 177 DOTATATE for metastatic well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) (ENETS 2026) - P1 | "The combination of oral peposertib with Lu-177 do - tatate is safe, a promising radiation sensitizer in NET patients, and should be investigated in larger randomized clinical trials."

Combination therapy • Metastases • P1 data • Gastrointestinal Neuroendocrine Tumor • Neuroendocrine Tumor • Oncology • Solid Tumor • SSTR

ETCTN 10450: A phase I trial of peposertib and lutetium 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). (ASCO-GI 2023) - "In addition, the study will correlate clinical outcome with somatic tumor mutations and germline mutations. Clinical trial information: 04750954."

P1 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • SSTR

Differential Radiobiological Effects of Αlpha- and Beta-Minus-Emitter Targeted Radionuclide Therapy: DNA Damage and Survival. (PubMed, Int J Radiat Oncol Biol Phys) - "Our study defines key determinants for optimizing TRT. Cellular internalization is critical for short-range α-emitters, whereas β⁻-emitters depend on high binding affinity and retention, providing experimental guidance for radiopharmaceutical design and radionuclide selection. Distinct DNA repair kinetics underscore radionuclide‑specific biological effects. Combining TRT with DNA‑PK inhibition represents a promising strategy to enhance efficacy, enable activity de‑escalation, and potentially mitigate toxicity."

Journal • Gene Therapies • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Testing the Combination of Two Anti-cancer Drugs, Peposertib (M3814) and Tuvusertib (M1774) for Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=66 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Aug 2026 ➔ Aug 2027 | Trial primary completion date: Aug 2026 ➔ Aug 2027

Trial completion date • Trial primary completion date • Oncology • Solid Tumor • ARID1A • ARID1B • ARID2 • ATM • ATRX • CCNE1 • FBXW7 • MYC • PBRM1 • SMARCA2 • SMARCB1 • SS18

A Study Combining the Peposertib (M3814) Pill With Standard Chemotherapy in Patients With Ovarian Cancer With an Expansion in High Grade Serous Ovarian Cancer and Low Grade Serous Ovarian Cancer (clinicaltrials.gov) - P1 | N=55 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2026 ➔ Jun 2027 | Trial primary completion date: Jun 2026 ➔ Feb 2026

Platinum resistant • Platinum sensitive • Trial completion date • Trial primary completion date • Carcinosarcoma • Fallopian Tube Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Peritoneal Cancer • Sarcoma • Solid Tumor • Urothelial Cancer

ETCTN 10366: Testing the Addition of a New Anti-cancer Drug, M3814 (Peposertib), to the Usual Radiotherapy in Patients With Locally Advanced Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=92 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Aug 2026 ➔ Aug 2027 | Trial primary completion date: Aug 2026 ➔ Aug 2027

Trial completion date • Trial primary completion date • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

A novel combination approach targeting P300 and DNA-PK exploits epigenetic dependencies in acute myeloid leukemia. (PubMed, Mol Ther Oncol) - "Consequently, our results show that CARM1 dependencies could also be exploited by utilizing inobrodib, a p300/CBP bromodomain inhibitor that synergizes with peposertib treatment in AML cells. Overall, these data demonstrate a rational approach for combination therapy by exploiting dependencies through inhibition of proximal effector function in addition to essential NHEJ repair, targeting its rate-limiting enzyme complex, thereby resulting in synergistic inhibition in primary AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Phase I Trial of DNA-PK Inhibitor (PEPOSERTIB ) in Combination With Radiation and Adjuvant Temozolomide in Newly Diagnosed MGMT Unmethylated and Recurrent Glioblastoma (clinicaltrials.gov) - P1 | N=29 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting

Enrollment closed • Brain Cancer • Glioblastoma • Gliosarcoma • Oncology • Sarcoma • Solid Tumor • IDH1 • MGMT

Radiation Medication (Radium-223 Dichloride) Versus Radium-223 Dichloride Plus Radiation Enhancing Medication (M3814) Versus Radium-223 Dichloride Plus M3814 Plus Avelumab (a Type of Immunotherapy) for Advanced Prostate Cancer Not Responsive to Hormonal Therapy (clinicaltrials.gov) - P1/2 | N=90 | Suspended | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Suspended

Trial suspension • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Resistance-centered pharmacology of DNA damage response-targeted therapy: Mechanisms, predictive biomarkers, and biomarker-guided adaptive treatment strategies in solid tumors. (PubMed, Biomed Pharmacother) - "Yet inevitable therapeutic resistance limits durability of clinical benefit and now defines the central pharmacological challenge of the field, driving development of next-generation DDR inhibitors including saruparib, ART6043, RP-3467, ART0380/alnodesertib, ceralasertib, and peposertib. We propose a biomarker-guided adaptive treatment algorithm integrating longitudinal circulating tumor DNA monitoring, functional RAD51 foci assays, and AI-driven multi-omics integration to enable real-time resistance detection and mechanism-guided therapy switching. This framework advances DDR-targeted oncology from static biomarker selection toward a dynamic, resistance-aware, mechanism-matched therapeutic strategy for patients with metastatic solid tumors."

Biomarker • Journal • Review • Oncology • Solid Tumor • ABCB1 • BRCA1 • BRCA2 • RAD51 • STING • TP53BP1

VENETOCLAX IN COMBINATION WITH THE DNA-PK INHIBITOR M3814 (PEPOSERTIB) AS A NOVEL THERAPEUTIC STRATEGY FOR RESISTANT CHRONIC LYMPHOCYTIC LEUKEMIA (EHA 2026) - "We previously found that M3814 is synergistic with chemotherapy, but not ibrutinib, in CLL cells (Kost, S. et al 2023, Blood Cancer J). Summary/Conclusion These novel results indicate that DNA-PK inhibition by M3814 is cytotoxic to CLL cells and enhances the activity of VEN particularly in VEN-resistant cells, possibly due to M3814 toxicity to mitochondria. As M3814 is not myelosuppressive it may clinically improve the therapeutic efficacy of VEN, in addition to potentially reversing drug resistance."

Combination therapy • IO biomarker • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • ANXA5 • BCL2 • CD40LG • IGH • TP53

Testing the Addition of An Anti-cancer Drug, M3814 (Peposertib), to the Usual Radiation-Based Treatment (Lutetium Lu 177 Dotatate) for Pancreatic Neuroendocrine Tumors (clinicaltrials.gov) - P1 | N=29 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2026 ➔ Dec 2026 | Trial primary completion date: Jun 2026 ➔ Dec 2026

Trial completion date • Trial primary completion date • Endocrine Cancer • Gastrointestinal Neuroendocrine Tumor • Neuroendocrine Tumor • Oncology • Solid Tumor

Testing the Addition of an Anti-cancer Drug, M3814, to the Usual Treatment (Mitoxantrone, Etoposide, and Cytarabine) for Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=48 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2026 ➔ Jun 2027 | Trial primary completion date: Jun 2026 ➔ Jun 2027

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD4 • PML • RARA

A Dual-Viral Delivery Platform Enables Efficient Site-Specific Integration of Therapeutic-Length Genes in Human Primary Stem Cells. (PubMed, Hum Gene Ther) - "In head-to-head comparisons, TIVID outperformed lentivirus-derived nanoparticles (∼50% vs. <10% at AAVS1 in K562 with M3814) and plasmid-based eePASSIGE in iPSCs (∼20% vs. ∼1.5%). Compared with traditional electroporation delivery, TIVID offers lower early cytotoxicity, promotes predominantly mono-allelic integration, and exhibits enhanced compatibility with primary stem cells. By decoupling nuclease and donor delivery, TIVID circumvents the payload constraints of single-vector systems and the toxicity of physical transfection, providing a robust ex vivo engineering platform for complex gene replacement therapies."

Journal • Beta-Thalassemia • Gene Therapies • Genetic Disorders • CD34

Oncolytic HSV Synergizes with DNA-PKcs Inhibition to Abrogate Stemness and DNA Repair in Glioblastoma (ASGCT 2026) - "DNA-PKcs pharmacological inhibitors included NU7441, AZD7648, VX-984, and predominantly M3814 (Peposertib), a selective, brain-penetrant inhibitor currently in clinical trial...GSCs transduced with doxycycline-inducible DNA-PKcs shRNA were used to validate selectivity...Integrating DDR inhibition with oHSV therapy simultaneously attacked stemness and DNA repair, two critical survival pathways, offering a novel synthetic lethal-like approach. These results warrant further clinical investigation of oHSV and DNA-PKcs inhibitors in GBM and potentially other solid tumors."

Brain Cancer • Glioblastoma • Herpes Simplex • Infectious Disease • Solid Tumor • MYC • SOX2

Non-viral knock-in of long HDR donors in hematopoietic stem and progenitor cells using circular single-stranded DNA for CDAII gene therapy (ASGCT 2026) - "The incorporation of HDR enhancers, such as M3814 and AZD7648 (DNA-PK inhibitors) and XL413 (CDC7 inhibitor), nearly doubled the knock-in efficiency for both donor types. Conclusion These results demonstrate that the cssDNA platform is a feasible system for the knock-in of long HDR donors in engraftable HSPCs. Our study establishes cssDNA as a promising non-viral HDR donor format for targeted gene therapy of CDAII and other hematopoietic disorders, paving the way for safer HDR strategies in HSPCs."

Gene therapy • IO biomarker • Bone Marrow Transplantation • Gene Therapies • Hematological Disorders • CD34 • CD38 • CDC7 • SEC23B • THY1

ETCTN 10563: Testing Low-Dose Common Chemotherapy (Liposomal Doxorubicin) in Combination With an Anti-Cancer Drug, Peposertib, in Advanced Sarcoma (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: May 2026 ➔ Nov 2026 | Trial primary completion date: May 2026 ➔ Nov 2026

Trial completion date • Trial primary completion date • Leiomyosarcoma • Liposarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma • Undifferentiated Pleomorphic Sarcoma

A phase 1 trial of M3814 (peposertib) in combination with lutetium 177 DOTATATE for metastatic well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) (AACR 2026) - P1 | "Combination of oral peposertib with Lu-177 dotatate is a safe and promising radiation sensitizer in NET patients. This combination is suitable for investigation in a larger randomized clinical trial."

Combination therapy • Metastases • P1 data • Gastrointestinal Neuroendocrine Tumor • Neuroendocrine Tumor • Oncology • Solid Tumor • SSTR

Radiation Medication (Radium-223 Dichloride) Versus Radium-223 Dichloride Plus Radiation Enhancing Medication (M3814) Versus Radium-223 Dichloride Plus M3814 Plus Avelumab (a Type of Immunotherapy) for Advanced Prostate Cancer Not Responsive to Hormonal Therapy (clinicaltrials.gov) - P1/2 | N=90 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Apr 2026 ➔ Apr 2027 | Trial primary completion date: Apr 2026 ➔ Apr 2027

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

WNC0901 is a novel DNA-PK inhibitor and potent radiosensitizer of otherwise radioresistant solid tumors (AACR 2026) - "The in vivo efficacy of 50 mg/kg WNC0901 combined with 8 Gy was evaluated and compared to another DNA-PK inhibitor, 50 mg/kg peposertib, in A549 tumor heterotopic xenografts. In a second study, similarly robust sensitizing effects of WNC0901 was observed in HT29 xenografts (placebo - median 45 days; RT - median 75 days; RT + WNC0901 - median >110 days; p=.03 relative to RT). Together, these findings demonstrate the robust radiosensitizing effects of WNC0901 in radioresistant tumors and provide a rationale for continued development of this drug."

Lung Cancer • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

PRKDC regulates CDK2 expression and pancreatic neuroendocrine cancer sensitivity to chemotherapy (AACR 2026) - "These findings support a role for DNA-PK in mediating CDK2 upregulation in response to chemotherapy and highlight the clinical relevance of low PRKDC and CDK2 expression with improved survival in NET patients. Collectively, these findings identify a PRKDC-CDK2 survival axis as a driver of chemoresistance and demonstrate that sustained, low‑intensity DNA damage, when coupled with selective DNA‑PK inhibition, disrupts this adaptive program, substantially reduces metastatic burden, and delivers more durable responses in pNETs.AI use disclosure: Portions of this abstract were revised with the assistance of generative AI and were fully reviewed and verified by the authors."

Endocrine Cancer • Gastrointestinal Neuroendocrine Tumor • Neuroendocrine Tumor • Oncology • Solid Tumor • CDK2 • PRKDC

Synthetic lethality opportunities for tumors with MMEJ deficiency (AACR 2026) - "In addition, the combination of Peposertib and the topoisomerase inhibitor etoposide synergistically eliminated EwS cells in vitro and in vivo. Third, the EWS-FLI1 fusion oncoprotein binds and inactivates EWSR1 and causes an exon 25 splicing defect, leading to exon skipping and loss of POLQ protein expression. Fourth, the MMEJ deficiency of EwS cells results in enhanced cellular sensitivity to inhibitors of other DNA Repair pathways, providing a strategy for synthetic lethality therapy."

Synthetic lethality • Breast Cancer • Ewing Sarcoma • Oncology • Osteosarcoma • Ovarian Cancer • Sarcoma • Solid Tumor • BRCA1 • BRCA2 • EWSR1 • FLI1 • FUBP1 • HRD • LIG3 • POLQ

Targeting the DNA double-strand break repair pathways in MYCN-amplified neuroblastoma increases tumor sensitivity to chemotherapy (AACR 2025) - "High-risk NB is correlated with extensive genomic instability, and here we showed that upregulation of NHEJ is associated MNA high-risk NB. DNA-PKcs knockdown studies revealed that the survival of MNA NB cells depends on the activity of NHEJ pathway, paving the way for more targeted treatments. The significant response of NB cells to the combination of Peposertib and Olaparib highlights a promising strategy to enhance NB cell sensitivity to conventional therapies, particularly Doxorubicin."

Neuroblastoma • Oncology • Solid Tumor • MYCN • PRKDC • XRCC5