• Patients must have pathologically confirmed pancreatic adenocarcinoma. Patients with alternative or mixed histologies (i.e., squamous, neuroendocrine, acinar, colloid) are not eligible

• Received 4-6 months of induction chemotherapy with fluorouracil, irinotecan, leucovorin and oxaliplatin (FOLFIRINOX), fluorouracil, liposomal irinotecan, luecovorin, oxaliplatin (NALIRIFOX), or gemcitabine/Abraxane, as per standard of care

• Patients must have locally advanced pancreatic cancer according to National Comprehensive Cancer Network (NCCN) Guidelines (version 1.2020) on pancreas protocol CT scan performed within 21 days of registration. Locally advanced disease is defined as any of the following:

‣ For head or uncinate process tumors:

• Solid tumor contact with superior mesenteric artery \> 180 degrees

∙ Solid tumor contact with the celiac axis \> 180 degrees

∙ Solid tumor contact with the common or proper hepatic arteries \> 180 degrees or

⁃ For pancreatic body or tail tumors:

• Solid tumor contact of \> 180 degrees with the superior mesenteric artery or celiac axis

∙ Solid tumor contact with the celiac axis and aortic involvement or

⁃ Unreconstructible superior mesenteric vein or portal vein due to tumor involvement or occlusion (can be due to tumor or bland thrombus)

• The determination of locally advanced pancreatic cancer and plan for non-operative treatment on this clinical trial must be confirmed through local multi-disciplinary review

• Measurable disease per response evaluation criteria in solid tumors (RECIST) version (v)1.1

• Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of M3814 (peposertib) in combination with hypofractionated radiation in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials

• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)

• Leukocytes \>= 4,000/mcL

• Absolute neutrophil count \>= 1.5 x 10\^9/L.

• Hemoglobin \>= 9 g/dL

• Platelets \>= 100 x 10\^9/L

• Total bilirubin =\< 2.0 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 3 x institutional ULN

• Creatinine =\< 1.5 x institutional ULN

• Glomerular filtration rate (GFR) \>= 51 mL/min/1.73 m\^2

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

• Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female patients of childbearing potential and male patients must be willing to use an adequate method of contraception for the course of the study through 12 weeks after the last dose of study medication.

‣ Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.

• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function. To be eligible for this trial, patients should be American Heart Association Stage B (people without current or previous symptoms of heart failure but with either structural heart disease, increased filling pressures in the heart or other risk factors) or better and New York Heart Association Functional Classification II (slight limitation of physical activity, comfortable at rest, ordinary physical activity results in fatigue, palpitation, shortness of breath or chest pain), or better

• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) and/or family member available will also be eligible