The researchers are doing this study to find out whether using the chemotherapy regimen NALIRIFOX in combination with ablative dose radiation therapy (AD-XRT) and the standard chemotherapy drug capecitabine is an effective treatment approach for people with locally advanced or borderline resectable pancreatic ductal adenocarcinoma (PDAC) before surgery. This type of treatment approach is called total neoadjuvant therapy (TNT). The researchers will also look at whether the sequence of the treatment approach (NALIRIFOX + ADXRT and capecitabine followed by surgery, when it is possible) is effective and causes few or mild side effects in participants. An important purpose of the study is to see how the study treatment (NALIRIFOX + AD-XRT and capecitabine) affects participants' quality of life. The researchers will measure quality of life by having participants fill out questionnaires

Inclusion Criteria:

1. Subject has been informed about the nature of the study, has agreed to participate in the study, and has signed the informed consent form before participation in any study-related activities.

2. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 2 years and are deemed by the investigator to be at low risk for recurrence of that malignancy.

   Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, DCIS, stage I prostate cancer, and basal cell or squamous cell carcinoma of the skin.

3. A multidisciplinary discussion has been undertaken/planned which can include (a) discussion with medical/surgery oncology, (b) Hepatopancreaticobiliary Disease Management Team conference presentation, (c) direct consultation, with confirmation on consensus plan for TNT strategy and potential for future surgery. This plan needs to be documented in the medical record prior to initiation of treatment.

4. Male or nonpregnant and nonlactating female aged ≥18 years.

   1. Women of child-bearing potential (i.e., fertile, following menarche, and until becoming postmenopausal unless permanently sterile; permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) must test negative for pregnancy at the time of screening on the basis of a urine or serum pregnancy test. Postmenopausal women are defined as those who have had an absence of menstruation for at least 2 years. If necessary, follicle-stimulating hormone results >50 IU/L at screening are confirmatory in the absence of a clear postmenopausal history.
   2. Female subjects of reproductive potential must agree to use two effective methods of birth control during the study and for 9 months after the last dose of study medication.
   3. Male subjects must agree to use condoms during the study and for 4 months after the last dose of study medication'

Disease-specific inclusion criteria:

1. Histologically or cytologically confirmed PDAC that has not been previously treated.

2. Radiographically BR or LA PDAC in accordance with the NCCN 2.2021 definition, without evidence of distant metastases by CT.

3. Inoperable status after surgical exploration due to presence of locally advanced, unresectable disease without metastases, in patients who have recovered from surgery, is allowed.

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

5. Hematological, biochemical, and organ function inclusion criteria:

   1. Absolute neutrophil count (ANC) ≥1500/mm^3 without the use of hemopoietic growth factors within 7 days before treatment
   2. Platelet count ≥100,000/mm^3 .
   3. International normalized ratio (INR) <1.5 unless the patient is receiving anticoagulation therapy, in which case a therapeutic INR is acceptable. Anticoagulation therapy with low-molecularweight heparin or warfarin, whether medically indicated, is permitted.
   4. Adequate renal function, as evidenced by serum/plasma creatinine level <1.6 mg/dL

Exclusion Criteria:

1. Presence of metastatic pancreatic cancer (M1 disease)

2. Any other medical or social condition deemed by the investigator to be likely to interfere with a subject's ability to sign informed consent, cooperate, and participate in the study or who is likely to interfere with the interpretation of the results.

3. Unwilling or unable to comply with study procedures and/or study visits.

4. Medical co-morbidities, that preclude major abdominal surgery

5. Histologic diagnosis other than adenocarcinoma; however, adenosquamous variants are acceptable.

6. Receipt of chemotherapy, prior abdominal radiotherapy, and/or definitive resection for pancreatic cancer.

7. Grade >2 neuropathy.

8. Pregnant and/or nursing.

9. Uncontrolled active infection, which would preclude with the exception of resolving cholangitis which in the investigator opinion would render the treatment hazardous.

10. Known hypersensitivity to any of the components of the chemotherapeutic agents

11. Receipt of concurrent investigational therapy or within 30 days of protocol initiation.

    Additional criterion for the immunoPET imaging sub-study (n=20)

12. Previous anaphylactic reaction to human, humanized or chimeric antibody.

13. Refusal or inability to tolerate the scanning procedure (e.g. due to claustrophobia).

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.