NeoOPTIMIZE: Early Switching of mFOLFIRINOX or Gemcitabine/Nab-Paclitaxel Before Surgery for the Treatment of Resectable, Borderline Resectable, or Locally-Advanced Unresectable Pancreatic Cancer

• Ability to understand and the willingness to sign a written informed consent document
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

• Cytologic or histologic proof pancreatic ductal carcinoma is required prior to study entry

  • If a biopsy (e.g., endoscopic ultrasound [EUS]-guided fine needle aspiration [FNA]) is planned per standard of care, the participant may be asked to consent to the additional collection of tumor tissue for research

• No evidence of metastatic disease as determined by chest computed tomography (CT) scan, abdomen/pelvis computed tomography (CT) scan (or magnetic resonance imaging [MRI] with gadolinium and/or manganese) within the 45-day window of study entry or prior to the one cycle of standard of care (SOC) administered before study entry, which is consistent with the standard of care

  • Note: On a case by case basis, for participants who enroll on trial after having received up to 1 month of standard of care chemotherapy per Investigator discretion, baseline radiographic imaging performed per institutional guidelines prior to SOC chemotherapy treatment may be used per investigator discretion to fulfill baseline radiographic imaging criteria even if performed > 45 days prior to official study entry.

• Diagnostic staging laparoscopy is not required for study eligibility

  • If staging laparoscopy is planned per standard of care, the participant may be asked to consent to the collection of tumor tissue for research

• At time of screening, per National Comprehensive Cancer Network (NCCN) criteria, must have either:

  • Resectable pancreatic ductal adenocarcinoma (PDAC), defined as no arterial tumor contact (celiac axis [CA], superior mesenteric artery [SMA], or common hepatic artery [CHA]), or
  • Node positive disease as defined by CT, MRI, or EUS imaging, or

  • Borderline resectable PDAC, defined as:

    • For tumors of the head or uncinate process:

      • Solid tumor contact with the superior mesenteric vein (SMV) or portal vein of > 180 degrees with contour irregularity of the vein or thrombosis of the vein, but with suitable vessel proximal and distal to the site of involvement, allowing for safe and complete resection and vein reconstruction
      • Solid tumor contact with the inferior vena cava
      • Solid tumor contact with the common hepatic artery without extension to the celiac axis or hepatic artery bifurcation, allowing for safe and complete resection and reconstruction
      • Solid tumor contact with the SMA =\< 180 degrees
      • Solid tumor contact with variable anatomy (e.g., accessory right hepatic artery, replaced right hepatic artery, replaced common hepatic artery, and the origin of replaced or accessory artery), and the presence and degree of tumor contact should be noted if present, as it may affect surgical planning

    • For tumors of the body/tail:

      • Solid tumor contact with the celiac axis of =\< 180 degrees
      • Solid tumor contact with the celiac axis >180 degrees without involvement of the aorta and with an intact and uninvolved gastroduodenal artery, thereby permitting a modified Appleby procedure (although some members of the consensus committee preferred this criterion to be in the unresectable category)

  • Locally-advanced, unresectable disease as defined by NCCN guidelines as follows:

    • Tumors of the head with SMA >= 180 degrees, or any celiac abutment, unreconstractable SMV or portal occlusion, or aortic invasion or encasement
    • Tumors of the body with SMA or celiac encasement 180 degrees, unreconstractable SMV or portal occlusion, or aortic invasion
    • Tumors of the tail with SMA or celiac encasement >= 180 degrees
    • Irrespective of location, all tumors with evidence of nodal metastasis outside of the resection field that are considered unresectable
• Must be deemed fit to undergo planned curative resection as determined by institutional standards
• No history of previous chemotherapy for pancreatic cancer. At the discretion of the principal investigator (PI), patient that have received no more than 1 month of systemic chemotherapy (e.g., mFOLFIRINOX), per standard of care, for the treatment of their PDAC may be eligible to participate
• For participants who will get INV losartan, baseline systolic blood pressure (BP) > 100 mm Hg taken as the average of 3 blood pressure readings

• Hemoglobin > 9 g/dL with no blood transfusion within 28 days of starting treatment (prior to the one month of standard of care chemotherapy allowed by the protocol or within 4 weeks of screening)

  • Note: On a case by case basis, for participants who enroll on trial after having received up to 1 month of standard of care chemotherapy per Investigator discretion, labs prior to initiation of SOC chemotherapy treatment may be used per Investigator discretion to fulfill screening lab requirements even if performed > 4 weeks prior to official study entry and/or there are more recent labs available from during chemotherapy treatment

• Absolute neutrophil count (ANC) >= 1.0 x 10\^9/L (> 1000 cells/mm\^3) (prior to the one month of standard of care chemotherapy allowed by the protocol or within 4 weeks of screening)

  • Note: On a case by case basis, for participants who enroll on trial after having received up to 1 month of standard of care chemotherapy per Investigator discretion, labs prior to initiation of SOC chemotherapy treatment may be used per Investigator discretion to fulfill screening lab requirements even if performed > 4 weeks prior to official study entry and/or there are more recent labs available from during chemotherapy treatment
  • May be waived on a case-by-case basis for patient populations recognized to have normal baseline values below this level
• Platelet count >= 100 x 10\^9/L (> 100,000 per mm\^3) (at time of registration and within 4 weeks prior to initiating study therapy)

• Creatinine =\< 1.5 mg/dL OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30 mL/min/1.73 m\^2 for participants with creatinine levels > 1.5 x institutional upper limit of normal (ULN) prior to the one month of standard of care chemotherapy allowed by the protocol or within 4 weeks of screening)

  • Note: On a case by case basis, for participants who enroll on trial after having received up to 1 month of standard of care chemotherapy per Investigator discretion, labs prior to initiation of SOC chemotherapy treatment may be used per Investigator discretion to fulfill screening lab requirements even if performed > 4 weeks prior to official study entry and/or there are more recent labs available from during chemotherapy treatment
  • Creatinine clearance should be calculated per institutional standard. For participants with a baseline calculated creatinine clearance below normal institutional laboratory values, a measured baseline creatinine clearance should be determined. Individuals with higher values felt to be consistent with inborn errors of metabolism will be considered on a case-by-case basis

• Serum bilirubin =\< 1.5 x institutional upper limit of normal (ULN); or =\< 2 x ULN or 2 down-trending values for individuals who have undergone biliary stenting prior to the one month of standard of care chemotherapy allowed by the protocol or within 4 weeks of screening)

  • Note: On a case by case basis, for participants who enroll on trial after having received up to 1 month of standard of care chemotherapy per Investigator discretion, labs prior to initiation of SOC chemotherapy treatment may be used per Investigator discretion to fulfill screening lab requirements even if performed > 4 weeks prior to official study entry and/or there are more recent labs available from during chemotherapy treatment

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =\< 2.5 x ULN, OR two consecutive down-trending values for individuals who have undergone biliary stenting prior to the one month of standard of care chemotherapy allowed by the protocol or within 4 weeks of screening)

  • Note: On a case by case basis, for participants who enroll on trial after having received up to 1 month of standard of care chemotherapy per Investigator discretion, labs prior to initiation of SOC chemotherapy treatment may be used per Investigator discretion to fulfill screening lab requirements even if performed > 4 weeks prior to official study entry and/or there are more recent labs available from during chemotherapy treatment
• Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to initiating study therapy. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Female participants of childbearing potential agree to use adequate methods of contraception starting with the first dose of study therapy through 30 days after the last dose of study therapy

  • Participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year without an alternative medical cause
• Male participants must agree to use an adequate method of contraception starting with the first dose of study therapy through 30 days after the last dose of study therapy
• Male patients must use a condom during treatment when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male participant should also use a highly effective form of contraception if they are of childbearing potential
• Participants currently receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) will remain eligible for study participation. In such cases, losartan will not be assigned as part of the study intervention. These participants will continue to receive their ACE inhibitor or ARB per standard-of-care. The ACE inhibitor or ARB type should be recorded as a concomitant medication (including dose and frequency)

Exclusion Criteria:

• History of previous chemotherapy (other than no more than one cycle of standard systemic chemotherapy), targeted/biologic therapy, or radiation therapy for the treatment of their PDAC
• Evidence of metastasis to distant organs (liver, peritoneum, lung, others)
• Any other active malignancy or prior history of malignancy with less than a 90% cure rate in the judgement of the investigators
• Medical co-morbidities that are deemed to make risk of surgery unacceptably high as determined by institutional standards
• Personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. Patients with cardiovascular conditions that are well-controlled in the clinical judgement of the treating oncologist are eligible to participate
• Recent major surgery (excluding laparoscopy) within 4 weeks prior to starting study treatment. Minor surgery within 2 weeks of starting study treatment. Patients must be recovered from effects of surgery
• Concomitant use of other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy [hormone replacement therapy is acceptable]), not otherwise allowed in this study. Note: participation in other trials for supportive cancer care (e.g., cancer-related cachexia) interventions is permitted per PI discretion.
• Participants with a history of hypersensitivity reactions to study agents or their excipients. In cases of losartan hypersensitivity, losartan will be omitted and patient may still be eligible to participate
• Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 30 days after the last dose of trial therapy
• Psychiatric illness/social situations, or any condition that, in the opinion of the investigator, would: interfere with evaluation of study treatment or interpretation of participant safety or study results, or substantially increase risk of incurring adverse events (AEs), or compromise the ability of the patient to give written informed consent
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements