Inclusion Criteria:
* The clinical, radiographic, and pathologic evidence support a diagnosis of pancreatic adenocarcinoma, with histology confirmatory for adenocarcinoma, adenosquamous carcinoma, or poorly differentiated carcinoma.
* Subjects must be determined to meet the criteria for resectable pancreatic cancer based on National Comprehensive Cancer Network (NCCN) criteria at initial diagnosis (Table 2). Patients with borderline resectable, locally advanced, or metastatic disease are not eligible for this trial.
Resectability status
* Resectable
* Borderline resectable
* Locally advanced
Arterial
* No arterial tumor contact (celiac axis (CA), superior mesenteric artery (SMA), or common hepatic artery (CHA))
* Pancreatic head/uncinate process:
* Solid tumor contact with CHA without extension to CA or hepatic artery bifurcation allowing for safe and complete resection and reconstruction.
* Solid tumor contact with the SMA of ≤180°.
* Solid tumor contact with variant arterial anatomy (eg, accessory right hepatic artery, replaced right hepatic artery, replaced CHA, 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.
Pancreatic body/tail:
* Solid tumor contact with the CA of ≤180°.
Head/uncinate process:
* Solid tumor contact \>180° with the SMA or CA.
Pancreatic body/tail:
* Solid tumor contact of \>180° with the SMA or CA.
* Solid tumor contact with the CA and aortic involvement.
Venous -No tumor contact with the superior mesenteric vein (SMV) or portal vein (PV) OR ≤ 180° of contact without vein contour irregularity.
Solid tumor contact with the SMV or PV of \>180°, contact of ≤180° 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 (IVC). Not currently amenable to resection and primary reconstruction due to complete occlusion of SMV/PV
\*NCCN guideline definition of resectability status
* Prospective determination of RAS mutation status is not required
* Participants must be ≥ 18 years old
* Participants must have an ECOG performance status of 0 or 1
Participants must have adequate organ and marrow function as defined as:
* Absolute neutrophil count ≥1,500/mcL
* Platelets ≥100,000/mcL
* Hemoglobin ≥ 8 g/dL
* Total bilirubin ≤1.5 × institutional upper limit of normal (ULN) or \<2 x ULN in patients with Gilbert syndrome
* AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN
* Creatinine Calculated estimated glomerular filtration rate ≥60 mL/min
* Coagulation function PT/INR/PTT \<1.5 x ULN, or ≤ 2 x ULN for those on anticoagulation
* Female subjects of childbearing potential should have a negative urine or serum pregnancy 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 subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 9 months after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year.
* Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 6 months after the last dose of study therapy.
* Ability to swallow oral medications and willing to keep daily adherence record.
* Ability to understand and the willingness to sign a written informed consent document
* Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
* Presence of metastatic disease
* Requirement of pre-operative or neoadjuvant radiation therapy to primary pancreatic tumor as determined by multi-disciplinary tumor board.
* Tumors with the following histologic features in addition to an adenocarcinoma component are excluded: neuroendocrine, undifferentiated with osteoclast like giant cells, acinar, hepatoid, medullary carcinomas.
* Known BRAF activating mutation or gene rearrangement that is suggestive of resistance to daraxonrasib
* Prior treatment with MAPK targeted therapy including pan-RAS, pan-KRAS, KRAS mutant allele specific, BRAF, MEK, or ERK inhibitors.
* Treatment with any investigational agents within the last 14 days or 5 half-lives, whichever is shorter, from C1D1 of this trial drug. No prior treatment for pancreatic cancer is allowed.
* Has a left ventricular ejection fraction \<50% within 4 weeks, symptomatic heart failure within 4 weeks, acute coronary syndrome within 6 months or medically uncontrolled hypertension (\>160 mmHg systolic blood pressure or \>100 diastolic blood pressure) based on average of 3 readings.
* Prolonged QTc interval \>470ms, averaged from 3 electrocardiograms (EKGs).
* History of or active interstitial lung disease, pneumonitis, pulmonary fibrosis which required steroid treatment within 6 months.
* Known or suspected gastrointestinal disorder which may hinder ability to take PO drug or hinder absorption
* Requires treatment with systemic cyclosporine A or derivative
* Has had consumption within the last 14 days or 5 half-lives, whichever is shorter, from C1D1 of this trial drug or requires ongoing consumption of P-gp or CYP3A inducers or inhibitor (See APPENDIX B)
* Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study.
* Has a history of other cancers diagnosed or treated within last 3 years. Clinically insignificant cancers which require no significant treatment or tumors treated with definitive intent and with low risk of recurrence are not excluded. Discussion with sponsor investigator is encouraged.
* Subject is unable or unwilling to participate in a study related procedure.
* Has an active serious infection requiring systemic therapy
* Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
