Testing the Combination of Anti-Cancer Drugs, Selumetinib and DS-8201a (Trastuzumab Deruxtecan), for Advanced Pancreatic Ductal Adenocarcinoma

Inclusion Criteria: * Review of eligibility criteria by the study principal investigator (PI) is required prior to enrollment * Patients must have histologically or cytologically confirmed adenocarcinoma of the pancreas * Patients must have unresectable or metastatic disease with KRAS mutation per Next Generation Sequencing (NGS) tumor testing and HER2 immunohistochemistry (IHC) positivity (2+ or above for dose escalation and per decision rule for phase II), as determined by a Clinical Laboratory Improvement Act (CLIA)-certified kit using gastric cancer criteria * Patients must have measurable disease that can fulfill Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria * Patients must have exposure to at least one line of systemic chemotherapy for metastatic or unresectable PDAC (for both escalation and phase II cohorts) or a documented patient decision to forego therapy that has an otherwise proven survival advantage (for escalation cohort only) * Patients who have received prior topoisomerase inhibitors including irinotecan and nanoliposomal irinotecan will be eligible for this study * Only 1 prior line of therapy for metastatic or unresectable PDAC will be allowed for patients in the phase II cohort. Adjuvant or neoadjuvant therapy does not count, assuming it was completed \> 6 months prior to the start of systemic therapy for metastatic or unresectable disease * Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of selumetinib (AZD6244 hydrogen sulfate) in combination with DS-8201a (trastuzumab deruxtecan) in patients \< 18 years of age, children are excluded from this study * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 70%). Regardless of performance status, enrollment should be based on the judgment of the treating physician that the patient will be able to be safely treated with the proposed therapeutic intervention * Hemoglobin ≥ 9 g/dL (within 14 days of enrollment) * No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment * Leukocytes ≥ 3,000/mcL (within 14 days of enrollment) * Absolute neutrophil count ≥ 1,500/mcL (within 14 days of enrollment) * No administration of granulocyte colony-stimulating factor (G-CSF) is allowed within 1 week prior to screening assessment * Platelets ≥ 100,000/mcL (within 14 days of enrollment) * Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN), (\< 3 × ULN in the presence of documented Gilbert's syndrome or liver metastases at baseline) (within 14 days of enrollment) * Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) \< 5 × ULN in participants with liver metastases (within 14 days of enrollment) * Serum albumin ≥ 2.5 g/dL (within 14 days of enrollment) * International Normalized Ratio (INR)/Prothrombin Time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (within 14 days of enrollment) * Creatine phosphokinase (CPK) ≤ 2.5 × ULN (within 14 days of enrollment) * Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m\^2 (within 14 days of enrollment) * 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 * Patients with treated brain metastases are eligible if follow-up brain imaging, performed at least 6 months after central nervous system (CNS)-directed therapy, shows no evidence of progression * Patients 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 * Patients with a known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must undergo a clinical risk assessment of cardiac function using the New York Heart Association (NYHA) Functional Classification. To be eligible, patients must be NYHA Class II or better and have no history of myocardial infarction within 6 months prior to enrollment, no symptomatic congestive heart failure (NYHA Class IIb-IV), and no troponin levels consistent with myocardial infarction (as defined by the manufacturer) within 28 days prior to enrollment * Patients must have a baseline left ventricular ejection fraction (LVEF) ≥ 50% as measured by echocardiogram (ECHO) or mutilated acquisition scan (MUGA) scan within 28 days before randomization/enrollment * Patients must be willing to undergo baseline ophthalmic evaluation, including visual acuity and slit-lamp examination * The effects of selumetinib (AZD6244 hydrogen sulfate) and DS-8201a (trastuzumab deruxtecan) on the developing human fetus are unknown. For this reason and because MEK inhibitor agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 7 months (for WOCBP) or 4 months (for men) after completion of drug administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately * Women of non-child-bearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrh