Inclusion Criteria:
* Must have histologically confirmed FLC (Fibrolamellar Carcinoma) that is metastatic or unresectable.
* Presence of DNAJB1-PRKACA fusion transcript, assessed by RNA-sequencing, DNA-sequencing, or in situ hybridization in the archival tissue.
* Must have demonstrated radiographic progression on prior or current immunotherapy.
* Age ≥ 12 years.
* Patients \< 18 years old must have a body weight ≥ 40 kg.
* Eastern Cooperative Oncology Group (ECOG) performance status of ≤2
* Patients must have adequate organ and marrow function defined by study-specified laboratory tests.
* Patients must have adequate kidney and liver function defined by study-specified laboratory tests.
* Must have measurable disease per RECIST 1.1
* Willingness to provide tissue and blood samples for mandatory translational research.
* Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test.
* For both Women and Men, must use acceptable form of birth control while on study.
* Ability to understand and willingness to sign a written informed consent document.
Exclusion Criteria:
* Must have had chemotherapy or other systemic therapy or radiotherapy, as follows:
* Patients who have had chemotherapy, biological cancer therapy, or radiation 21 days prior to the first dose of study drug.
* Patients who have had surgery within 28 days of dosing of investigational agent, excluding minor procedures.
* Patients who have received other approved or investigational agents or device within 21 days of the first dose of study drug.
* Patients who have not recovered from acute adverse events to grade ≤1 or baseline due to agents administered, with exception of grade 2 fatigue, rash, and endocrinopathy successfully managed hormone replacement therapy, or alopecia or stable neuropathy, unless approved by the investigational new drug (IND) Sponsor.
* Patients with corrected QT interval (QTc) prolongation \> 470 ms according to Fridericia formula.
* Patients receiving potent inducers of Cytochrome P450 3A (CYP 3A4/5) (including apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin and St. John's Wort) that cannot be discontinued at least 14 days prior to Cycle 1 Day 1.
* Known sensitivity to or history of allergic reactions attributed to compounds of similar chemical or biologic composition of DRP-104 or durvalumab.
* Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
* Has a pulse oximetry of \<92% on room air or is on supplemental home oxygen.
* Active or untreated brain metastases or leptomeningeal metastases.
* Uncontrolled intercurrent active medical and/or psychiatric illness/social psychosocial problems that that would limit compliance with study requirements.
* Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, metastatic cancer, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant or breastfeeding.
* Has a known history of Human Immunodeficiency Virus (HIV)/AIDS.
* Has active hepatitis B. Patients with chronic or acute hepatitis B virus (HBV) infection .
* Have had evidence of active or acute diverticulitis, intra-abdominal abscess, or GI obstruction which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study.
* Patient is unwilling or unable to follow the study schedule for any reason.
* Patient is at the time of signing informed consent a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
* Evidence of clinical ascites.
* Participants a with history of prior unacceptable and/or life-threatening toxicities attributed to anti-programmed death-receptor 1 (PD1) or anti-PD-L1 (anti-programmed death-receptor 1) therapy.
* Has active autoimmune disease that has required systemic treatment in the past 2 years.
* Prior allogeneic stem cell transplantation or organ transplantation.
* Has a diagnosis of immunodeficiency.
* Systemic corticosteroids at immunosuppressive doses.
* Patients who have had either of the following procedures or medications within 4 weeks prior to initiation of study treatment:
* Any live, attenuated vaccine
* Allergen hypo sensitization therapy in the last 2 weeks
