Inclusion Criteria:

• Male and/or female.
• Age ≥ 18 years at the time of screening. For patients aged < 20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.
• Confirmed HCC (by imaging or histopathologically from biopsy specimen).
• No evidence of extrahepatic disease on any available imaging.
• Disease not amenable to curative surgery or transplantation or curative ablation.
• Disease must be amenable to TACE and anticipated to require no more than 4 TACE treatments to treat sites of disease within a ≤ 16-week period (Permitted modalities are DEB-TACE or cTACE (using an emulsion of Lipiodol® and a permitted chemotherapeutic agent as per institutional practice, followed by embolizing agents).
• Child-Pugh score class A to B7.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment 10. Patients with HBV infection, which is characterized by positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV DNA (≥ 10 IU/ml or above the limit of detection per local lab standard), must be treated with antiviral therapy, as per institutional practice. HBV antiviral therapy must be initiated prior to randomization and patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication. Patients must show evidence HBV stabilization or signs of viral response (e.g., reduction HBV DNA levels) prior to starting IP. Patients who test positive for anti-hepatitis B core (HBc) with undetectable HBV DNA (< 10 IU/ml or under the limit of detection per local lab standard) do not require antiviral therapy prior to randomization. These subjects will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥ 10 IU/ml or above the limit of detection per local lab standard). HBV DNA detectable subjects must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication.
• Patients with HCV infection must have management of this disease per local institutional practice throughout the study. HCV diagnosis is characterized by the presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody upon enrollment.
• At least 1 measurable intrahepatic lesion suitable for repeat assessments according to the following mRECIST criteria:
  • Liver lesions that show typical features of HCC on IV contrast-enhanced CT or MRI scans; i.e., hypervascularity in the arterial phase with washout in the portal or the late venous phase;
  • Viable, non-necrotic portion (arterial phase IV contrast-enhancing) that can be accurately measured at baseline as ≥ 10 mm in the longest diameter.
• Adequate organ and marrow function as defined below. Criteria “a,” “b,” “c,” and “f” may not be met with transfusions, infusions, or growth factor support administered within 14 days of starting the first dose:
  • Hemoglobin ≥ 9.0 g/dL;
  • Absolute neutrophil count ≥1000/µL;
  • Platelet count ≥ 75000/µL;
  • Total bilirubin ≤ 2.0 × the upper limit of normal (ULN);
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 × ULN;
  • Albumin ≥2.8 g/dL;
  • International normalized ratio ≤1.6;
  • 2+ proteinuria or less urine dipstick reading;
  • Calculated creatinine clearance (CL) ≥ 30 mL/min as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine CL.
  • Males: Creatinine CL = Weight (kg) × (140 - Age) (mL/min) 72 × serum creatinine (mg/dL);
  • Females: Creatinine CL = Weight (kg) × (140 - Age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL). 
• Must have a life expectancy of at least 12 weeks.
• Upper Endoscopy to evaluate varices and risk of bleeding is required within 6 months of randomization.
• Body weight >30 kg

Exclusion Criteria:

• Any history of nephrotic or nephritic syndrome.
• Clinically significant (e.g., active) cardiovascular disease, including:
  • Unstable angina within ≤ 6 months of randomization;
  • New York Heart Association Grade ≥ 2 congestive heart failure;
  • Poorly controlled cardiac arrhythmia despite medication (patient with rate controlled atrial fibrillation are eligible), or any clinically significant abnormal finding on resting ECG.
• Peripheral vascular disease Grade ≥ 3 (e.g., symptomatic and interfering with activities of daily living requiring repair or revision).
• Significant traumatic injury during 4 weeks prior to randomization.
• Known hereditary predisposition to bleeding or thrombosis; any prior or current evidence of bleeding diathesis.
• Systemic anticoagulation allowed, excluding Vitamin K antagonists.
• History of arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization 
• Non-healing wound, active ulcer, or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require wound examinations every 3 weeks.
• History of abdominal fistula or GI perforation, nonhealed gastric ulcer that is refractory to treatment, or active GI bleeding within 6 months prior to enrollment.
• Patients who have had any kind of surgery in the past 28 days (biopsy from any type of surgery within 28 days is not an exclusion criteria. Nor are procedures to treat varices.) 
• Uncontrolled hypertension defined by a systolic pressure > 150 mmHg or diastolic pressure > 90 mmHg, with or without antihypertensive medication. Patients with initial blood pressure (BP) elevations are eligible if initiation or adjustment of antihypertensive medication lowers pressure to meet entry criteria.
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• History of hepatic encephalopathy within past 12 months or requirement for medications to prevent or control encephalopathy (no lactulose, rifaximin, etc, if used for purposes of hepatic encephalopathy).
• Clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (e.g., paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose:
  • Patients with ascites that has required pharmacologic intervention (e.g., diuretics) and who have been on stable doses of diuretics for ascites for ≥ 2 months are eligible;
  • Major portal vein thrombosis visible on baseline/eligibility imaging, patients with Vp3 and Vp4 are excluded.
• Patients with infiltrative-type HCC.
• History of allogeneic organ transplantation.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [eg, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, and uveitis]). The following are exceptions to this criterion:
  • Patients with vitiligo or alopecia;
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement;
  • Any chronic skin condition that does not require systemic therapy;
  • Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician;
  • Patients with celiac disease controlled by diet alone.
  • Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection (except for noted HBV or HCV as detailed above), symptomatic congestive heart failure, poorly controlled diabetes mellitus, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• History of another primary malignancy except for:
  • Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of IP and of low potential risk for recurrence;
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
  • Adequately treated carcinoma in situ without evidence of disease.
• History of leptomeningeal carcinomatosis.
• History of active primary immunodeficiency.
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice) or human immunodeficiency virus (positive HIV 1/2 antibodies).
• Patients co-infected with HBV and hepatitis D virus (HDV). (HBV infection is indicated by the presence of HBsAg and/or anti-HBcAb with detectable HBV DNA ≥ 10 IU/mL or above the limit of detection per local lab standard ; HDV positive infection is indicated by the presence of anti-HDV antibodies.)
• Any unresolved toxicity National Cancer Institute (NCI) CTCAE v 5.0 Grade ≥ 2 from previous anticancer therapy, with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• History of allogeneic bone marrow transplant and active chronic graft versus host disease.
• Receipt of anti-PD-1, anti-PD-L1, or anti-CTLA-4 prior to the first dose of IP.
• Receipt of prior TACE, prior bland embolization, or prior radioembolization. Use of TACE or TAE as part of a curative therapy (e.g., in conjuntion with ablation or surgery) can be acceptable if it is used in the lesions where curative therapy was attempted. However, TACE or TAE cannot have been used as sole modalities in prior curative therapy.
• Receipt of prior systemic anticancer therapies for HCC.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
  • Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 90 days after the last dose of IP.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of IP. The following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection);
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent;
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
• Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study.
• Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment group assignment.
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 6 months after the last dose of IP. Not engaging in sexual activity, as per the patient’s preferred and usual lifestyle, for the total duration of the treatment and 6 months after the last dose of study treatment is an acceptable practice.
• 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.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).