Inclusion Criteria:

• Age ≥ 18 years at the time of screening.
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol (as described in Appendix A). This includes compliance with the requirements and restrictions listed in the ICF and in this protocol, written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the US) obtained from the participant/legal representative prior to performing any protocol-related procedures, including screening evaluations.
• BCG-naïve (defined as participants not having received prior intravesical BCG or who previously received but stopped BCG more than 3 years before study entry).
• Local histological confirmation (based on cytology and/or pathology report) of high-risk transitional cell carcinoma of the urothelium of the urinary bladder confined to the mucosa or submucosa. A high-risk tumor is defined as one of the following:
  • T1 tumor;
  • High-grade/G3 tumor;
  • CIS.
• Complete resection of all Ta/T1 papillary disease prior to enrollment, with the TURBT removing high-risk NMIBC performed not more than 4 months before enrollment in the study. Participants with residual CIS after TURBT are eligible.
• No prior radiotherapy for bladder cancer.
• World Health Organization/Eastern Cooperative Oncology Group performance status of 0 or 1 at screening.
• Body weight > 30 kg.
• A life expectancy of at least 12 weeks (90 days).
• No prior exposure to immune-mediated therapy of cancer including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 antibodies. Participants who have been treated with anticancer vaccines will be excluded.
• A candidate for BCG treatment.
• Adequate organ and marrow function as defined below:
  • Hemoglobin ≥ 9.0 g/dL;
  • Absolute neutrophil count ≥ 1.0 × 10^9/L;
  • Platelet count ≥ 75 × 10^9/L;
  • Serum bilirubin ≤ 1.5 × the ULN. This will not apply to participants with confirmed Gilbert’s syndrome, who will be allowed in consultation with their physician;
  • ALT and AST ≤ 2.5 × ULN;
  • Measured CL > 30 mL/min or calculated creatinine CL > 30 mL/min as determined by Cockcroft-Gault (using actual body weight);
• Evidence of post-menopausal status or negative urinary (dipstick) or serum pregnancy test for female pre-menopausal participants. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
  • Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy);
  • Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

Exclusion Criteria:

• Evidence of muscle-invasive, locally advanced, metastatic, and/or extra-vesical bladder cancer (i.e., T2, T3, T4, and / or Stage IV).
• Predominantly variant histology such as micropapillary, plasmacytoid, nested, sarcomatoid, microcystic, squamous and adeno variants of UC representing > 50% of tumor tissue or other than urothelial tumors as assessed by pathology.
• Evidence of lymphovascular invasion of bladder tumor, except if treatment with BCG is deemed to be the only clinically viable treatment (ie, clinical candidates of cystectomy and/or chemotherapy, etc are excluded).
• Immediate cystectomy is indicated.
• Known or documented absolute and/or relative contraindication of adjuvant intravesical BCG treatment.
• Concurrent extravesical (ie, urethra, ureter, or renal pelvis), non-muscle-invasive transitional cell carcinoma of the urothelium.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• Previous treatment in the present study.
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
• Participation in another clinical study with a study intervention during the last 28 days or 5 half-lives of the respective study intervention, whichever is longer, prior to study enrollment.
• Any concurrent chemotherapy, study intervention, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for noncancer-related conditions (eg, hormone replacement therapy) is acceptable. Chemotherapy for previous instances of NMIBC is acceptable:
  • Participants who have received a single instillation of mitomycin C or equivalent chemotherapy agent immediately after TURBT can be enrolled in the study.
• Previous or concurrent treatment with potent systemic immunostimulatory agents (ie, systemic use of interleukins, interferons, glatiramer or similar agents).
• Major surgical procedure (as defined by the Investigator) within 28 days prior to enrollment or major surgical procedure (as defined by the Investigator) anticipated to be needed during the course of the study. These cases should be discussed with AstraZeneca physician prior to excluding participants.
• History of allogenic organ transplantation. Participants with any history of allogenic stem cell transplantation are also excluded.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], chronic diverticulitis or previous complicated diverticulitis, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
  • Participants with vitiligo or alopecia;
  • Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement;
  • Any chronic skin condition that does not require systemic therapy;
  • Participants without active disease in the last 5 years may be included but only after consultation with the Study Physician;
  • Participants with celiac disease controlled by diet alone.
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, ILD, serious chronic gastrointestinal 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 participant to give written informed consent.
• History of another primary malignancy except for:
  • Malignancy treated with curative intent and with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence during the study period;
  • Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease;
  • Adequately treated CIS without evidence of disease;
  • Prostate cancer of stage ≤ T2cN0M0 without biochemical recurrence or progression that in the opinion of the Investigator does not require active intervention.
• History of active primary immunodeficiency.
• Active infection including hepatitis B (known positive HBV/HBsAg result), HCV, or HIV 1/2 (positive HIV) antibodies. Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible. Participants positive for hepatitis C antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Participants co-infected with HBV and HCV, or co-infected with HBV and HDV, namely: HBV positive (presence of HBsAg and/or anti-hepatitis B core antibody with detectable HBV DNA); AND
  • HCV positive (presence of anti-HCV antibodies); OR
  • HDV positive (presence of anti-HDV antibodies).
• Current or prior use of immunosuppressive medication within 14 days before the first durvalumab dose. The following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids, or local steroid injections (eg, 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 (eg, CT scan premedication).
• Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention.
  • Note: Participants, if enrolled, should not receive live vaccine while receiving study intervention and up to 90 days (approximately 5 half-lives) after the last durvalumab dose.
• Female participants who are pregnant or breastfeeding or male or female participants of reproductive potential who are not willing to employ highly effective birth control from screening to 90 days after the last durvalumab dose.
• Known allergy or hypersensitivity to any of the study interventions or any of the study intervention excipients.
• Prior enrollment or treatment in a previous durvalumab clinical study regardless of treatment group assignment.
• Signs or symptoms of localized bladder infection or urinary tract infection within 2 weeks prior to the first dose of study intervention. This includes all active bacterial infections until documented as clear of infection by urinalysis after an adequate course of antibiotic therapy.
• Treatment with therapeutic oral or iv antibiotics within 1 week prior to the start of treatment with BCG.
• Judgement by the Investigator that the participant is unsuitable to participate in the study and the participant is unlikely to comply with study procedures, restrictions, and requirements.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 12/8/23. Questions regarding updates should be directed to the study team contact.