Testing MK-3475 (Pembrolizumab) After Surgery for Localized Muscle-Invasive Bladder Cancer and Locally Advanced Urothelial Cancer

Inclusion Criteria:

• PRE-REGISTRATION ELIGIBILITY CRITERIA

• Histologically confirmed muscle-invasive urothelial carcinoma of the bladder, urethra, upper tract, or lymph node positive (LN+) disease; variant histology allowed as long as urothelial carcinoma is predominant (any amount of squamous differentiation is allowed); any component of neuroendocrine carcinoma is excluded

• Paraffin tissue samples obtained by transurethral resection of muscle-invasive bladder tumor, upper tract resection, or radical cystectomy/nephrectomy/ureterectomy/nephroureterectomy/cystoprostatectomy or urethrectomy must be available; this specimen submission is mandatory prior to registration as results will be used for stratification; specimens from radical/definitive surgery (radical cystectomy/nephrectomy/ureterectomy /nephroureterectomy/cystoprostatectomy and LN dissection) are preferred over transurethral resection, if available

• Patient must fit into one of the following three categories:

• Patients who received neoadjuvant chemotherapy and pathologic stage at surgical resection is >= pT2 and/or N+ OR

• Patients who are not cisplatin-eligible (according to >= 1 of the following criteria: Eastern Cooperative Oncology Group [ECOG] performance status of 2, creatinine clearance < 60 mL/min, grade >= 2 hearing loss, grade >= 2 neuropathy, or New York Heart Association class III heart failure and pathologic stage at surgical resection is >= pT3 or pN+) OR

• Patients that decline adjuvant cisplatin-based or other systemic chemotherapy based on an informed discussion with the physician and pathologic stage at surgical resection is >= pT3 or pN+

• The 7th edition of American Joint Committee on Cancer (AJCC) staging will be utilized; patient must have had radical cystectomy (cystoprostatectomy for men) and lymph node dissection (for bladder primary), or nephrectomy, nephroureterectomy or ureterectomy (for uppertract tumors) or urethrectomy (in addition to a radical cystectomy-either simultaneously or in the past) >= 4 weeks but =< 16 weeks prior to pre-registration; patients who have had a partial cystectomy as definitive therapy are not eligible

• No gross cancer at the surgical margins; microscopic invasive urothelial carcinoma positive margins are allowed; carcinoma in situ (CIS) at margins is considered negative margins

• No evidence of residual cancer or metastasis after surgery; patients with upper tract urothelial carcinoma must have a negative cystoscopy within 3 months prior to pre-registration; if the bladder has been removed a cystoscopy is not required

• No metastatic disease (or radiologic findings "concerning" for metastatic disease) on cross-sectional imaging (according to Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1 criteria)

• No active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome because of the risk of recurrence or exacerbation of disease; human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible

• No current pneumonitis or prior history of non-infectious pneumonitis that required steroids within the previous 5 years

• Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible

• Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible

• No known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)

• No live vaccine within 30 days prior to the first dose of study drug; examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine; seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed

• No postoperative/adjuvant systemic therapy

• No prior treatment with any therapy on the PD-1/PD-L1 axis

• No treatment with any other type of investigational agent =< 4 weeks before pre-registration

• No major surgery =< 4 weeks before pre-registration

• No radiation therapy =< 4 weeks before pre-registration

• No neoadjuvant chemotherapy =< 4 weeks before pre-registration

• Not currently requiring hemodialysis

• Age >= 18 years

• Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown

• ECOG performance status =< 2

• Absolute neutrophil count (ANC) >= 1,200/mm^3

• Leukocytes >= 3,000/ mm^3

• Platelet count >= 75,000/mm^3

• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L

• Total bilirubin =< 1.5 x upper limit of normal (ULN)

• Bilirubin for patients with Gilbert's =< 3.0 x ULN

• Calculated (calc.) creatinine clearance >= 30 mL/min (using either Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation or Cockcroft-Gault formula)

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x upper limit of normal (ULN)

• Serum albumin >= 2.8 g/dL

• For women of childbearing potential only: a negative urine or serum pregnancy test done =< 7 days prior to pre-registration is required

• REGISTRATION ELIGIBILITY CRITERIA: Results of central PD-L1 testing available; Q2 Solutions will forward the PD-L1 results to the statistical center and the statistical center will notify the site that the result is available; since the results with be blinded to the site the notification from the Alliance registration/randomization office will serve as a confirmation of this eligibility criteria; after sites receive the confirmation e-mail from Alliance they can register the patient