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