Inclusion Criteria:

* Age ≥ 18 years
* Histologically proven urothelial carcinoma \[American Joint Committee on Cancer (AJCC) 2017\] of the bladder (BCa) or upper urothelial tract (UTUC), that has progressed despite enfortumab vedotin and pembrolizumab treatment

* NOTE: Primary or secondary progression are allowed, therapies are not required to be concurrent or immediately antecedent to enrollment)
* Measurable disease per RECIST version (v)1.1
* Eastern Cooperative Oncology Group (ECOG) performance status grade 0, 1, or 2
* Hemoglobin \> 7.0 g/dL (obtained ≤ 30 days prior to registration)
* Platelet count ≥ 75,000/mm\^3 (obtained ≤ 30 days prior to registration)
* Alanine aminotransferase (ALT) OR aspartate transaminase (AST) ≤ 3.5 x upper limit of normal (ULN) OR total bilirubin ≤ 3 x ULN OR direct bilirubin ≤ 3 x ULN (obtained ≤ 30 days prior to registration)
* Estimated glomerular filtration rate (GFR) ≥ 15 ml/min (obtained ≤ 30 days prior to registration)
* Negative pregnancy test ≤ 8 days prior to registration, for persons of childbearing potential only
* Provide written informed consent
* Ability to complete questionnaire(s) by themselves or with assistance
* Willingness to undergo treatment on either treatment arm (group A: TPE + EV/pembro; OR group B: next line standard of care)
* Willingness to provide mandatory blood and fluid specimens for correlative research
* Willingness to provide tissue specimens for correlative research
* Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)

Exclusion Criteria:

* Any of the following because this study involves an investigational agent, the genotoxic, mutagenic, and teratogenic effects of which on the developing fetus and newborn are unknown

* Pregnant persons
* Nursing persons
* Persons of childbearing potential or able to father a child who are unwilling to employ adequate contraception
* Any of the following histologic variants/divergent differentiation: Any amount of neuroendocrine, micropapillary, or signet ring cell features
* Active malignancies (i.e., progressing or requiring treatment change ≤ 24 months before registration) other than the disease being treated under study

* EXCEPTIONS:

* Skin cancer (melanoma or non-melanoma) that is considered completely cured
* Non-invasive cervical cancer that is considered completely cured
* Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ considered to have a very low risk of recurrence
* Localized prostate cancer (T1c/T2N0M0):

* Gleason score 6, treated by either surgery or ablation ≤ 24 months prior to registration or untreated and under active surveillance
* Gleason score 3+4 that has been treated (may include surgery or ablation) ≤ 24 months prior to registration and considered to have a very low risk of recurrence (i.e., cT1c or pT2 on prostatectomy specimen)
* History of uncontrolled cardiovascular disease including any of the following ≤ 6 months prior to registration:

* Significant cardiovascular disease \[New York Heart Association (NYHA) class ≥ III\], symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction, ventricular fibrillation, Torsades de Pointes, cerebrovascular accident, or transient ischemic attack
* Psychiatric illness/social situations (e.g., substance abuse) that would limit compliance with study requirements
* Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participants (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments

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

Eligibility last updated 7/25/2025. Questions regarding updates should be directed to the study team contact.