A Study to Evaluate Enfortumab Vedotin Versus (vs) Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301)

Inclusion Criteria: * Subject is legally an adult according to local regulation at the time of signing informed consent. * Subject has histologically or cytologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Subjects with urothelial carcinoma (transitional cell) with squamous differentiation or mixed cell types are eligible. * Subject must have experienced radiographic progression or relapse during or after a checkpoint inhibitor (CPI) (anti-programmed cell death protein 1 (PD1) or anti-programmed death-ligand 1 (PD-L1)) for locally advanced or metastatic disease. Subjects who discontinued CPI treatment due to toxicity are eligible provided that the subjects have evidence of disease progression following discontinuation. The CPI need not be the most recent therapy. Subjects for whom the most recent therapy has been a non-CPI based regimen are eligible if the subjects have progressed/relapsed during or after the subjects most recent therapy. Locally advanced disease must not be amenable to resection with curative intent per the treating physician. * Subject must have received a platinum containing regimen (cisplatin or carboplatin) in the metastatic/locally advanced, neoadjuvant or adjuvant setting. If platinum was administered in the adjuvant/neoadjuvant setting subject must have progressed within 12 months of completion. * Subject has radiologically documented metastatic or locally advanced disease at baseline. * An archival tumor tissue sample should be available for submission to central laboratory prior to study treatment. If an archival tumor tissue sample is not available, a fresh tissue sample should be provided. If a fresh tissue sample cannot be provided due to safety concerns, enrollment into the study must be discussed with the medical monitor. * Subject has ECOG PS of 0 or 1 * The subject has the following baseline laboratory data: * absolute neutrophil count (ANC) ≥ 1500/mm3 * platelet count ≥ 100 × 10\^9/L * hemoglobin ≥ 9 g/dL * serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with Gilbert's disease * creatinine clearance (CrCl) ≥ 30 mL/min as estimated per institutional standards or as measured by 24 hour urine collection (glomerular filtration rate \[GFR\] can also be used instead of CrCl) * alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 3 x ULN for subjects with liver metastases * Female subject must either: * Be of nonchildbearing potential: Postmenopausal (defined as at least 1 year without any menses for which there is no other obvious pathological or physiological cause) prior to screening, or documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy). * Or, if of childbearing potential: Agree not to try to become pregnant during the study and for at least 6 months after the final study drug administration, and have a negative urine or serum pregnancy test within 7 days prior to Day 1 (Females with false positive results and documented verification of negative pregnancy status are eligible for participation), and if heterosexually active, agree to consistently use a condom plus 1 form of highly effective birth control per locally accepted standards starting at screening and throughout the study period and for at least 6 months after the final study drug administration. * Female subject must agree not to breastfeed or donate ova starting at screening and throughout the study period, and for at least 6 months after the final study drug administration. * A sexually active male subject with female partner(s) who is of childbearing potential is eligible if: * Agrees to use a male condom starting at screening and continue throughout the study treatment and for at least 6 months after final study drug administration. If the male subject has not had a vasectomy or is not sterile as defined below the subjects female partner(s) is utilizing 1 form of highly effective birth control per locally accepted standards starting at screening and continue throughout study treatment and for at least 6 months after the male subject receives final study drug administration. * Male subject must not donate sperm starting at screening and throughout the study period, and for at least 6 months after the final study drug administration. * Male subject with a pregnant or breastfeeding partner(s) must agree to abstinence or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for at least 6 months after the final study drug administration. * Subject agrees not to participate in another interventional study while on treatment in present study. Inclusion Criteria for COE: * Subject is eligible for the COE if they continue to meet all inclusion criteria from the main protocol in addition to the following when the patient is evaluated for eligibility to participate in the COE portion of the study: * Institutional review board (IRB)/ independent ethics committee (IEC) approved written COE informed consent and privacy language as per national regulations (e.g., health insurance portability and accountability act \[HIPAA\] Authorization for US sites) must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable). * Subject was randomized to Arm B and is either currently on study treatment or has discontinued study treatment due to intolerance, AE or progression of disease and has not started a new systemic anticancer treatment. Exclusion Criteria: * Subject has preexisting sensory or motor neuropathy Grade ≥ 2. * Subject has active central nervous system (CNS) metastases. Subjects with treated CNS metastases are permitted on study if all the following are true: * CNS metastases have been clinically stable for at least 6 weeks prior to screening * If requiring steroid treatment for CNS metastases, the subject is on a stable dose ≤ 20 mg/day of prednisone or equivalent for at least 2 weeks * Baseline scans show no evidence of new or enlarged brain metastasis * Subject does not have leptomeningeal disease * Subject has ongoing clinically significant toxicity (Grade 2 or higher with the exception of alopecia) associated with prior treatment (including systemic therapy, radiotherapy or surgery). Subject with ≤ Grade 2 immunotherapy-related hypothyroidism or panhypopituitarism may be enrolled when well-maintained/controlled on a stable dose of hormone replacement therapy (if indicated). Subjects with ongoing ≥ Grade 3 immunotherapy-related hypothyroidism or panhypopituitarism are excluded. Subjects with ongoing immunotherapy related colitis, uveitis, or pneumonitis or subjects with other immunotherapy related AEs requiring high doses of steroids (\> 20 mg/day of prednisone or equivalent) are excluded. * Subject has prior treatment with EV or other monomethyl auristatin E (MMAE)-based Antibody drug conjugates (ADCs). * Subject has received prior chemotherapy for urothelial cancer with all available study therapies in the control arm (i.e., both prior paclitaxel and docetaxel in regions where vinflunine is not an approved therapy, or prior paclitaxel, docetaxel and vinflunine in regions where vinflunine is an approved therapy). * Subject has received more than 1 prior chemotherapy regimen for locally advanced or metastatic urothelial cancer, including chemotherapy for adjuvant or neo-adjuvant disease if recurrence occurred within 12 months of completing therapy. The substitution of carboplatin for cisplatin does not constitute a new regimen provided no new chemotherapeutic agents were added to the regimen. * Subject has history of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Subjects with nonmelanoma skin cancer, localized prostate cancer treated with curative intent with no evidence of progression, low-risk or very low-risk (per standard guidelines) localized prostate cancer under active surveillance/watchful waiting without intent to treat, or carcinoma in situ of any type (if complete resection was performed) are allowed. * Subject is currently receiving systemic antimicrobial treatment for viral, bacterial, or fungal infection at the time of first dose of EV. Routine antimicrobial prophylaxis is permitted. * Subject has known active Hepatitis B (e.g., hepatitis B surface antigen (HBsAg) reactive) or active hepatitis C (e.g., hepatitis C virus (HCV) Ribonucleic Acid (RNA) \[qualitative\] is detected). * Subject has known history of human immunodeficiency virus (HIV) infection (HIV 1 or 2). * Subject has documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms (including congestive heart failure) consistent with New York Heart Association Class III-IV within 6 months prior to the first dose of study drug. * Subject has radiotherapy or major surgery within 4 weeks prior to first dose of study drug. * Subject has had chemotherapy, biologics, investigational agents, and/or antitumor treatment with immunotherapy that is not completed 2 weeks prior to first dose of study drug. * Subject has known hypersensitivity to EV or to any excipient contained in the drug formulation of EV; OR subject has known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary (CHO) cells. * Subject has known hypersensitivity to the following: docetaxel or to any of the other excipients listed in product label, including polysorbate 80, paclitaxel or to any of the other excipients listed in product label, such as macrogolglycerol ricinoleate 35 (Ph.Eur.); and vinflunine or to any of the other excipients listed in product label such as other vinca alkaloids (vinblastine,vincristine, vindesine, vinorelbine). * Subject has known active keratitis or corneal ulcerations. * Subject has other underlying medical condition that would impair the ability of the subject to receive or tolerate the planned treatment and follow-up. * History of uncontrolled diabetes mellitus within 3 months of the first dose of study drug. Uncontrolled diabetes is defined as hemoglobin A1C (HbA1c) ≥ 8% or HbA1c between 7 and \< 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained. Exclusion Criteria for COE * Subject will be excluded from participation in the COE if they meet any of the exclusion criteria listed in the main protocol or if any of the following apply when the patient is evaluated for eligibility to participate in the COE portion of the study: * Subject has been diagnosed with a new malignancy while on Arm B in the EV-301 study. Subjects with nonmelanoma skin cancer, localized prostate cancer treated with curative intent with no evidence of progression, low-risk or very low-risk (per standard guidelines) localized prostate cancer under active surveillance/watchful waiting without intent to treat, or carcinoma in situ of any type (if complete resection was performed) are allowed. * Subject has already started commercial EV or arrangements have been made for subject to start commercial EV which is reimbursed in their country. Additionally, if EV is commercially available with reimbursement in the potential subject's country, the subject can consider transitioning to the commercial product unless otherwise discussed with sponsor.