Enzalutamide in Combination With Gemcitabine and Cisplatin in Bladder Cancer

Inclusion Criteria: * Cytologically or histologically confirmed evidence of transitional cell carcinoma of bladder, renal pelvis, ureter or urethra. * Patients with Stage IV (locally advanced or metastatic) disease. Must have measurable disease, as per Response Evaluation Criteria in Solid Tumors (RECIST). * Minimum of 4 weeks since any major surgery, completion of radiation. * Prior treatment with cytotoxic chemotherapy is not a requirement, but allowed only if used in neoadjuvant, adjuvant or for bladder preserving protocols, as long as was administered \> 6 months prior to starting study. * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. * Life expectancy 12 weeks or more. * Must have normal organ and marrow function. * Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days of the administration of the first study treatment. Women must not be lactating. * Sexually active women of childbearing age and men should be willing to follow birth control guidelines. * Should be able to swallow enzalutamide and comply with study requirements. Exclusion Criteria: * Prior treatment with any cytotoxic chemotherapy in metastatic setting. Prior treatment with cytotoxic chemotherapy is allowed only if used in neoadjuvant, adjuvant or for bladder preserving protocols, as long as was administered \> 6 months prior to starting study. * Have undergone major surgery within 4 weeks prior to study enrollment. * Chronic treatment with steroids or any other immunosuppressant drugs. * Should not receive immunization with attenuated live vaccines during study period or within 1 week of study entry. * History of seizures, predisposing factors for seizures, including underlying brain injury with loss of consciousness within previous 12 months, transient ischemic attack within previous 12 months, cerebral vascular accident or brain arteriovenous malformation. * Untreated brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases. * Congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia, advanced heart block or a history of acute myocardial infarction within the 6 months preceding enrollment. * Known history of HIV. * Have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study. * Women who are pregnant or breast feeding, or women/men able to conceive and unwilling to practice birth control guidelines. * Concurrent medications which strongly inhibit or induce CYP enzymes (gemfibrozil, Rifampin, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, bosentan, efavirenz, etravirine, modafinil, nafcillin, St. John's Wort). * History of stage III or greater cancer, except basal or squamous cell skin cancers adequately treated or any other stage I or II cancer adequately treated and disease-free for ≥ 2 years. Incidental findings of stage I or II prostate cancer that is considered to be cured with radical cystoprostatectomy is allowed. * Prior use of enzalutamide. * Radiation therapy via external beam or brachytherapy within 28 days of registration. * Patients who are ineligible to receive cisplatin: Creatinine clearance of less than 60 mL/minute, hearing loss of 25 decibel (dB) at 2 contiguous frequencies, grade 2 or higher peripheral neuropathy, or New York Heart Association Class III or higher heart failure. * Allergy/sensitivity to any study drug (gemcitabine, cisplatin, enzalutamide), or drugs chemically related to study drug, or excipients. * Brain metastases (including treated or stable brain metastases)