Checkpoint Inhibitor and Radiation Therapy in Bulky, Node-Positive Bladder Cancer

Inclusion Criteria * Bladder cancer, confirmed pathologically on transurethral resection of bladder tumor (TURBT) or on bladder biopsy. Pure urothelial, variant urothelial, or any proportion of squamous cell carcinoma are permitted. Questions about eligibility may be resolved by consultation with UTSW pathology but formal pathologic review is not required. * Bulky, clinically node positive disease (cN+) defined as: 1) a single pelvic lymph node of ≥ 1.5 cm largest diameter on CT or MRI; or 2) multiple pelvic lymph nodes ≥ 1 cm largest diameter on CT or MRI. Pathologic confirmation is not required. Imaging to establish eligibility must have been obtained no more than 60 days prior to trial enrollment. The scans must be personally reviewed by the enrolling clinician. For imaging studies obtained outside of UT Southwestern, imaging review of node status and sign off by the enrolling investigator is required. Review and sign off by a UTSW radiologist is optional in ambiguous or questionable cases, but is not mandatory. * Age ≥ 18 years. * ECOG performance status 0-1. * Appropriate candidate for radical cystectomy, as determined by the treating urologist. * Appropriate candidate for stereotactic ablative radiotherapy, as determined by the treating radiation oncologist. * Patient is planned to initiate or is within 1-3 weeks of initiation of FDA-approved immune checkpoint inhibitor therapy based on ineligibility to receive platinum-based downstaging chemotherapy (DCT) (Cohort 1, as detailed below) or failure to achieve clinical complete response to platinum-based DCT (Cohort 2, as detailed below). Cohort 1 (chemotherapy-ineligible) - either of: * patient staged with bulky cN+ disease as defined above, medically ineligible to receive any platinum-based chemotherapy or, after appropriate and documented counseling, refusing to receive any-platinum-based chemotherapy; or * patient staged with bulky cN+ disease as defined above, medically ineligible to receive cisplatin-based chemotherapy, with PD-L1 positive tumor (according to methodology described in the FDA approval label for the respective ICI agent) Cohort 2 (chemotherapy non-responding) - any of: * patient, initially staged with bulky cN+ disease as defined above, with radiologic progression after two cycles of platinum-based DCT (per RECIST 1.1 criteria: ≥20% increase in summed short-axis diameter of visible lesions with ≥ 5 mm absolute increase) * patient, initially staged with bulky cN+ disease as defined above, failing to achieve radiologic complete response after three or four cycles of platinum-based DCT (failure of all enlarged lymph nodes to decrease to \< 1 cm short-axis diameter) * patient, initially staged with bulky cN+ disease as defined above, failing to achieve radiologic complete response after one or two cycles of platinum-based DCT which was discontinued due to patient intolerance * patient, initially not staged with bulky cN+ disease as defined above, who progresses to cN+ disease as defined above after two or more of cycles of platinum-based DCT * Permitted downstaging chemotherapy regimens are gemcitabine/cisplatin (gem/cis), gemcitabine/carboplatin (gem/carbo), and methotrexate/vinblastine/doxorubin/cisplatin (MVAC, in any dose variant). * Permitted immune checkpoint inhibitor agents are those FDA-approved for platinum-ineligible (Cohort 1) or platinum-refractory (Cohort 2) bladder cancer: atezolizumab or pembrolizumab for Cohort 1; atezolizumab, avelumab, nivolumab, or pembrolizumab for Cohort 2. If additional immune checkpoint inhibitor (anti-PD1, anti-PD-L1, and/or anti-CTLA4) agents are approved for use in advanced urothelial carcinoma during the study, these agents will be permitted as well. * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. * Ability to understand and the willingness to sign a written informed consent. Exclusion Criteria * Medical or anatomic contraindication to any of the study treatment modalities (radical cystectomy, stereotactic ablative radiotherapy, immune checkpoint inhibitor therapy). * Non-urothelial histology (other than pure squamous cell, which is permitted) including pure adenocarcinoma, pure small cell carcinoma, sarcoma, lymphoma, non-genitourinary primary (e.g. colorectal). * Metastatic (cM1) disease, defined as 1) lymph nodes ≥ 1 cm above the aortic bifurcation (cM1a), or metastases to bone, brain, or any visceral site (cM1b). Patients with a single enlarged retroperitoneal lymph node will be eligible with an adequately performed lymph node biopsy showing no metastatic disease or with a PET scan showing absence of FDG avidity. * Second primary malignancy, except: 1) non-metastatic (cM0) prostate cancer, 2) non-metastatic (cM0) endometrial cancer, 3) non-melanoma skin cancer, 4) cervical squamous cell carcinoma in situ, 4) any AJCC Stage I/II or organ-confined primary malignancy for which the patient has undergone curative treatment and has been without evidence of disease for three years. * Prior pelvic radiation therapy. * Autoimmune disease rendering the patient ineligible for ICI. * Treatment with any immunosuppressive agent within 14 days of study entry, excluding topical or inhaled corticosteroids or adrenal-replacement steroids. * End stage renal disease requiring dialysis. * HIV infection, unless stable on HAART with CD4+ count \> 400. * Subjects may not be receiving any other investigational agents for the treatment of the cancer under study. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to atezolizumab, avelumab, durvalumab, nivolumab, pembrolizumab, or other agents used in study. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (other than atrial fibrillation / atrial flutter), or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements. * Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.