NEO-BLAST: Neoadjuvant Therapy for Bladder Cancer Followed by Active Surveillance vs Treatment

Inclusion Criteria:

* Male or female \>18 years
* Primary urothelial or predominantly (\>50%) urothelial carcinoma of the bladder with histologic evidence of muscularis propria invasion.
* Clinical stage T2-T4aN0M0 (Radiographic lymphadenopathy greater than 1.5 cm in short axis by imaging must be proven by biopsy to be free of cancer)
* No concomitant multifocal carcinoma in situ; a single focus is allowed.
* ECOG performance status 0, 1, or 2.
* Participants must be able to undergo pelvis MRI.
* Medically appropriate candidate for radical cystectomy (assessed by uro-oncologist) or chemo-radiation (assess by radiation-oncologist and medical-oncologist)
* Participants must be candidate to received standard of care (SOC) neoadjuvant systemic treatment at time of enrolment (assessed by medical-oncologist): 4 or more cycles of cisplatin-based chemotherapy (gemcitabine/cisplatin (GC) or methotrexate/vinblastine/Adriamycin/cisplatin (MVAC) or dose-dense MVAC (ddMVAC). If SOC evolves from the time of trial design and enrolment, eligibility to any SOC NAT (for example immunotherapy and/or antibody drug conjugate, as per NCCN guideline) will be allowed.
* Adequate bladder function and/or absence of significant urethral stricture to allow cystoscopic surveillance, as evaluate by urologist.

Exclusion Criteria:

* Any component of small cell or plasmacytoid histology.
* Prior systemic chemotherapy or immunotherapy (an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) or antibody-drug conjugate (NECTIN-4, HER2 or other) : Participants who have received any previous systemic therapy for urothelial carcinoma or cytotoxic chemotherapy, immunotherapy or other targeted therapy for another malignancy within 2 year of study entry are ineligible.
* No available bladder tumor tissue from prior TURBT for tumor sequencing.
* Prior or concurrent malignancy of any other site EXCEPT for non-melanoma skin cancer OR low risk malignancy not requiring treatment (such as prostate cancer Grade Group 1 under adequate surveillance, carcinoma in situ of the breast, cervix, etc.) AND unless free of disease for ≥ 5 years. Other cancers at low risk of recurrence may be allowed after review by principal investigator.
* Prior radiation therapy for bladder cancer.
* Participants who have received experimental agents within 4 weeks of study entry.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (defined by current oral or intravenous antibiotic therapy), symptomatic congestive heart failure (NYHA \>2), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnancy. People of childbearing potential must have a negative serum pregnancy test before general anesthesia procedure and MRI
* No concurrent treatment on another clinical trial; supportive care trials or non-therapeutic trials (e.g., quality of life) are allowed.