Main
MIBC, DDR, muscle-invasive bladder cancer
DNA DAMAGE, RECURRENCE
Radical cystectomy is a standard treatment for muscle-invasive bladder cancer (MIBC). However, radical cystectomy is a life-changing operation due to the need for urinary diversion and is associated with a 90-d mortality risk of up to 6–8% (ref. Given the potential to achieve a pCR with TURBT followed by neoadjuvant chemotherapy, the need for cystectomy to achieve cure in all patients has been questioned. Early single-center retrospective studies reported that long-term bladder-intact disease-free survival is achievable in a select subset of patients with MIBC treated with TURBT plus systemic therapy, and contemporary retrospective series have substantiated such resultsSingle-agent PD-1/PD-L1 immune checkpoint blockade followed by cystectomy for the treatment of MIBC has been shown to yield a pCR in 30–40% of patientsThe integration of molecular biomarkers may further improve selection of patients with MIBC who could be treated definitively with TURBT plus systemic therapy. Somatic alterations in genes encoding proteins involved in DNA damage repair (DDR) in pre-treatment TURBT tissue have been correlated with a higher pCR rate with cisplatin-based neoadjuvant chemotherapyTo further evaluate the role of TURBT plus systemic therapy as definitive treatment for MIBC, we designed a phase 2 trial integrating (1) cisplatin-based chemotherapy plus PD-1 blockade; (2) standardized clinical restaging; and (3) translational analyses seeking to explore genomic, radiologic and immunologic biomarkers to refine future patient selection for this approach. Our primary goal was to test whether uniformly assessed and consistently defined cCR could identify patients who could safely forgo immediate cystectomy. We reasoned that a potentially effective personalized risk-adapted strategy would (1) tolerate missing some patients who might have been suitable candidates to forgo immediate cystectomy in favor of maximizing identification of patients who fare well without immediate cystectomy and (2) incorporate the ability of later cystectomy to achieve favorable cancer-related outcomes in the subset of patients with a cCR who experience local recurrence after initial surveillance. Therefore, our primary objectives were to estimate the cCR rate and to assess the positive predictive value of cCR for a composite outcome measure (2-year metastasis-free survival in patients forgoing immediate cystectomy or <ypT1N0 in patients electing immediate cystectomy; Extended Data Fig. 