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Purpose: The PURE-01 study (NCT02736266) pioneered the neoadjuvant immune-checkpoint inhibitor (ICI) therapy before radical cystectomy (RC) in patients with muscle-invasive urothelial bladder carcinoma (MIBC). We herein present the survival outcomes after a median follow-up of three years. Patients and Methods: The intention-to-treat (ITT) population included 155 patients. Event-free survival (EFS) was defined as the time from pembrolizumab initiation until radiographic disease progression precluding RC, initiation of neoadjuvant chemotherapy, recurrence after RC, or death. Further outcomes were recurrence-free survival (RFS) post-RC and overall survival (OS). Multivariable Cox regression analyses for EFS were performed. Kaplan–Meier analyses compared EFS outcomes according with baseline programmed cell-death-ligand-1 (PD-L1) combined positive score (CPS) and according to the molecular subtypes. Results: After a median (interquartile range, IQR) follow-up of 39 (30–47) months, 36-month EFS and OS were 74.4% [95% confidence interval (CI), 67.8–81.7] and 83.8% (95% CI, 77.8–90.2) in the ITT population, respectively. Overall, 143 (92.3%) patients underwent RC. Within the cohort of patients who did not receive additional chemotherapy (N = 125), 36-month RFS was 96.3% (95% CI, 91.6–100) for patients achieving a ypT0N0, 96.1% (95% CI, 89–100) for ypT1/a/isN0, 74.9% (95% CI, 60.2–93) for ypT2–4N0, and 58.3% (95% CI, 36.2–94.1) for ypTanyN1–3 response. EFS was significantly stratified among PD-L1 tertiles (lower tertile: 59.7% vs. medium tertile: 76.7% vs. higher tertile: 89.8%, P = 0.0013). The claudin-low and basal/squamous subtypes displayed the lowest rates of events. Conclusions: At a median follow-up of three years, PURE-01 results further confirm the sustained efficacy of neoadjuvant pembrolizumab before RC. PD-L1 expression was the strongest predictor of sustained response post-RC.

Purpose:The PURE-01 study (NCT02736266) pioneered the neoadjuvant immune-checkpoint inhibitor (ICI) therapy before radical cystectomy (RC) in patients with muscle-invasive urothelial bladder carcinoma (MIBC). We herein present the survival outcomes after a median follow-up of three years.Patients and Methods:The intention-to-treat (ITT) population included 155 patients. Event-free survival (EFS) was defined as the time from pembrolizumab initiation until radiographic disease progression precluding RC, initiation of neoadjuvant chemotherapy, recurrence after RC, or death. Further outcomes were recurrence-free survival (RFS) post-RC and overall survival (OS). Multivariable Cox regression analyses for EFS were performed. Kaplan–Meier analyses compared EFS outcomes according with baseline programmed cell-death-ligand-1 (PD-L1) combined positive score (CPS) and according to the molecular subtypes.Results:After a median (interquartile range, IQR) follow-up of 39 (30–47) months, 36-month EFS and OS were 74.4% [95% confidence interval (CI), 67.8–81.7] and 83.8% (95% CI, 77.8–90.2) in the ITT population, respectively. Overall, 143 (92.3%) patients underwent RC. Within the cohort of patients who did not receive additional chemotherapy (N = 125), 36-month RFS was 96.3% (95% CI, 91.6–100) for patients achieving a ypT0N0, 96.1% (95% CI, 89–100) for ypT1/a/isN0, 74.9% (95% CI, 60.2–93) for ypT2–4N0, and 58.3% (95% CI, 36.2–94.1) for ypTanyN1–3 response. EFS was significantly stratified among PD-L1 tertiles (lower tertile: 59.7% vs. medium tertile: 76.7% vs. higher tertile: 89.8%, P = 0.0013). The claudin-low and basal/squamous subtypes displayed the lowest rates of events.Conclusions:At a median follow-up of three years, PURE-01 results further confirm the sustained efficacy of neoadjuvant pembrolizumab before RC. PD-L1 expression was the strongest predictor of sustained response post-RC.

Surgical safety outcomes in PURE-01 trial

Supplementary Figure 1: Study flow-chart. Supplementary Figure 2: Kaplan-Meier curves of event-free survival according to tertile-split tumor mutational burden. Supplementary Figure 3. Kaplan-Meier curves of recurrence-free survival according to the molecular subtype. Supplementary Figure 4: PD-L1 staining values (CPS percentages) according to molecular subtypes, split by the three subtyping classifiers GSC/Decipher, Consensus classification, and TCGA.

552 Background: The possibility to predict the pathologic complete response (pT0) or downstaging (pT≤1) after neoadjuvant therapy may have profound impact on the management of MIBC and orient next-generation bladder-sparing trials. The VIRADS is a standardized reporting system that uses mpMRI parameters to predict the probability of MIBC. No studies have analyzed the ability of VIRADS to predict the pT0 or pT≤1 response post-immunotherapy (IO). Methods: In PURE-01 patients (pts) were staged with bladder multiparametric magnetic resonance imaging (mpMRI: T2-weighted imaging, diffusion-weighted imaging, dynamic contrast enhancement) before and after treatment (3 cycles of pembro) prior to radical cystectomy (RC). All mpMRI scans were centrally reviewed. Logistic regression models analyzed pre- and post-pembro VIRADS against pT≤1 (primary endpoint) and pT0 (secondary endpoint). VIRADS scores were dichotomized between 0-3 and 4-5. Covariates included cT-stage, age, gender, PD-L1 combined positive score (CPS) and tumor mutational burden (TMB). Results: In total, 58 pts were had centrally-reviewed MRI scans (N=116 mpMRI), treated between 02/17 and 08/18. Demographic characteristics and outcomes were generally similar between the all-treated and VIRADS-evaluable populations of PURE-01. Median age was 65 years, 52 (89%) had pure/predominant urothelial carcinoma (UC) histology, 25 (43.1%) had cT3-4N0 MIBC. Pre-pembro: 8 pts (13.8%) had no measurable disease (VIRADS=0), 20 (34.5%) a VIRADS 1-3 score, and 30 (51.7%) had a VIRADS 4-5 score. Six pts (10.3%) had a downstage from VIRADS 4-5 to VIRADS 0-3 post-pembro. Both pre-pembro and post-pembro VIRADS 0-3 scores were significantly associated with pT≤1 endpoint on multivariable analyses (MVA): the strongest effect was seen with post-pembro VIRADS 0-3 against pT≤1 response (OR: 30.2, 95%CI: 6.2-223.2, p

549 Background: The PURE-01 clinical trial reported the use of neoadjuvant treatment with pembrolizumab prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC; cT2–3N0M0; PMID 30343614). We have previously reported that specific molecular subtypes (i.e. basal or claudin-low) and immune signatures are associated with more favorable survival. However, reports on the detailed tumor biology of patients (pts) who relapsed after neoadjuvant pembrolizumab are lacking. Herein, we provide a detailed characterization of relapsing pts and identify distinct gene expression patterns with potential utility as novel biomarkers. Methods: Microarray data from transurethral resection of the bladder tumor (TURBT; N=102) and matched RC (N=25) tissue from the PURE-01 trial were analyzed. Gene expression signatures and molecular subtypes were assigned as previously described (PMID 32165065). The Kaplan-Meier method was used to estimate differences in patient outcomes. Immune-signatures were split by median for survival analysis. All significance testing used a two-sided t-test at a threshold of 0.05. Results: Differential gene expression analysis identified KRT20 and H19 to be enriched in relapsing patients (both p