Narayan, Vikram M.

TPS4632 Background: There is currently no Food and Drug Administration (FDA)-approved treatment for intermediate-risk non–muscle-invasive bladder cancer (IR NMIBC), defined as recurrence of low-grade (LG) Ta within 1 year, solitary LG Ta > 3 cm, multifocal LG Ta, high-grade (HG) Ta (≤3 cm), and/or LG T1. Nadofaragene firadenovec-vncg is the first FDA-approved intravesical nonreplicating gene therapy for treating high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) ± papillary tumors. In a nonrandomized, multicenter, open-label, repeat-dose, phase 3 study, 53.4% of participants (55/103) with CIS ± HG Ta/T1 achieved complete response 3 months after the first instillation. Nadofaragene firadenovec was well tolerated, with no grade 4/5 study drug-related AEs. Because maintenance treatment with nadofaragene firadenovec following tumor resection may improve clinical outcomes in patients with IR NMIBC, the ABLE-32 open-label randomized study is being conducted to evaluate the efficacy of nadofaragene firadenovec administered every 3 months versus observation in participants with IR NMIBC. Methods: This phase 3 study includes approximately 100 global sites with 454 anticipated participants. Adults aged ≥18 years, diagnosed with new or recurrent IR NMIBC, and having undergone transurethral resection of bladder tumor within 60 days prior to randomization are eligible. Participants will be randomly assigned 1:1 to receive nadofaragene firadenovec or continue observation. The nadofaragene firadenovec group will receive quarterly doses unless disease recurs or progresses. The observation group will be followed quarterly and may receive nadofaragene firadenovec if IR NMIBC recurs within 24 months. All participants will be evaluated for recurrence and progression using cytology, cystoscopy, and for-cause biopsy for up to 5 years. The primary endpoint is recurrence-free survival (RFS), from randomization to first documented recurrence, progression, or death. Secondary endpoints include RFS at 12 and 24 months and safety. Exploratory endpoints include effect on potential biomarkers and health-related quality of life. Final results are expected in 2031. Clinical trial information: NCT06510374 .

TPS888 Background: There is currently no Food and Drug Administration (FDA)-approved treatment for intermediate-risk non–muscle-invasive bladder cancer (IR NMIBC), defined by the AUA as recurrence of low-grade (LG) Ta within 1 year, solitary LG Ta >3 cm, multifocal LG Ta, high-grade (HG) Ta (≤3 cm), and/or LG T1. Nadofaragene firadenovec-vncg is the first FDA-approved intravesical nonreplicating gene therapy for the treatment of adult patients with high-risk Bacillus Calmette Guérin (BCG)-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumors. In a nonrandomized, multicenter, open-label, repeat-dose, phase 3 study, 53.4% of participants (55/103) with CIS ± HG Ta/T1 achieved complete response 3 months after the first instillation. Nadofaragene firadenovec was well tolerated, with no grade 4/5 study drug-related AEs. Because maintenance treatment with nadofaragene firadenovec following tumor resection may improve clinical outcomes in patients with IR NMIBC, the ABLE-32 open-label randomized study is being conducted to evaluate the efficacy of nadofaragene firadenovec administered every 3 months versus observation in participants with IR NMIBC. Methods: This phase 3 study includes approximately 100 global sites with 454 anticipated participants. Adults diagnosed with new or recurrent IR NMIBC and having undergone transurethral resection of bladder tumor within 60 days prior to randomization are eligible. Participants will be randomly assigned 1:1 to receive nadofaragene firadenovec or continue observation. The nadofaragene firadenovec group will receive quarterly doses unless disease recurs or progresses. The observation group will be followed quarterly and may receive nadofaragene firadenovec if IR NMIBC recurs within 24 months. All participants will be evaluated for recurrence and progression using cytology, cystoscopy, and for-cause biopsy for up to 5 years. The primary endpoint is recurrence-free survival (RFS), from randomization to first documented recurrence, progression, or death. Secondary endpoints include RFS at 12 and 24 months and safety. Exploratory endpoints include effect on potential biomarkers and health-related quality of life. Final results are expected in 2031. Clinical trial information: NCT06510374 .

831 Background: Long non-coding RNA (lncRNA)-based genomic profiling has suggested utility to identify a distinct tumor subgroup corresponding to a favorable prognosis in patients with bladder cancer. Here, we further evaluate a genomic classifier in a cohort of patients undergoing radical cystectomy (RC). Methods: Transcriptome-wide expression profiling using Decipher Bladder was performed on TURBT samples from a cohort of patients with high grade, clinically organ confined (cTa-T2N0M0) UC who subsequently underwent RC without any neoadjuvant therapy (n=226). LncRNA-based luminal favorable status was determined using a previously developed genomic classifier. The primary endpoint was overall survival (OS) following surgery. Secondary endpoints included cancer-specific mortality and upstaging at RC. Results: In the study, 134 patients were clinical NMIBC (cTa/Tis/T1) and 92 patients were cT2. We identified 60 patients with luminal favorable subtype, all of which showed robust gene expression patterns associated with less aggressive bladder cancer biology. On MVA, patients with the luminal favorable subtype (vs. without) were significantly associated with lower odds of upstaging to pT3+ disease (OR [95% CI] 0.32 [0.12-0.82], p = 0.02), any upstaging (OR [95% CI] 0.41 [0.20-0.83], p = 0.01), and any upstaging and/or pN+ (OR [95% CI] 0.50 [0.25-1.00], p = 0.05). Luminal favorable bladder cancer was significantly associated with better OS (HR 0.33 [95% CI 0.15-0.74], p=0.007). Conclusions: This study validates the performance of the genomic classifier for identifying urothelial carcinomas with a luminal favorable subtype, harboring less aggressive tumor biology.

Objective To further evaluate a genomic classifier (GC) in a cohort of patients undergoing radical cystectomy (RC), as long non‐coding RNA (lncRNA)‐based genomic profiling has suggested utility in identifying a distinct tumour subgroup corresponding to a favourable prognosis in patients with bladder cancer. Patients and Methods Transcriptome‐wide expression profiling using Decipher Bladder was performed on transurethral resection of bladder tumour samples from a cohort of patients with high‐grade, clinically organ‐confined (cTa–T2N0M0) urothelial carcinoma (UC) who subsequently underwent RC without any neoadjuvant therapy ( n = 226). The lncRNA‐based luminal favourable status was determined using a previously developed GC. The primary endpoint was overall survival (OS) after RC. Secondary endpoints included cancer‐specific mortality and upstaging at RC. Results In the study, 134 patients were clinical non‐muscle‐invasive bladder cancer (cTa/Tis/T1) and 92 patients were cT2. We identified 60 patients with luminal favourable subtype, all of which showed robust gene expression patterns associated with less aggressive bladder cancer biology. On multivariate analysis, patients with the luminal favourable subtype (vs without) were significantly associated with lower odds of upstaging to pathological (p)T3+ disease (odds ratio [OR] 0.32, 95% confidence interval [CI] 0.12–0.82; P = 0.02), any upstaging (OR 0.41, 95% CI 0.20–0.83; P = 0.01), and any upstaging and/or pN+ (OR 0.50, 95% CI 0.25–1.00; P = 0.05). Luminal favourable bladder cancer was significantly associated with better OS (hazard ratio 0.33, 95% CI 0.15–0.74; P = 0.007). Conclusions This study validates the performance of the GC for identifying UCs with a luminal favourable subtype, harbouring less aggressive tumour biology.

AbstractBackgroundThe 2018 Leibovich prognostic model for nonmetastatic renal cell carcinoma (RCC) combines clinical, surgical, and pathologic factors to predict progression‐free survival (PFS) and cancer‐specific survival (CSS) for patients with clear cell (ccRCC), papillary (pRCC), and chromophobe (chRCC) histology. Despite high accuracy, <1% of the original cohort was Black. Here, the authors examined this model in a large population with greater Black patient representation.MethodsBy using a prospectively maintained RCC institutional database, patients were assigned Leibovich model risk scores. Survival outcomes included 5‐year and 10‐year PFS and CSS. Prognostic accuracy was determined using area under the curve (AUC) analysis and calibration plots. Black patient subanalyses were conducted.ResultsIn total, 657 (29%) of 2295 patients analyzed identified as Black. Declines in PFS and CSS were observed as scores increased. Discrimination for ccRCC was strong for PFS (AUC: 5‐year PFS, 0.81; 10‐year PFS, 0.78) and for CSS (AUC: 5‐year CSS, 0.82; 10‐year CSS, 0.74). The pRCC AUC for PFS was 0.74 at 5 years and 0.71 at 10 years; and the AUC for CSS was 0.74 at 5 years and 0.70 at 10 years. In chRCC, better performance was observed for CSS (AUC at 5 years, 0.75) than for PFS (AUC: 0.66 at 5 years; 0.55 at 10 years). Black patient subanalysis revealed similar‐to‐improved performance for ccRCC at 5 years (AUC: PFS, 0.79; CSS, 0.87). For pRCC, performance was lower for PFS (AUC at 5 years, 0.63) and was similar for CSS (AUC at 5 years, 0.77). Sample size limited Black patient 10‐year and chRCC analyses.ConclusionsThe authors externally validated the 2018 Leibovich RCC prognostic model and found optimal performance for ccRCC, followed by pRCC, and then chRCC. Importantly, the results were consistent in this large representation of Black patients.Plain Language Summary In 2018, a model to predict survival in patients with renal cell carcinoma (kidney cancer) was introduced by Leibovich et al. This model has performed well; however, Black patients have been under‐represented in examination of its performance. In this study, 657 Black patients (29%) were included, and the results were consistent. This work is important for making sure the model can be applied to all patient populations.

Abstract Introduction Low creatinine to cystatin-C ratio (Cr/Cys-C) may be a biomarker for low-muscle mass. Furthermore, low Cr/Cys-C is associated with decreased overall survival (OS), but to date, has not been examined in patients with renal cell carcinoma (RCC). Our objective is to evaluate associations between low Cr/Cys-C ratio and OS and recurrence-free survival (RFS) in patients with RCC treated with nephrectomy. Methods We performed a retrospective review of patients with RCC treated with nephrectomy. Patients with end-stage renal disease and less than 1-year follow up were excluded. Cr/Cys-C was dichotomized at the median for the cohort (low vs. high). OS and RFS for patients with high versus low Cr/Cys-C were estimated with the Kaplan-Meier method, and associations with the outcomes of interest were modeled using Cox proportional Hazards models. Associations between Cr/Cys-C and skeletal muscle mass were assessed with correlations and logistic regression. Results A total of 255 patients were analyzed, with a median age of 64. Median (IQR) Cr/Cys-C was 1 (0.8-1.2). Low Cr/Cys-C was associated with age, female sex, Eastern Cooperative Oncology Group Performance Status ≥1, TNM stage, and tumor size. Kaplan-Meier and Cox regression analysis demonstrated an association between low Cr/Cys-C and decreased OS (HR = 2.97, 95%CI, 1.12-7.90, P =0.029) and RFS (HR = 3.31, 95%CI, 1.26-8.66, P = .015). Furthermore, a low Cr/Cys-C indicated a 2-3 increase in risk of radiographic sarcopenia. Conclusions Lower Cr/Cys-C is associated with inferior oncologic outcomes in RCC and, pending validation, may have utility as a serum biomarker for the presence of sarcopenia in patients with RCC treated with nephrectomy.