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503 Background: Pts presenting with NMIBC carcinoma in situ (CIS) have a high risk of progression. FGFR inhibition may benefit CIS pts with FGFRalt who are unresponsive to first-line BCG, for whom treatment (tx) options, other than radical cystectomy, are limited. Erdafitinib (erda), an oral selective pan-FGFR tyrosine kinase inhibitor, is approved for locally advanced or metastatic urothelial cancer in adults with FGFR3/2alt who have progressed during or after ≥1 line of platinum-containing chemotherapy. THOR-2 (NCT04172675) is a multicohort phase 2 study of erda in pts with HR-NMIBC. Here we report results from an exploratory cohort of pts with BCG-unresponsive CIS with FGFRalt with or without papillary disease (Cohort 2). Methods: Inclusion criteria: age ≥18 y, with histologically confirmed, BCG-unresponsive HR-NMIBC with FGFR3/2alt (by local/central testing) presenting as CIS, with or without a papillary tumor and who refused or were not eligible for cystectomy. In this cohort, pts received continuous oral erda 6 mg once daily without uptitration in 28-d cycles (dose selected to improve tolerability while maintaining activity to prevent disease recurrence, for this population). Erda was discontinued if no complete response (CR) was observed within 3 mos. Exploratory efficacy end points are CR rates at the Cycle 3 Day 1 (C3D1) disease evaluation and the Cycle 6 Day 1 (C6D1) disease evaluation; safety was a key secondary end point. Results: As of the data cutoff (Sep 2022) (median follow-up of 10 mos), 10 pts have received erda (enrolled population; median age 72 y [range 52-83]; 90% CIS [1 pt with Ta was mis-enrolled]). Pts received erda for a median duration 5.9 mos (range 1.1-17.0). Of 10 enrolled pts, the CR rates at first evaluation (C3D1) and second evaluation (C6D1) were 100% (9/9 evaluable pts) and 75% (6/8 evaluable pts), respectively. The median duration of response was 3.0 mos. The most common tx-emergent adverse events (TEAEs) were dry mouth (60%; n=6), hyperphosphatemia (50%; n=5), dysgeusia (50%; n=5), and diarrhea (50.0%; n=5). 1 pt (10%) had Gr 2 retinal detachment which led to tx discontinuation and 1 pt (10%) had Gr 1 subretinal fluid; both reported as resolved. Gr ≥3 tx-related TEAEs occurred in 3 pts (30%), and included dry mouth, stomatitis, nail disorder, onychomadesis, acute kidney injury, chronic kidney disease, sepsis, and hypotension in 1 pt each. 1 pt (10%) had serious tx-related TEAEs (dry mouth, hypotension, pneumonitis, acute kidney injury, and sepsis), and 1 pt (10%) discontinued tx due to a tx-related TEAE. No tx-related deaths were observed. Conclusions: Data from Cohort 2 of THOR-2 demonstrate efficacy at C3D1 and C6D1 evaluations in pts with HR-NMIBC with FGFRalt. Safety data were consistent with the known safety profile of erda. Clinical trial information: NCT04172675 .

TPS582 Background: The majority of patients with bladder cancer present with non-muscle invasive disease (Chang 2016; Woldu 2017; Kates 2020; Li 2020). The standard of care for treatment of high risk NMIBC involves transurethral resection of the bladder tumor (TURBT) followed by intravesical Bacillus Calmette-Guerin (BCG) or chemotherapy. Although the response rate to BCG therapy is high, many patients recur within 1–5 years (Matulay JU 2021). For patients who have BCG unresponsive disease after adequate course of BCG, there are limited options. While radical cystectomy (RC) is still considered the standard of care, most patients are reluctant to undergo RC and their options are limited to intravesical chemotherapy or pembrolizumab. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in bladder tumors. In EV-301, a phase 3 study, EV showed an OS benefit vs chemotherapy in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor (Powles NEJM 2021). Based on its demonstrated benefit in la/mUC, EV is currently being evaluated in earlier UC settings. The purpose of this study is to investigate the intravesical administration of EV for patients with NMIBC. Methods: EV-104 (NCT05014139) is a phase 1, open-label, multicenter, dose-escalation and dose-expansion study designed to evaluate the safety, tolerability, PK, and antitumor activity of intravesical EV in adults with high-risk BCG-unresponsive NMIBC (carcinoma in situ with or without papillary disease) who are ineligible for or refuse RC. The dose escalation part of the trial aims to identify the maximum tolerated dose (MTD) and/or recommended dose of intravesical EV. The dose expansion part will evaluate patients at the MTD or recommended dose and further characterize safety and antitumor activity of intravesical EV. The study treatment regimen will include an induction phase, where patients will receive intravesical EV weekly for 6 weeks followed by monthly maintenance for a total of 9 additional EV doses. Patients will be assessed for response every 3 months by cystoscopy and urine cytology, while on study. Safety and antitumor activity endpoints will be summarized using descriptive statistics. The study is currently enrolling in the US with additional sites planned in Canada and the EU. Clinical trial information: NCT05014139 .

4547 Background: Surgery is the standard of care for localized kidney cancer. Diagnostic imaging plays a critical role in disease staging and informs the extent of surgical resection (partial or radical nephrectomy, extended resection). In clinical routine, up to 15% of the tumors initially assessed as T1-T2 on imaging is upgraded to pT3a status post-surgery, implying a higher risk of relapse. The ability to correctly predict pT3a status pre-surgery would inform the surgical approach. An individualized prediction of the risk of clinical T1 or T2 tumors to be upstaged to pT3a is thus of high surgical interest. Methods: UroCCR is a French national network of 37 multidisciplinary teams for kidney cancer management that collects longitudinal data on the routine clinical care of its patients. A retrospective cohort of 4,395 cases of clinical T1-T2 kidney tumors was analyzed to develop a machine learning-based algorithm predictive of post-surgical pT3a upstaging risk at the individual patient level. For each patient, pre-surgical data were collected, including gender, age, symptoms, tumor size, tumor location, RENAL score, ECOG performance status, ASA score, and post-surgical pathological status. Sites were randomly assigned to the training or testing cohort, and their respective patient cases split between cohorts in a 60/40 ratio. Missing values were addressed through imputation performed with a k-nearest neighbor algorithm. Algorithms were trained on a data set of 2,636 patients and hyperparameters were optimized using a Bayes cross-validation (10-fold) approach. The area under the precision-recall curve (prAUC) was used as optimization metric. The performance of the algorithms for pT3a status prediction was then evaluated on the test dataset of 1,759 patients using precision-recall curves. Results: A logistic regression algorithm reached an AUC of 0.77 and a prAUC of 0.41. Higher values of the tumor size or age at surgery, the hilar location and the presence of symptoms at diagnosis were all associated with an increase of the predicted probability of pT3a upstaging. For each patient, Shapley values graphs were generated to display the pT3a upstaging probability and the relative contribution of each feature to the prediction. Three risk groups were defined based on the relative computed probability of pT3a upstaging, which displayed a statistically significant difference in Disease-Free Survival (DFS) (p < 0.0001), suggesting that pre-surgical multimodal data analysis could help predict long-term outcomes. Conclusions: This study suggests that machine learning applied to pre-surgical multimodal data can predict the risk of pT3a upstaging of a localized kidney tumor and inform long-term outcomes at the individual patient level. The results have been validated on an external cohort of 1,759 patients with data from the clinical routine.

62 Background: The use of androgen deprivation therapy (ADT), has increased over time in the treatment of prostate cancer (PCa). ATD is accompanied by side effects, some of which may increase the cardiovascular (CV) risk. The aim of this study was to evaluate the prevalence of cardiovascular risks and quality of life at the initiation of degarelix, a GnRH antagonist, and 6 months later, in patients with advanced hormone-sensitive PCa. Methods: The DUO study is a PASS, pharmaco-epidemiologic, longitudinal, multicenter observational study. It prospectively enrolled PCa patients during the first 6 months of treatment with degarelix. cohort to describe the prevalence of real-life cardiovascular co-morbidities in. The study was carried out in 46 French urology centers. At D0 and M6, the prevalence of CV, osteoporotic, metabolic, mood disorder, geriatric and sexual morbidity and risk factors were recorded using validated tools and questionnaires. EQ-5D questionnaire measured quality of life. The evolution of the disease (PSA levels) and the tolerance of the treatments were also reported. Results: A total of 124 patients with advanced hormone-dependent PCa (of whom 26.6% were metastatic) were included. At D0 57.7% of patients had a CV morbidity and CV risk factors. Metabolic co-morbidities were also present in 60.6% of patients, osteoporotic risk factors in 34%, sexual disorders in 58%, and mood disorders in 36%. ONCO-G8 score ≤ 14 was observed in 45.6% of patients aged ≥ 70 years. The percentage of patients with CV co-morbidities remained stable (56.7%). The rates of osteoporotic, metabolic, sexual, and mood-related morbidity and risk factors also remained unaltered. Likewise, quality of life remained stable between D0 and M6 (Scores: 0.765 and 0.813 respectively). At the same time, the median PSA rate decreased by -98.4% from D0 (p < 0.001). 42 adverse events (AEs) were reported in 22 patients: degarelix-related AEs were reported in 4.4% of patients. Conclusions: The results of the DUO study showed high prevalence of CV co-morbidity and risk factors in patients with advanced PCa. It also showed no significant increase in CV co-morbidities and risk-factors during the first 6 months of treatment with degarelix as it was observed for osteoporotic, metabolic, sexual, and mood-related disorders. The GnRH antagonist was well tolerated without major impact on quality of life. Assessment of multiple co-morbidities at the initiation and during ADT is mandatory for the optimal management of patients.

535 Background: Immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1 antibodies, have emerged as a successful immunotherapeutic strategy for advanced and metastatic urothelial cancer (UC). Therapeutic blockade of PD-1 or PD-L1 with monoclonal antibodies leads to durable tumor regressions in up to 25% metastatic muscle invasive UC (MIBC). Neoadjuvant use of ICI also showed remarkable efficacy and represents a unique opportunity to study immunodynamics during PD-1 blockade to decipher functional predictors of response and resistance. Methods: Patients diagnosed with T2-T4aN0M0 MIBC were treated with 3 cycles of neoadjuvant pembrolizumab before cystectomy in the PANDORE trial (NCT03212651). The primary endpoint was pathologic complete response (ypT0N0). Secondary endpoints focused on safety, progression-free survival (PFS) and biomarker analysis. We performed longitudinal analysis of peripheral and tumor infiltrating lymphocytes, tumor microbiome as well as soluble factors using high dimensionnal immune phenotyping by mass cytometry, immuno-fluorescence and -histochemistry and multiplex immunoassays. Humoral and cellular recall immune memory against urinary tract commensals were studied. Results: Thirty-nine patients were enrolled from October 2017 to December 2019. All but 5 (n = 34 patients (87.2%)) proceeded with cystectomy. Ten patients presented with ypT0N0 (29.4%; 95% CI: 15.1 %-47.5 %). Multidimensional biomarkers analysis showed that baseline follicular T helper (Tfh) and post-pembrolizumab tertiary lymphoid structure (TLS) and activated B cells were associated with outcome ( p= 0.005, p= 0.01 and p= 0.04, respectively). Plasma CXCL13 (the prototypic chemokine secreted by Tfh and involved in TLS functions) increased after 1 cycle of PD-1 blockade in responders and patients without progression at 24 months ( p= 0.002 and p= 0.0001, respectively). Focusing on MIBC tumor microbiome, we showed that intracellular Gram negative bacteria and other commensals were more frequent in tumoral than in normal urothelium ( p= 0.04). Interestingly, basal CXCL13-secreting CD4+ T cells and IgG directed against urinary pathobionts such as Escherichia coli predicted prolonged PFS ( p= 0.01 and p= 0.001, respectively). Conclusions: Our results suggest that urothelial commensals could induce specific Tfh and B cell responses that were re-invigorated by PD-1 blockade and associated with clinical benefit to pembrolizumab. Further analyses are needed to validate the predictive value of commensal-specific Tfh in UC and other epithelial cancers that are directly or indirectly exposed to bacteria. Clinical trial information: NCT03212651.

4560 Background: Upper-tract urothelial carcinomas (UTUC) may harbor similar genetic profile as compared to bladder cancer, although frequencies of mutated genes have been shown to differ between them. However, to the best of our knowledge, the epigenetic landscapes of UTUC and their association with genetic alterations and clinico-pathological tumor features remain unknown. Methods: We collected 40 UTUC samples (20 non-muscle invasive (NMI) and 20 muscle-invasive (MI) and carried out whole-exome sequencing (n = 30), DNA methylation using Infinium EPIC arrays (n = 35) and RNA sequencing (n = 20). Validation was performed on TCGA bladder cancer dataset. Results: We identified 3232 putative somatic mutations with an average of 2.1+/-2.6 mutations per megabase. Significantly mutated genes were FGFR3 (50%), KDM6A (27%), MLL2 (27%) and ARID1A/B (23%). No difference in term of genetic alterations were identified between MI- and NMI- UTUC. Unsupervised hierarchical clustering using most variable DNA methylation probes uncovered two robust DNA methylation epi-clusters. Epi-cluster C1 (n = 23; 65.7%) displayed markedly higher DNA methylation relative to Epi-cluster C2 (n = 12; 34.3%). Notably, all muscle-invasive samples were enriched in C1 (16/17, 94.1%); conversely, C2 was enriched with non-muscle-invasive samples (p = 0.0009). Overall, 14.209 probes were significantly hypermethylated in C1 as compared to C2 epi-cluster; Gene Set Enrichment Analysis (GSEA) demonstrated that those were enriched for PRC2 targets (p = 6x10-65). Integrative analysis with tumor genetic landscape showed that C1 epi-cluster was enriched for mutations in SWI/SNF complex as compared to C2 (p = 0.02). We then applied our epi-signature to bladder TCGA cohort and obtained two similar epi-clusters associated with patients overall survival (p = 0.035). Conclusions: Our study demonstrate for the first time that difference between MI- and NM- invasive UTUC might be related to epigenetic rather than genetic alterations. This might pave the way for testing epigenetic therapies in non-muscle invasive tumors with the aim to prevent recurrence and distant metastasis.