Radical cystectomy is the gold-standard treatment for patients with muscle-invasive and very high-risk non-muscle-invasive bladder cancer. In female patients, radical cystectomy has traditionally included removal of the uterus, ovaries, fallopian tubes and anterior vaginal wall. The majority of female patients undergoing radical cystectomy are postmenopausal, but a subset of patients are premenopausal and experience surgical menopause as a result of bilateral oophorectomy. Surgical menopause results from an abrupt loss of sex steroid hormones, resulting in symptoms such as vasomotor instability and sexual dysfunction, while also increasing the long-term risk of osteoporosis, cardiovascular disease and cognitive decline. The importance of ovarian preservation during radical cystectomy is increasingly recognized; however, oophorectomy might still be indicated in selected premenopausal patients for oncological control. In these individuals, awareness and management of surgical menopause among urologists is often limited, resulting in avoidable morbidity. Thus, when surgical menopause is unavoidable, patients should be counselled regarding symptom management, cardiovascular risk and bone protection; and appropriate hormonal and non-hormonal therapeutic strategies should be implemented where indicated. Surgical menopause occurs in premenopausal women who undergo radical cystectomy with bilateral oophorectomy to treat bladder cancer. This Review discusses the pathophysiology of surgical menopause in these patients and highlights current strategies to mitigate associated symptoms and long-term health risks.

Background/Objectives: Most patients with metastatic renal cell carcinoma (mRCC) progress on first-line immune checkpoint inhibitor (ICI). Subsequent vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) is standard. Due to the rapid evolution in treatment landscape, data directly comparing outcomes of VEGF-TKI following ICI versus VEGF-TKI alone are limited. This scoping review aimed to explore whether VEGF-TKI following prior ICI is associated with improved outcome, potentially reflecting a treatment sequence effect. Methods: PubMed/MEDLINE and ClinicalTrials.gov were searched systematically to identify phase 2/3 prospective clinical trials that investigated VEGF-TKI in patients who had progressed after ≥1 therapy published from 2004. Included studies were summarised by prior therapy and reported outcomes. Data from subgroups/arms were extracted and weighted overall response rate (ORR), progression free survival (PFS) and overall survival (OS) calculated for patients pretreated with VEGF-TKI versus ICI. An exploratory, hypothesis generating analysis was performed comparing outcomes between patients who received prior VEGF-TKI only or ICI-based therapy. Results: In total, 17 clinical trials were included: 2538 patients had prior VEGF-TKI (15 subgroups/arms) and 724 prior ICI-based therapy (11 subgroups/arms). In prior VEGF-TKI, weighted mORR was 8% (IQR 6-16%) versus 28% (IQR 20-41%) post-ICI. Weighted mPFS was 3.9 m (IQR 3.6-5.4) with prior VEGF-TKI versus 8.3 m (IQR 7.4-10.3) in prior ICI group. Weighted mOS was 15.2 m (IQR 11.1-16.6) versus 22.1 m (IQR 10.9-22.1) with prior ICI. Conclusions: Improved outcomes in ICI pretreated population in this exploratory analysis suggests ongoing biological benefit of ICI therapy. As prospective 2L randomised studies are not feasible, we conclude that VEGF therapy in pretreated mRCC is at least as good, if not better, since the introduction of 1st line ICI.

Notable large-scale immuno-oncology consortia formed in the recent era.

BACKGROUND:The optimal number of chemotherapy cycles prior to maintenance avelumab in frontline metastatic urothelial cancer (mUC) remains unknown. We hypothesize that baseline characteristics can identify which patients will complete six cycles of chemotherapy without radiographic disease progression, versus those who may benefit from stopping chemotherapy earlier and switching to maintenance avelumab. METHODS:A retrospective audit was performed at Barts Cancer Centre for consecutive patients from January 2010 until August 2023. Patients who received frontline chemotherapy for mUC were included. Patients who completed six cycles of chemotherapy without radiographic disease progression (PD) were compared to those who discontinued treatment earlier or progressed during chemotherapy. Baseline characteristics and treatment factors were compared between patient groups using chi-squared tests (SPSS v29). RESULTS:194 patients receiving frontline platinum-based chemotherapy were identified. Only 85 of 193 patients (44%) completed six cycles without progression. Baseline characteristics were broadly comparable between patients who completed six cycles and those who did not, including ECOG performance status 0-1 (84% vs. 76%), presence of liver metastases (17% vs. 22%), baseline hemoglobin < 100 g/L (6% vs. 19%), and cisplatin use (59% vs. 54%), respectively. Early dose reduction (DR) prior to cycle 4 was the only factor significantly associated with failure to complete six cycles of chemotherapy without PD (14% vs. 43%, p < 0.001). Among patients requiring early dose reduction, only 19% subsequently completed six cycles without progression, while 43% progressed before reaching cycle 6, with a median PFS of 3 months (95% CI: 2.4-4.1). CONCLUSION:Baseline characteristics do not reliably predict the ability to complete six cycles frontline chemotherapy in mUC. However, early dose reduction in the first four cycles highly predicted inability to complete six cycles of chemotherapy.

Abstract Objectives This study aimed to understand clinical pathways for patients with high‐risk non‐muscle‐invasive bladder cancer (HR‐NMIBC) from diagnosis to follow‐up and to identify opportunities to improve care. Materials and Methods A cross‐sectional survey was conducted via structured online interviews with consented NHS healthcare professionals (HCPs) from the United Kingdom (UK) between June and September 2025. Topics surveyed included MDT structures/roles, diagnostic timelines, adjuvant treatment, radical cystectomy (RC) decision making, current bladder‐sparing treatment and clinical trial access. Quantitative data were analysed descriptively. Qualitative responses were analysed thematically. Results Seventy HCPs were included and reported that typically; 88.5% of patients achieve diagnosis within 6–8 weeks of referral, and 11.4% reported delays beyond 8 weeks. BCG maintenance duration and completion rates varied. Following BCG induction, a median (IQR) of 20.0% (5.0–32.5%) and 60.0% (40.0–70.0%) of patients completed ≥2 or ≤1 years of maintenance, respectively; 1.0% (1.0–2.0%) failed to complete induction. For BCG‐unresponsive HR‐NMIBC, HCPs reported that a mean ( SD ) proportion of 53.4 (18.1)% of patients tend to be eligible for and consent to RC, 22.0 (12.6)% tend to be eligible but decline RC and 24.6 (14.9)% tend to be ineligible. Bladder‐sparing options remain limited, with 60% of HCPs regarding further BCG as the most appropriate option. All respondents agreed that adherence to quality performance indicators (QPIs) and a national bladder cancer audit would be beneficial. Insufficient specialist nurse capacity to meet foreseeable demands of HR‐NMIBC patient care was reported by 70% ( n = 49) of HCPs. Conclusion Results reveal variability in real‐world HR‐NMIBC care within the NHS. Delays in diagnosis, inconsistent BCG maintenance duration, lack of evidence‐based alternatives to BCG and a lack of bladder‐sparing treatment and trial options in the BCG‐unresponsive setting were identified. Findings highlight unmet needs in relation to MDT resourcing, diagnostic efficiency, trial access, QPI adherence and a national bladder cancer audit.

MANIFEST Consortium List of Authors

OBJECTIVE:To evaluate the concordance between clinical complete response (cCR) and pathological complete response (pCR) in muscle-invasive bladder cancer (MIBC) to assess the surrogacy and prognostic value of cCR for guiding bladder-sparing strategies. METHODS:In this prospectively registered systematic review and meta-analysis (CRD420251066540), we searched MEDLINE, EMBASE, and Web of Science in June 2025 for studies reporting clinical and pathological complete response rates in patients with MIBC undergoing neoadjuvant therapy followed by radical cystectomy (RC). Pooled concordance was estimated via random-effects meta-analysis. Risk-of-bias was assessed using the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I). RESULTS:Out of 1947 individual records, 10 (n = 894) retrospective and three (n = 181) prospective studies comprising 1075 patients were included. Restaging modalities for cCR assessment included transurethral resection of the bladder (TURB; n = 188, two studies), computed tomography (n = 221, two studies), magnetic resonance imaging (MRI; n = 122, two studies), and fluorodeoxyglucose positron emission tomography (n = 45). One study (n = 56) used perioperative cystoscopy, while the remaining five studies (n = 499) combined imaging with cystoscopy or TURB. The concordance (n = 779, nine studies) between cCR and pCR was 0.51 (95% confidence interval [CI] 0.42-0.60), the concordance (n = 536, seven studies) between non-cCR and non-pCR was 0.84 (95% CI 0.70-0.92). Most studies were rated as having moderate concerns regarding bias, and one as serious due to examiner-dependent bias of cystoscopy-based cCR assessment. CONCLUSION:Current evidence does not support relying on the current definition of cCR alone, which poorly predicts pCR, to guide treatment decisions. Ongoing trials assessing the combination of MRI plus TURB with urine and/or blood based circulating tumour DNA may help refine cCR evaluation and support the sole introduction of bladder-sparing approaches in patients with MIBC who respond to neoadjuvant systemic therapy.

Figure S9: Gene expression of select cancer-associated markers located on chromosomes frequently altered in muscle-invasive bladder cancer.

PURPOSE:Standard of care for muscle-invasive bladder cancer (MIBC) is radical cystectomy (RC) with neoadjuvant cisplatin-based chemotherapy (NAC). However, many patients are ineligible for or refuse cisplatin. SunRISe-4 (ClinicalTrials.gov identifier: NCT04919512) is an open-label, multicenter, parallel-cohort phase II study assessing neoadjuvant gemcitabine intravesical system (TAR-200/gem-iDRS) plus cetrelimab or cetrelimab monotherapy in patients with MIBC. METHODS:Adults with Eastern Cooperative Oncology Group performance status 0-1, cT2-T4a N0M0, ineligible/refusing NAC, and planned for RC were randomly assigned 5:3, stratified by transurethral resection of bladder tumor completeness (residual tumor ≤3 cm permitted) and T stage, to receive TAR-200 plus cetrelimab (cohort 1) or cetrelimab monotherapy (cohort 2). The primary end point was pathologic complete response (pCR) at RC. Secondary end points included recurrence-free survival (RFS) and safety. Exploratory end points included pathologic overall response (pOR; ≤ypT1N0) and circulating tumor (ct) and urinary tumor (ut) DNA molecular residual disease (MRD). Side-by-side descriptive efficacy summary was planned. RESULTS:At the May 9, 2025, data cutoff, 159 patients were treated; 88 in cohort 1 and 46 in cohort 2 underwent RC. pCR, pOR, and 1-year RFS rates were 38%, 53%, and 77% in cohort 1 and 28%, 44%, and 64% in cohort 2, respectively. pCR rates were consistent across subgroups. No new safety signals were observed. Across cohorts, utDNA- status before RC (week 12) and utDNA clearance correlated with pCR (P < 10-5 and < 10-3, respectively). ctDNA- status at baseline and week 12 was associated with longer RFS compared with ctDNA+ status at the same time point (P = .04 and 0.01, respectively). CONCLUSION:TAR-200 plus cetrelimab provided higher pCR, pOR, and 1-year RFS rates compared with cetrelimab monotherapy, supporting further investigation of the neoadjuvant combination in MIBC. utDNA and ctDNA MRD results support further investigation as biomarkers for residual local and nonlocal disease, respectively.

525 Background: HRQoL tools and adverse event criteria were designed around outdated therapies and require re-evaluation in the era of immune checkpoint inhibitors (ICI). Attempts have been made to create a novel HRQoL tool (Bergerot et al) but this has not been validated in prospective data sets. To our knowledge no attempts have been made to re-evaluate current toxicity grading systems. Data from PRISM, a randomized ph2 trial which explored scheduling of 1 st line ipilimumab/nivolumab in advanced renal cell carcinoma (RCC), was used to validate these novel tools. Methods: HRQoL (EORTC QLQ-C30 & FKSI-19) and irAE data graded using common terminology criteria for adverse events (CTCAE) were analysed in treatment naïve patients with advanced RCC recruited to PRISM. Patients were randomised 2:1 to 4 doses of ipilimumab 12-weekly (modified) or 3-weekly (standard) in combination with nivolumab. The novel QoL tool, created with patient engagement and expert input, was prospectively tested and compared with scores for FKSI-19 (0-76) and QLQ-C30 (0-100). irAEs (graded 1-5 CTCAEv5) were reclassified by patient advocates into 3 groups; life changing (LC), significant (S), non-significant (NS). These were further classified into short term (ST) or long term (LT). Results: In PRISM 192 patients were randomised 2:1 (128 modified, 64 standard schedule). HRQoL scores were available for 157 patients at baseline, week 13 and 25. Baseline scores were comparable across all 3 (QLQ-C30, FKSI-19, novel tool) tools. IMDC good risk patients had higher QOL scores at baseline across all three questionnaires compared to intermediate/poor risk (FSKI 64 vs 58, QLQC-30 86 vs 77, novel tool 59 vs 53, p <0.05). Only the novel tool showed significantly improved QoL (57 v 51, p >0.05) at 13 weeks. There was no correlation between occurrence of grade 3/4 irAEs and reduction in QOL as reported in PRISM. QoL scores in patients with progressive disease were worse across all tools (FSKI 52.3 v 58.9, QLQC-30 60.3 v 75.2, novel tool 48 v 56.4, p <0.02). 1158 irAEs were reported and reclassified. All grade 1 irAEs were deemed NS. The table shows the frequency of significant or life changing toxicity as perceived by patients. Incidence of life changing and significant toxicity was 15% and 24% respectively, which was associated with reduction in HRQoL across all tools. Conclusions: Here we describe the frequency of significant or life changing toxicity associated with ICI which will help clinicians in describing risk/benefit ratios to patients. Refining these tools facilitates more accurate future data collection in trials which better reflects the patient experience. irAE Life changing (LC) Significant short term (SST) Significant long term (SLT) Non-significant (NS) Grade 2n=281 17 (6%) 17 (6%) 10 (4%) 237 (84%) Grade 3n=122 14 (12%) 53 (43%) 9 (7%) 46 (38%) Grade 4n=8 2 (25%) 4 (50%) 1 (12.5%) 1 (12.5%)

Molecularly targeted agents and immune checkpoint inhibitors (ICIs) are transforming the treatment landscape for patients with advanced-stage urothelial carcinoma (aUC), although trials testing these novel agents have shown mixed results. In this context, the identification of biomarkers has seen limited success: while activating mutations in FGFR3 are now established as an actionable biomarker to guide treatment with FGFR inhibitors, PD-L1 expression has shown inconsistent value as a predictive biomarker of response to ICIs. The identification of prognostic and predictive biomarkers for ICIs, antibody–drug conjugates and targeted therapies is an active area of research; promising candidates include tumour mutational burden and HER2 overexpression. In the past few years, circulating tumour DNA has emerged as a minimally invasive biomarker, with increasing data supporting its prognostic value and utility for monitoring clinical responses. In this Review, we address these developments and discuss biomarkers that could have clinical utility in patients with aUC. The identification of prognostic and predictive biomarkers for immune checkpoint inhibitors, antibody–drug conjugates and targeted therapies for urothelial carcinoma is currently an active area of research. In this setting, circulating tumour DNA is emerging as a minimally invasive biomarker with utility for monitoring clinical responses. The authors of this Review discuss biomarkers that could have clinical utility in patients with this malignancy

Objective:To describe real-world outcomes of patients with BCG failure undergoing bladder-sparing treatments (BSTs) vs radical cystectomy in the UK. Patients and Methods:A single institution audit was conducted at a tertiary bladder cancer referral service (UCLH, London, UK). Patients with BCG failure treated between January 2017 and September 2022 were included. BSTs included endoscopic surveillance, hyperthermic mitomycin and further BCG. The primary outcome was event free survival (EFS). Complete response (CR) rate and duration of response (DoR) were investigated in patients undergoing BST. The secondary outcomes were 3- and 5-year cancer-specific (CSS) and overall survival (OS). Results:A total of 112 patients were included: 30% (34/112), 32% (36/112) and 27% (30/112) had BCG unresponsive, exposed and intolerant disease and 11% (12/112) had progressed to muscle invasive disease (MIBC).In the BCG unresponsive and exposed groups, 79% (27/34) and 72% (26/36) underwent RC, with the remaining receiving BSTs. Comparing RC vs BST in BCG unresponsive and exposed groups combined, there was a significantly poorer EFS in the BST group (p < 0.001); 35.3% (6/17) patients transitioned to second-line BST due to recurrence or intolerance and a further 50% (3/6) transitioned a third line BST. There was no significant difference in CSS or OS rates. In BCG intolerance, the EFS rate was 90% as three patients experienced high-grade recurrence and underwent RC. There were no cancer-related deaths. In MIBC group, 5/12 presented with metastatic disease and 3- and 5-year CSS rates was 66% and 0%. Conclusion:This data reports real-world practice in a UK centre. BSTs in BCG unresponsive and exposed disease are supported as an alternative to RC providing the increased risk of recurrence is accepted. Additionally, consideration of formal guidance supporting BST is needed in BCG intolerance, which appears to have an excellent outcome in a cohort managed with endoscopic surveillance. Upstaging to MIBC remains a poor prognostic factor and is key to improving survival outcomes in BCG failure.

BACKGROUND AND OBJECTIVE:While the benefit of cabozantinib in metastatic renal cell carcinoma (mRCC) is well established post-tyrosine kinase inhibitor therapy, its comparative effectiveness versus sunitinib after first-line (1L) nivolumab-ipilimumab is uncertain. METHODS:A target trial emulation was designed using data from the IMDC to estimate the effect of second-line (2L) cabozantinib versus sunitinib within 18 months of discontinuing 1L nivolumab-ipilimumab on overall survival (OS). Patients diagnosed after January 1, 2017 were followed from initiation of 2L until death or last known contact. Inverse-probability of treatment weighting was used to adjust for hemoglobin, calcium, platelets, and neutrophils at 2L, Karnofsky performance score (KPS) at 2L, time from diagnosis to initiation of 2L, and response to 1L nivolumab-ipilimumab. Treatments were compared using adjusted Kaplan-Meier curves and adjusted hazard ratios (HR) from a Cox regression model. Missing data were addressed with multiple imputation by chained equations. E-values were used to assess the likelihood findings could be explained by residual confounding. KEY FINDINGS AND LIMITATIONS:A total of 120 and 121 patients who received cabozantinib or sunitinib after 1L nivolumab-ipilimumab were included. The proportion with a KPS < 80% at 2L (21% vs. 46% P = .001) and the overall response rate to first line therapy (12.7% vs. 17.9% P = .002) differed significantly between cabozantinib and sunitinib. The objective response was 27% for cabozantinib versus 20% for sunitinib with a median time to treatment failure of 8.5 (95% CI: 6.9-12.9) and 4.5 (95% CI: 3.7-5.8) months. Median OS was 21.4 (95% CI: 17.9-NA) months from initiation of cabozantinib and 10.1 (95% CI: 7.6-17.7) months for sunitinib (Adjusted HR 0.44 (95% CI: 0.22-0.86)). The E-value was 2.92, suggesting a low likelihood of findings being due to residual confounding alone. CONCLUSIONS:These data provide real-world evidence supporting cabozantinib as a second-line treatment option in mRCC following 1L nivolumab-ipilimumab.

Figure S7. ESTIMATE tumor purity scores for the ABACUS cohort, stratified by LumP, LumNS, LumU, Basal-Sq, NE-like, and Stroma-rich vs Scar-like and the former tumor bed.

Table S2: Clinical, pathological tumor- and pathological node status of patients identified by the scar-like signature.

PURPOSE:Many patients have residual disease after neoadjuvant therapy, but their prognosis and need for adjuvant therapy are unclear. This study evaluates patient prognosis based on the molecular profiling of residual disease at cystectomy. EXPERIMENTAL DESIGN:RNA sequencing data from TURBT samples were available from N = 84 ABACUS patients, of whom N = 64 had matched radical cystectomy (RC) samples, including 10 patients with pathologic complete response (ypT0N0). Pre- and post-atezolizumab tumor gene expression data were classified into molecular subtypes using the consensus subtyping model as a benchmark. Unsupervised consensus clustering was performed to categorize RC samples de novo, and each cluster was characterized using gene expression signatures. Two RC cohorts (neoadjuvant chemotherapy, N = 133 and University of Texas Southwestern, N = 94) known to harbor a scar-like biologic cluster were used for training and testing of a single-sample transcriptomic classifier that was validated in two independent (PURE-01, N = 26 ad ABACUS, N = 64) RC cohorts after neoadjuvant immunotherapy. RESULTS:Unsupervised consensus clustering revealed four distinct post-atezolizumab clusters (scar-like, basal, luminal-stromal, and luminal). The scar-like cluster was present in 25% (16/64) of the post-atezolizumab samples and expressed genes associated with wound healing/scarring. A transcriptomic classifier trained to identify a favorable scar-like transcriptomic profile in residual bladder tumors showed robust performance in two validation cohorts, indicating a patient subgroup with favorable prognosis among neoadjuvant chemotherapy-treated, pembrolizumab-treated, and atezolizumab-treated patients with residual bladder cancer. CONCLUSIONS:This study contributes to the framework for defining molecular subtypes at RC. Residual bladder cancer with a scar-like transcriptomic profile may predict favorable patient prognosis after neoadjuvant chemotherapy and immunotherapy, identifying potential candidates for treatment deintensification.

Figure S1. Disease Free Survival Outcomes for N = 84 TURBT cases from the ABACUS trial subtyped by Lund (A), Consensus (B) and TCGA (C) subtyping models.