Antibody-drug conjugates (ADCs), particularly enfortumab vedotin (EV) in combination with pembrolizumab, have emerged as transformative treatments for advanced bladder cancer (BC). However, platinum-based chemotherapy, especially gemcitabine-cisplatin (GC), remains a widely used, first-line standard globally. This study investigated the impact of GC-therapy on subsequent ADC responsiveness. Using novel, patient-derived BC models, in vitro selection for acquired GC-resistance consistently resulted in downregulation of the EV target, Nectin-4, and corresponding EV cross-resistance in GC-resistant (GC/R) cells. This decrease in membranous Nectin-4 expression was validated in two independent human BC cohorts: (1) matched transurethral resections and radical cystectomy/lymph node specimens during neoadjuvant therapy and (2) primary tumors and distant metastases during adjuvant GC chemotherapy. Transcriptomic profiling indicated that GC-resistance and Nectin-4 downregulation were linked to a transcriptional shift toward an epithelial-to-mesenchymal transition (EMT)-like phenotype. Large-scale drug screening and transcriptomic data highlighted potential vulnerabilities in GC/R cells, notably associated with the transforming growth factor beta (TGF-beta) signaling pathway. These findings suggest that platinum-based chemotherapy may promote EMT-like transcriptional reprogramming in BC, associated with Nectin-4 loss and EV resistance. As such, assessing membranous Nectin-4 expression prior to EV therapy might be particularly relevant in postplatinum settings. Additionally, identifying alternative, chemotherapy-induced druggable vulnerabilities can inform more effective treatment strategies.
Androgen deprivation therapy remains the cornerstone of treating prostate cancer and is now available in multiple formulations based on several randomized phase 3 trials. The estradiol patch offers numerous potential advantages, including fewer hot flashes, less adverse impact on bone health, and less financial toxicity.
BACKGROUND AND OBJECTIVE:The Retzius-sparing (RS) robot-assisted radical prostatectomy (RARP) was proposed in 2010 to enhance early postoperative continence recovery. However, long-term oncological outcomes following this approach remain insufficiently characterized. This study reports the long-term oncological outcomes of a randomized controlled trial originally designed to compare early continence recovery in patients treated using the RS versus standard (anterior) approach. DESIGN, SETTING, PARTICIPATNS AND INTERVENTION:A total of 120 men aged 40-75 yr with low- to intermediate-risk prostate cancer underwent RARP at a tertiary referral center. Patients were randomized 1:1 to the anterior or RS approach (n = 60 per arm). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The primary end point was progression-free survival (PFS), defined as biochemical recurrence and/or the need for any additional treatment. Kaplan-Meier plots were used to depict and compare PFS between the approaches. Cox regression was used to examine the impact of the approach on PFS after adjusting for the Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) scores. RESULTS AND LIMITATIONS:Median follow-up was 77 mo (interquartile range 30-110). At 5 yr, PFS was 80.2% in the RS group versus 91.1% in the anterior group (p = 0.01). After adjusting for CAPRA-S score, patients undergoing the RS approach were 2.64-fold more likely to experience progression (p = 0.049). The main limitations of this study stem from its original design, which did not consider long-term oncological outcomes as a primary end point, and from surgeons' limited prior experience with the RS approach. CONCLUSIONS:Although RS RARP provides superior early continence outcomes, patients randomized to this approach experienced less favorable long-term oncological control, potentially because of the increased technical demands of the procedure.
Prostate cancer recurrence after radical prostatectomy (RP) is primarily driven by tumor aggressiveness, but accurate long-term prediction remains challenging. We evaluated long-term oncological outcomes using magnetic resonance imaging (MRI) and targeted biopsy data in 646 patients treated with RP between 2009 and 2018, and the median follow-up for survivors was 8.3 yr. The primary end point was metastatic recurrence and the secondary end point was biochemical recurrence (BCR). Preoperative variables included MRI-derived tumor volume and quantification of Gleason pattern 4/5 (GP4/5). Tumors were classified according to zonal origin as peripheral zone (PZ) or transition zone/anterior fibromuscular stroma (TZ/AFMS). At 10 yr, metastatic recurrence occurred in 11% (95% confidence interval [CI] = 9-15), including distant metastases in 7.3% (95% CI = 5.1-10). BCR occurred in 28% (95% CI = 24-32). MRI- and biopsy-derived GP4/5 burden strongly predicted metastatic recurrence (c-index 0.82, 95% CI = 0.76-0.88) and BCR (c-index 0.73, 95% CI = 0.69-0.78). Outcomes were consistently worse for PZ compared with TZ tumors, with higher 10-yr BCR rates (32% vs 14%, p = 0.004) and numerically higher metastatic recurrence (8.2% vs 3.7%), with overlapping CIs. These findings provide long-term validation of MRI-based quantification of tumor aggressiveness to predict metastatic recurrence after RP. Although PZ tumors showed consistently worse outcomes in unadjusted analyses, zonal origin was not an independent predictor after multivariable adjustment, suggesting mediation through higher GP4/5 burden.
BACKGROUND AND OBJECTIVE:Cystoscopy is a core component of haematuria investigations; however, it is invasive and resource intensive. GALEAS Bladder is a DNA-based diagnostic urine test that measures mutations in 23 bladder cancer (BC)-associated genes. OBJECTIVE:We aimed to assess the diagnostic performance of GALEAS Bladder in real-world patients with haematuria and its utility as a molecular triage tool in this setting. METHODS:Patients referred for urgent investigation of haematuria were prospectively enrolled across seven UK National Health Service urology departments between October 2024 and June 2025. Urine samples were collected prior to cystoscopy and analysed by GALEAS Bladder. Assay results were compared with cystoscopy and biopsy/transurethral resection of bladder tumour findings. KEY FINDINGS AND LIMITATIONS:Cystoscopic findings and GALEAS Bladder results were available for 964 participants (575 visible and 294 non-visible haematuria, 95 unknown), including 77 (8.0%) newly diagnosed with pathology-confirmed BC. The assay detected 71 of the 77 BCs, including all 17 muscle-invasive BCs and 35 of the 36 high-grade BCs, with negative predictive value >99% (95% confidence interval [CI] 98-100), positive predictive value 50% (95% CI 42-58), positive likelihood ratio (LR) 11.5, and negative LR 0.09. Decision curve analysis showed net benefit over cystoscopy for all referrals. Limitations include observational study design over a limited timeframe and absence of subsequent diagnoses for participants with positive GALEAS Bladder test results without cystoscopically visible tumour. CONCLUSIONS AND CLINICAL IMPLICATIONS:GALEAS Bladder is a clinically implementable molecular urine test that detects new cases of BC with high negative predictive value and favourable LRs in patients undergoing urgent investigation of haematuria. These data show that GALEAS Bladder can be used now to triage patients with haematuria to immediate or deferred cystoscopy.
BACKGROUND AND OBJECTIVE:The Food and Drug Administration and the European Medicine Agency approved erdafitinib for patients with FGFR3-altered metastatic urothelial carcinoma (mUC), highlighting the central role of tumor molecular profiling for patients with mUC. Although different studies described the molecular landscape of muscle-invasive bladder cancer (MIBC) using publicly-available data, a dedicated evaluation of real-world actionable alterations, with evidence-based therapeutic recommendations according to current Molecular Tumor Board (MTB) guidelines, is still lacking. DESIGN, SETTING, AND PARTICIPANTS:We characterized actionable genetic alterations in a retrospective cohort of 233 patients with MIBC/mUC (Muscle-Invasive Erlangen [MIER] cohort) using targeted sequencing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Clinically relevant variants were assessed through a custom bioinformatics workflow and expert medical review. To validate their clinical relevance in a real-world setting, we examined actionable alterations and associated therapy recommendations in a cohort of 40 patients with MIBC/mUC undergoing routine diagnostics (MTB cohort). RESULTS AND LIMITATIONS:In the MIER cohort, 95% of patients (n = 226/233; 95% confidence interval [CI], 94-99) harbored at least one pathogenic/likely pathogenic variant. Therapeutically relevant FGFR3 alterations were identified in 11% of patients (n = 26/233; 95% CI, 7.4-16). Additionally, 40% of patients (95% CI, 34-47) showed alterations in 24 biomarkers for FDA-approved therapies. In the MTB cohort, 55% of patients received either on-label (5.0%) or off-label (50%) therapy recommendations. Notably, the recommendation was implemented in only one patient, who achieved stable disease for 4 mo with off-label alpelisib. Retrospectively, similar on-label and off-label indications could have applied to 10% and 70% of patients in the MIER cohort, respectively. CONCLUSIONS:Overall, evidence-based indications for on-label and off-label therapies were observed for the majority of patients with MIBC/mUC. However, our results also revealed a significant gap between the high prevalence of actionable findings and the actual implementation of MTB-guided treatments in clinical practice, suggesting a need for enhanced therapy access and physician adherence to MTB recommendations.
PROpel (phase 3 randomized [1:1], double-blind trial: NCT03732820) met its primary endpoint, showing statistically significantly improved investigator-assessed radiographic progression-free survival (rPFS) with olaparib plus abiraterone versus placebo plus abiraterone in biomarker-unselected first-line metastatic castration-resistant prostate cancer (mCRPC; hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.54-0.81; p < 0.0001). Median overall survival (OS) was 42.1 mo with olaparib plus abiraterone, a 7.4-mo improvement versus placebo plus abiraterone. We report efficacy in patients with single homologous recombination repair gene mutations (HRRm). Before primary analysis, HRRm status was determined by aggregating tumor tissue (FoundationOne CDx) and circulating tumor DNA (FoundationOne Liquid CDx) assay results. Overall, 28.4% of patients had an HRRm, predominantly BRCA2 (7.3%), ATM (6.2%), and CDK12 (5.0%). HRs numerically favored olaparib plus abiraterone for rPFS (BRCA2, HR, 0.20; 95% CI, 0.08-0.44; ATM, HR, 0.55; 95% CI, 0.20-1.38; CDK12, HR, 0.51; 95% CI, 0.20-1.18) and OS (BRCA2, HR, 0.20; 95% CI, 0.07-0.48; ATM, HR, 0.79; 95% CI, 0.33-1.77; CDK12, HR, 0.57; 95% CI, 0.24-1.27). Other single-gene mutations were rare (<5 events in either arm), limiting interpretation. Findings support olaparib plus abiraterone as an important first-line option for patients with mCRPC. PREVIOUS PRESENTATION: Results were previously presented in part at the ASCO-GU 2024 congress, held on January 25-27, 2024: San Francisco, CA, USA.
BACKGROUND AND OBJECTIVE:Functional recovery after radical prostatectomy happens continually but is only measured at set times when questionnaires are given. This leads to what is known as interval censoring. In the urologic literature, patients are typically considered to have recovered function at the moment they complete a follow-up survey, although recovery may have occurred earlier, leading to systematic overestimation of recovery time. At our institution, patients completing function assessments are additionally asked to estimate when recovery occurred, and this estimate is incorporated into the analysis. We aimed to compare our approach with the standard method, which assigns recovery to the survey completion date. METHODS:We retrospectively identified 11 161 men who underwent radical prostatectomy between 2009 and 2025. Patients completed urinary and erectile function questionnaires at regular intervals after surgery; at the first response meeting recovery criteria (eg, pads no longer used), patients estimated the timing of recovery using predefined intervals. We used Kaplan-Meier analyses to estimate cumulative recovery over time, using both the survey completion date and the patient-reported estimate. KEY FINDINGS AND LIMITATIONS:We identified 7896 patients who recovered continence and 6521 who recovered erectile function. Patient-estimated recovery time was considerably earlier than recovery time based on the survey completion date. Median time to continence recovery was 5 mo using our approach versus 8 mo using the survey completion date approach, whereas median time to erectile function recovery was 18 mo versus 23 mo. At 6 mo, recovery rates were higher when based on patient-estimated dates compared with survey completion dates for both continence (57% vs 40%) and erectile function (35% vs 28%). CONCLUSIONS AND CLINICAL IMPLICATIONS:Functional questionnaires should include an additional item asking patients to report when recovery occurred. The reported time of recovery should be used in the analysis rather than the survey completion date.
BACKGROUND AND OBJECTIVE:Lynch syndrome (LS) and germline DNA damage repair (DDR) mutations have been described in urothelial carcinoma (UC). However, the incidence in unselected cohorts and the impact on outcomes remain unclear. DESIGN:We performed a retrospective study to determine the frequency of pathogenic/likely pathogenic (P/LP) germline variants in 78 known cancer predisposition genes among 273 patients with urinary tract cancer (UTC) of the bladder, renal pelvis, ureter, and/or urethra and validated the frequency in an independent cohort of 5972 patients. We identified variants in germline whole-exome sequencing that were overrepresented in UTC. We measured associations with treatment-related outcomes. RESULTS AND LIMITATIONS:In unselected cohorts, 9.3-9.5% of the patients with UTC harbored a variant in a cancer predisposition gene. No clinicodemographic variable predicted the presence of a P/LP variant. LS was found in 0.7-0.8% of the patients who were more likely to have upper tract disease and strong personal and family histories of malignancy. Non-Lynch DDR variants occurred in 6.6-8.0% of the patients, most often in CHEK2, BRCA1, BRCA2, and ATM. Very small cohorts of patients with UC and LS or a DDR variant responded well to immune checkpoint inhibitors (ICIs) or platinum chemotherapy, respectively. Standard variant calling methods may miss large deletions. CONCLUSIONS:The incidence of P/LP germline variants in UTC is clinically meaningful, and more than one-third of the patients are missed with current guidelines. The response of UC with LS to ICI and with DDR to platinum is hypothesis generating and warrants further investigation.
BACKGROUND AND OBJECTIVE:Bilateral or multifocal (BMF) papillary renal cell carcinoma (pRCC) arising without a confirmed pathogenic germline variant represents a clinically distinct entity with a poorly defined natural history. We aimed to establish clinical benchmarks for tumor growth kinetics, oncologic outcomes, and renal functional impact in this entity. PATIENTS AND METHODS:We identified 89 patients with histopathologically confirmed clinically sporadic BMF pRCC from a prospectively maintained, institutional review board-approved database at the National Cancer Institute (1999-2025). Tumor growth rate was calculated with a linear mixed-effects model. Active surveillance was assessed in 105 tumors from 44 patients with ≥6 mo of serial cross-sectional imaging. KEY FINDINGS AND LIMITATIONS:Over a median follow-up of 50 months, metastatic disease developed in six patients (6.7%), exclusively among patients whose largest tumor exceeded 3 cm at the time of assessment. A total of 156 renal procedures were performed, with partial nephrectomy predominating (81%). Variant pathology was identified in 18 of the 649 tumors (2.8%; 95% confidence interval 1.8%-4.3%). Among the 105 radiographically surveilled tumors, 64% demonstrated interval growth. The median tumor growth rate was 1.55 mm/yr (interquartile range 1.24-1.81). Repeat ipsilateral partial nephrectomy was associated with a significant decline in renal function (median estimated glomerular filtration rate 80.9-63.5 ml/min/1.73 m2; p = 0.002). CONCLUSIONS AND CLINICAL IMPLICATIONS:Sporadic BMF pRCC demonstrates predominantly indolent growth and low metastatic potential, with no metastatic events observed in patients presenting with a largest tumor <3 cm. These findings provide growth-rate benchmarks consistent with active surveillance for small renal masses and nephron-sparing surgery when intervention is warranted.
Prostate-specific membrane antigen positron emission tomography (PSMA PET) has become an integral component of contemporary prostate cancer (PCa) management, improving disease characterization in clinically relevant settings such as initial staging of higher-risk disease and biochemical recurrence. Beyond its superior diagnostic performance compared with conventional imaging, PSMA PET increasingly influences treatment planning, patient stratification, and multidisciplinary decision-making. However, despite growing incorporation into international clinical guidelines, access to PSMA PET remains heterogeneous across health care systems. Variability in reimbursement policies, regulatory frameworks, tracer availability, imaging capacity, referral pathways, and local expertise may limit timely access for eligible patients. These disparities have important clinical implications, potentially affecting staging accuracy, localization of recurrent disease, treatment selection, and equity of care. In this expert perspective, we discuss the evolving role of PSMA PET in PCa management, highlight the clinical consequences of unequal access, and identify key priorities to facilitate implementation across Europe. Improving access to high-quality PSMA PET should be regarded not only as a logistical objective but also as a clinical priority to ensure that advances in molecular imaging translate into more precise, timely, and equitable PCa care.
BACKGROUND:Erectile dysfunction remains a major morbidity after radical prostatectomy. The SAFE technique uses real-time, micro-ultrasound-guided low-pressure hydrodissection to enable atraumatic nerve sparing. OBJECTIVE:We compared functional and oncologic outcomes of SAFE versus standard robotic-assisted radical prostatectomy (RARP). DESIGN, SETTING, AND PARTICIPANTS:In this randomized trial, patients were assigned 1:1 to micro-ultrasound-guided SAFE-RARP or standard RARP. Surgeons were unblinded; patients and outcome assessors were blinded. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The primary endpoint was erectile function recovery at 6 mo (SHIM ≥17), with secondary functional and oncologic outcomes. The primary endpoint was assessed at the prespecified interim analysis using a one-sided pooled z-test within a group-sequential O'Brien-Fleming α-spending framework (interim efficacy boundary, one-sided p < 0.002). RESULTS AND LIMITATIONS:A total of 107 patients were analyzed (SAFE, n = 54; control, n = 53). At 6 mo, erectile function recovery was higher with SAFE than with standard RARP (52% vs 43%; absolute difference 8.5%, 95% CI -10% to 27%; one-sided p = 0.22), without crossing the prespecified interim efficacy boundary. At 6 weeks, early recovery rates were higher with SAFE (37% vs 21%; one-sided p = 0.032), with a smaller difference at 3 mo. Linear mixed-effects modeling showed earlier improvement in SHIM with SAFE, with convergence by 6 mo. Continence, oncologic outcomes, and complication rates were similar between groups. Limitations include the prespecified interim nature of the analysis, the relatively small sample size, and the need for longer follow-up to determine the durability and clinical significance of functional differences. CONCLUSIONS:In this prespecified interim analysis, the primary endpoint of 6-mo recovery was not met. Exploratory analyses suggested earlier postoperative recovery with SAFE, without evidence of compromised safety or oncologic outcomes; these findings are hypothesis-generating.
BACKGROUND AND OBJECTIVE:Detecting localized prostate cancer (PC) with metastatic potential-defined as unfavorable-histology PC (uhPC), comprising Grade Group (GG) ≥3 disease or GG 2 disease with cribriform/intraductal features-is critical for guiding appropriate intervention. We evaluated the utility of the Prostate Imaging Reporting and Data System (PI-RADS) and the automated Restriction Spectrum Imaging restriction score (RSIrs; a biophysics-based quantitative MRI biomarker) for uhPC detection and localization. METHODS:We evaluated patient-level detection of uhPC in a multicenter cohort with biopsy as the reference standard and lesion-level localization in a separate cohort with whole-mount histopathology (WMHP) from radical prostatectomy. The area under the receiver operating characteristic curve (AUC) was calculated to compare patient-level detection of uhPC using PI-RADS and RSIrs. PI-RADS and RSIrs were used to evaluate sensitivity for the most aggressive tumor within the prostate (index tumor) and for all uhPC tumors on WMHP. KEY FINDINGS AND LIMITATIONS:The AUC for patient-level detection of uhPC did not differ significantly between PI-RADS and RSIrs in 1022 patients from five centers (p = 0.13). At the lesion level (n = 103 patients), sensitivity for the index tumor was 87% (95% confidence intervals [CI], 79-94) for PI-RADS, 85% (95% CI, 78-93) for RSIrs, and 93% (95% CI, 86-98) for the two combined. For all uhPC tumors, sensitivity was 81% (95% CI, 73-90) for PI-RADS, 86% (95% CI, 78-93) for RSIrs, and 90% (95% CI, 82-97) for the two combined. A limitation of the lesion-level analyses was that only patients who opted for surgery could be included. CONCLUSIONS AND CLINICAL IMPLICATIONS:MRI showed high sensitivity for detecting uhPC, reinforcing its value for identifying biologically aggressive disease. Both PI-RADS and automated RSIrs may be useful for targeted biopsy and tumor-focused treatment, such as focal radiation dose escalation to aggressive intraprostatic lesions.
