Citations

352 Background: Glucagon-like peptide 1 (GLP1) receptor expression in prostate cancer tissue has raised concerns that GLP1 receptor agonists (GLP1A) may influence tumor growth or progression. We compared prostate cancer severity at diagnosis among patients receiving GLP1A versus other glucose lowering therapies. Methods: A retrospective chart review identified patients who received GLP1A or alternative second-line glucose lowering agents (DPP4/SGLT2 inhibitors) and were subsequently diagnosed with prostate cancer. Patients receiving both drug classes were excluded. Baseline demographics (race, ethnicity, age), comorbidities (diabetes, myocardial infarction, peripheral vascular disease) concomitant medications (insulin, metformin, statins), appointments (within past year) and laboratory values (HbA1c, eGFR) at therapy initiation were recorded. Primary outcomes included Gleason grade group and metastatic presentation within three months of diagnosis. Propensity score matching balanced baseline characteristics between groups. Mann-Whitney U tests compared grade groups. Chi-square tests compared metastatic presentation, reporting odds ratios (OR) with 95% confidence intervals (CI). Multivariable logistic regression identified predictors of grade group (low-grade: 1-2; high-grade: ≥3) and metastatic presentation, reporting OR with 95% CI. A p value <0.05 indicated a significant association. Results: Of 260 propensity-matched patients (GLP1A: 130, comparison: 130), 87% were White and 95% were Non-Hispanic/Non-Latino in each group. Median HbA1c was 7% (IQR: 6.4-8) in GLP1A group versus 7.5% (6.2-8.5) in comparison group. Median eGFR was 75mL/min/1.73m 2 (IQR: 61.5-90.0) in GLP1A group versus 60.0 (52.0-80.5) in comparison group. High-grade disease occurred in 33 (25%) GLP1A patients and 37 (29%) comparison patients. Among patients with available imaging (GLP1A: 40; comparison: 32), metastatic presentation occurred in 7 (18%) GLP1A group and 7 (22%) comparison group patients. No significant differences were observed in grade group (GLP1A median: 2; IQR: 1-2 vs. comparison median: 2; 1-3; p=0.44) or metastatic presentation (OR: 1.32; 95%CI: 0.41-4.25; p=0.64) between groups. In multivariable analysis, higher HbA1c was associated with high-grade disease in GLP1A group (OR: 1.83; 95%CI: 1.07-3.35; p=0.03) while higher eGFR was associated with low-grade disease in the comparison group (0.97; 0.93-0.99; p=0.04). Conclusions: GLP1A use was not associated with prostate cancer grade or metastatic presentation at diagnosis compared to alternative glucose-lowering agents. However, the association between elevated HbA1c and high-grade disease in GLP1A patients suggests a potential impact of poor glycemic control on tumor biology. Prospective studies are needed to elucidate the relationship between metabolic dysregulation and prostate cancer severity.

145 Background: Multiple trials have demonstrated addition of androgen-receptor pathway inhibitors (ARPIs) improve survival in patients with metastatic prostate cancer but there is a need to quantify cardiovascular toxicity. Understanding the nature and extent of ARPI-associated cardiovascular adverse events across disease states and toxicity grades is critical to inform treatment decisions and long-term patient safety. Methods: MEDLINE, and EMBASE were systematically searched from database inception through August 30, 2025, for phase III randomized controlled trials evaluating abiraterone, enzalutamide, apalutamide, darolutamide, orteronel in metastatic prostate cancer. Trials were included if they reported CVS toxicity. Meta-analysis using a random-effects model was performed to assess the difference of all-cause and treatment-emergent cardiovascular adverse events between ARPI+ADT and ADT alone. Summary effects were expressed as relative risk (RR) with associated 95% confidence intervals. Results: A total of 21 trials (45 references) with 25,576 patients (mCSPC: 12,537, mCRPC: 13,039) were included in this meta-analysis. Compared to ADT alone, ARPI+ADT significantly increased the risk of all cause, all grade hypertension in both mCSPC (RR 1.60, 1.22–2.10) and mCRPC (RR 1.61, 1.20–2.16) as well as grade ≥ 3 hypertension (RR 1.71, 1.17–2.48) in mCRPC setting. There was an increased risk of all-cause, all grade acute coronary syndrome (RR 2.21, 1.09–4.49) and AV nodal disease (RR 2.53, 1.18–5.43) with ARPI+ADT compared to ADT alone in mCSPC setting. There was increased risk of all cause, all grade, any cardiac events (RR 1.30, 1.10–1.54) as well as grade ≥ 3 any cardiac events (RR 1.70, 1.20–2.42) in mCRPC setting. Risk of all cause, all grade hot flashes (RR 1.47, 1.16–1.85) was also significantly increased with ARPI+ADT when compared to ADT alone. In terms of treatment-emergent adverse effects, a significant increase was observed only for pulmonary embolism with ARPI+ADT when compared to ADT alone (RR 1.66, 1.06–2.60) in mCRPC setting. Conclusions: Current evidence indicates potentially increased risk of hypertension, venous thromboembolic, and ischemic cardiac events with ARPI therapy in metastatic prostate cancer. Proactive CV risk assessment, particularly in patients with preexisting comorbidities or prolonged ARPI exposure, may optimize outcomes and minimize treatment interruptions. All cause adverse events. Adverse Event Disease State All Grade Grade ≥3 Any Cardiac Event mCSPC 0.81 (0.37–1.76) 0.88 (0.16–4.64) mCRPC 1.30 (1.10–1.54) 1.70 (1.20–2.42) Hypertension mCSPC 1.60 (1.22–2.10) 1.43 (0.82–2.52) mCRPC 1.61 (1.20–2.16) 1.71 (1.17–2.48) ACS mCSPC 2.21 (1.09–4.49) 1.77 (0.86–3.61) mCRPC – – Hot Flashes mCSPC – – mCRPC 1.47 (1.16–1.85) 1.46 (0.21–9.97)

144 Background: Androgen receptor pathway inhibitors (abiraterone acetate [AAP], apalutamide [APA], enzalutamide [E], darolutamide [DARO] have become the cornerstone for pts with PCa due to survival benefits. Comparative data on fracture risk among ARPi are limited. This study quantified the risk of bone fractures with ARPi plus androgen deprivation therapy (ADT) and compared fracture risk across different ARPi agents. Methods: MEDLINE and EMBASE were searched from inception through September 1 st 2025 to identify positive phase III trials assessing ARPi in addition to ADT in pts with PCa (m0CRPC, mCSPC, mCRPC). Trials were included if they reported bone fractures in either arm. Pairwise, random-effects meta-analysis was conducted using Paul-Mendel approach. Sensitivity analyses using Hartung-Knapp (HK) adjustment was performed to assess robustness of results. To assess the comparative risk of bone fractures among different ARPi agents, mixed treatment comparisons were made using frequentist network meta-analysis. P-scores were computed to assess relative treatment rankings. Treatment effect was expressed as odds ratio (OR) with 95% confidence intervals (CI). Results: This systematic review included 13 phase III trials with 15468 pts (8890 received ARPi+ADT, 6578 received ADT alone). A total of 596 (6.7%) bone fractures were observed with ARPi+ADT compared to 180 (2.74%) with ADT alone. Patients receiving ARPi+ADT were associated with an increased risk of bone fractures compared to those receiving ADT (OR: 2.40; 95% CI: 1.93-2.98). Sensitivity analyses with HK adjustment showed consistent results (2.40; 1.88-3.06). There was no statistically significant effect modification by PCa clinical setting (p: 0.27). Mixed treatment comparisons showed a statistically significant increased risk of bone fractures with AAP+ADT (2.35; 1.29-4.27), APA+ADT (2.04; 1.47-2.86), and E+ADT (3.13; 2.44-4.00) but not with DARO+ADT (1.30; 0.80-2.08) when compared to ADT alone. Among different ARPi agents, E+ADT was associated with an increased risk compared to APA+ADT (1.54; 1.01-2.33) and DARO+ADT (2.44; 1.41-4.17). Ranking analysis showed that E+ADT was ranked as potentially the least safe treatment (P score: 0.05) in terms of relative fracture risk followed by AAP+ADT (P score: 0.30), APA+ADT (P score: 0.43), DARO+ADT (P score: 0.76). Sensitivity analyses limiting to mCSPC trials only showed consistent results. Conclusions: The risk of bone fractures varies among different ARPi agents, with enzalutamide posing the highest relative risk and darolutamide the lowest. These differences may guide treatment selection, particularly in pts with mCSPC and bone metastases. Prospective studies adjusting for covariates are needed to evaluate bone-protective strategies to mitigate fracture risk particularly in mCSPC patients who are considering treatment with ARPi.

127 Background: Bone metastases affect up to 90 % of patients with metastatic hormone-resistant prostate cancer (mHRPC) and cause substantial morbidity from skeletal-related events (SREs) such as fracture, spinal-cord compression, and palliative interventions. Bone-modifying agents (BMAs) including bisphosphonates and denosumab reduce SRE risk and are NCCN-recommended, however, real-world use remains inconsistent. Methods: Patients with mHRPC treated from January 2017-September 2024 across Mayo Clinic sites were identified using SQL-based EHR queries confirmed by manual chart review. Bone Metastases were detected through keyword searchers of radiology reports and confirmed through manual chart review. SRE-prevention dosing was defined as zoledronic acid 4mg IV or denosumab 120mg SC; osteoporosis dosing was excluded. SREs were identified using diagnosis codes and text-pattern searches for radiotherapy, surgery, fracture, and spinal-cord compression. Descriptive statistics summarized BMA utilization and SRE incidence. Categorical variables were compared using Chi-square tests, and a risk ratio (RR) with 95% confidence intervals was calculated to evaluate association between early BMA initiation and SRE risk. Results: Among 778 patients with mHRPC, 685 (88 %) had bone metastases (mean age 70.5 years). Of these, 169 (24.7 %) had an SRE, and 261 (38.1 %) received BMAs at SRE-prevention doses (denosumab n = 157 [60 %]; zoledronic acid n = 104 [40 %]). Based on a chi-square test, combined SRE incidence did not differ significantly (No BMA 23 %, denosumab 23 %, zoledronic 33 %; p = 0.069). Bone pain at baseline was more common in patients who later received a BMA (136 [68 %]) than in those who did not (82 [41 %]; p < 0.001). Among 200 randomly sampled non-BMA patients, 83 had no recorded BMA discussion (66 also lacked bone pain), 38 lacked dental clearance, 32 had uncompleted plans and 18 declined therapy. Early BMA initiation (before first bone metastases) was associated with fewer SREs (16 % vs 29 %; RR 0.56, 95 % CI 0.33–0.96). Conclusions: Less than half of bone-metastatic mHRPC patients received BMAs. Non-initiation was often linked to modifiable factors such as delayed dental clearance or lack of treatment discussions, highlighting the need for system-level strategies to improve timely bone-directed care. SREs were common, affecting one quarter of patients. Small sample size precluded meaningful comparison of the impact of BMAs on SRE incidence however early BMA initiation may lower SREs. Incidence of SREs stratified by no BMA vs BMA treatment. SRE No BMA BMA Overall Pathological Fracture 6.4% (27/424) 4.9% (13/261) 5.8% (40/685) Radiotherapy to Bone 13.9% (59/424) 18.8% (49/261) 15.7% (108/685) Spinal Cord Compression 0.7% (3/424) 3.1% (8/261) 1.6% (11/685) Surgery to Bone 2.1% (9/424) 0.3% (1/261) 1.5% (10/685) Combined 23% (98/424) 27.2% (71/261) 24.7% (169/685)

483 Background: Sarcomatoid dedifferentiation (sRCC) in metastatic clear-cell renal cell carcinoma (mccRCC) confers aggressive disease and poor prognosis. We maintain a living meta-analysis of first-line immune checkpoint inhibitor (ICI)–based combinations in mccRCC (Riaz et al., Eur Urol Oncol 2021), which demonstrated improved survival with ICI-based regimens over sunitinib. Here, we present an updated synthesis focused on the comparative efficacy of ICI combinations in the sarcomatoid subset. Methods: A systematic search of MEDLINE, EMBASE, and CENTRAL through October 2025 was performed as part of our living meta-analysis of first-line mccRCC therapy. Eligible phase III RCTs compared ICI combinations (IO/IO or IO/TKI) versus sunitinib, including CheckMate 214, CheckMate 9ER, KEYNOTE-426, CLEAR/KEYNOTE-581, JAVELIN Renal 101, and IMmotion151. Extracted outcomes included overall (OS) and progression-free survival (PFS), and objective (ORR), complete (CR), and partial (PR) response rates. Random-effects meta-analyses generated pooled hazard ratios (HRs) for time-to-event outcomes and risk ratios (RRs) for response rates with 95% confidence intervals. Subgroup interaction analyses compared sarcomatoid versus non-sarcomatoid subgroups, with p < 0.1 considered significant. Results: Six phase III RCTs (n = 5,121; 624 sarcomatoid) were included. Across all ICI-based combinations, ICI therapy improved outcomes versus sunitinib in both sarcomatoid and non-sarcomatoid disease. In the pooled analysis, the OS interaction favored sRCC meeting the prespecified significance threshold for subgroup analyses (HR 0.53 vs 0.68; p-interaction = 0.06 < 0.10), while no significant interaction was seen for PFS. Response outcomes showed the strongest differential benefit, particularly with IO/TKI regimens. IO/IO results were directionally consistent but limited by smaller non-sarcomatoid samples. Conclusions: ICI-based combinations significantly improve survival and response outcomes versus sunitinib in mccRCC. Using a prespecified α = 0.10 for interaction testing, the pooled analysis showed a significant OS interaction and higher response rates in sRCC, indicating enhanced ICI sensitivity. These updated meta-analysis data support ICI regimens as the preferred first-line therapy for mRCC with sarcomatoid de-differentiation. Endpoint Regimen Subgroup (S = sarcomatoid; NS = non-sarcomatoid) Effect (95% CI) p-interaction PFS IO/IO S 0.51 (0.40–0.65) – IO/TKI S vs NS 0.48 (0.36–0.64) vs 0.46 (0.39–0.52) 0.81 OS IO/IO S 0.54 (0.07–4.42) – IO/TKI S vs NS 0.51 (0.17–1.48) vs 0.68 (0.30–1.58) 0.24 ORR IO/IO S 2.93 (0.49–17.37) – IO/TKI S vs NS 2.43 (1.84–3.21) vs 1.95 (1.67–2.28) 0.03 CR IO/IO S 3.81 (0.82–17.71) – IO/TKI S vs NS 5.93 (4.73–7.42) vs 2.85 (0.10–83.73) 0.007 PR IO/IO S 3.48 (1.70–7.11) – IO/TKI S vs NS 2.10 (1.78–2.47) vs 1.75 (1.18–2.61) <0.001

405 Background: Clinical trials are critical to advancing prostate cancer treatment, yet patient enrollment remains a major bottleneck. Despite strong interest in AI for trial matching, real-world use remains limited due to reasons such as complex infrastructure requirements. To address this, we developed a lightweight, scalable AI framework leveraging the Google Healthcare Search API—requiring minimal technical expertise—to automate trial eligibility screening. Methods: We used a pre-trained GPT-5 large language model (LLM) to decompose the eligibility criteria of 13 prostate cancer clinical trials into 269 YES/NO questions, such that for an eligible patient of a given trial, the chart review would yield YES for inclusion and NO for exclusion questions. From 348 patients enrolled in one of the trials, we built a dataset linking each eligibility question to each patient, resulting in 4,947 patient–question pairs (2,034 inclusion pairs with YES labels and 2,913 exclusion pairs with NO labels). The task was framed as binary classification. During evaluation, for each patient–question pair, the LLM extracted search phrases from the question to retrieve relevant EHR information via the Google Healthcare Search API, then used the question and retrieved information to predict YES or NO responses. Performance was measured using accuracy, precision, recall, specificity, and F1 score. Results: Across 4,947 question–patient pairs, our framework achieved 0.81 accuracy, 0.85 precision, 0.65 recall, 0.92 specificity and a F1 score of 0.74. Results for different phases of trials is reported in Table 1, which demonstrates the approach’s robustness across trial phases. Predictions for exclusion criteria were highly precise, while inclusion criteria were more challenging. Most errors were observed in criteria involving complex nested logical conditions, interpretable clinical definitions and data not explicitly measurable or recorded in the EHR (e.g., planned treatments or clinician-assessed scores). Conclusions: This work demonstrates a practical AI framework to support clinical trial matching. The system can identify complex disease states (biochemical recurrence vs radiographic metastasis), castration status (sensitive, resistant) and genomics. Future work should focus on developing human-in-the-loop supervision and improving question decomposition to reduce errors in complex eligibility criteria. Screening performance of the proposed framework across different phases of trials. Trial Phase #Patient-Question Pairs #YES/NO labels Accuracy Precision Recall Specificity F1 score I, II, I/II 4,227 Yes: 1,735 No: 2,492 0.80 0.84 0.66 0.92 0.74 III 720 Yes: 299 No: 421 0.82 0.90 0.63 0.95 0.74 All 4,947 Yes: 2,034 No: 2,913 0.81 0.85 0.65 0.92 0.74 #YES/NO labels: The number of patient-question pairs that are labeled YES/NO among total patient-question pairs of the same row.

Non-muscle-invasive bladder cancer (NMIBC) comprises approximately 75% of new bladder cancer cases and generally carries a favorable prognosis, yet high rates of recurrence and progression necessitate close surveillance with frequent cystoscopies and repeated transurethral resections. Upfront treatment for high-risk disease is typically Bacillus Calmette-Guérin (BCG), although combinations with immune checkpoint inhibitors have reported results. Patients with BCG-unresponsive, intolerant, or refractory disease represent a subset of patients with high risk of progression, with early radical cystectomy being the standard approach for this setting. Global BCG shortages and the substantial impact of cystectomy on quality of life underscore the need for therapeutic alternatives. Over the past decade, investigational trials in immunotherapy have expanded treatment options for BCG-unresponsive NMIBC with CIS, leading to FDA approval of intravesical nadofaragene firadenovec, nogapendekin alfa-inbakicept, and systemic pembrolizumab. This narrative review summarizes developments in intravesical and systemic immunotherapies for NMIBC, highlights ongoing trials, and addresses controversies in trial design, treatment sequencing, comparative efficacy, and safety.

Circulating tumor DNA (ctDNA) is increasingly being used to monitor minimal residual disease (MRD) in various solid tumors, including urothelial carcinoma (UC). It has emerged as a promising biomarker for MRD and may serve as a valuable tool to guide treatment decisions, particularly in patients at high risk of recurrence after definitive therapy or those experiencing favorable responses to systemic therapy in the setting of locally advanced or metastatic disease. ctDNA technology is largely agnostic to the type of tumor, which can be either hematologic or solid organ malignancies. Its clinical utility requires validation across different tumor types as ctDNA release kinetics and threshold values for testing often vary. Moreover, it is essential to evaluate ctDNA testing across a range of clinical scenarios, including screening, diagnosis, prognosis, and therapeutic decision making. The optimal frequency and duration of testing also need to be defined, particularly in settings such as postdefinitive therapy and ongoing chemotherapy for metastatic disease. In this study, we will summarize the current literature on the role of ctDNA in urothelial cancer. We will discuss the data that inform us of current clinical practice. Furthermore, we will explore evolving developments in the field from other tumor types and potential future directions in UC. Finally, we will highlight selected clinical scenarios for applications of ctDNA testing and its interpretation.

Abstract The combination of enfortumab vedotin and pembrolizumab (EVP) has recently revolutionized care for patients with previously untreated locally advanced and metastatic urothelial carcinoma. However, predictive biomarkers of response, the optimal duration of EVP for patients who respond well to therapy, and the role of circulating tumor DNA to monitor treatment response have not yet been fully elucidated. In this molecular tumor board, we summarize 6 patients from 4 different academic institutions with unresectable or oligometastatic urothelial carcinoma who achieved long-term remission on surveillance after a short duration of EVP treatment that resulted in complete response on follow-up imaging followed by consolidative radical cystectomy. We discuss potential predictive biomarkers for patients with exceptional response to EVP. These findings highlight the need to determine an optimal duration of EVP to maximize efficacy while minimizing adverse events. We aim to further define and explore the value of local therapy with consolidative cystectomy in the setting of unresectable, locally advanced, oligometastatic disease, or those with metastatic disease who achieve complete response of disease outside of the bladder. Identifying this subset of patients who may be candidates for this type of multidisciplinary management may result in durable treatment-free remission.