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Abstract Enfortumab vedotin (EV), pembrolizumab, and EV plus pembrolizumab (EV/P) have rapidly reshaped the treatment landscape of advanced urothelial carcinoma, but toxicity increasingly determines treatment delivery, treatment continuity, and real-world benefit. As EV/P moves into broader clinical use, clinicians must distinguish adverse events related to antibody-drug conjugate exposure from immune-mediated toxicities and recognize syndromes in which both mechanisms may contribute. In this practical, mechanism-informed review, we synthesize pivotal trials, mature follow-up reports, and representative real-world cohorts describing the safety of EV monotherapy, pembrolizumab monotherapy, and EV/P in urothelial carcinoma. Because adverse-event reporting and ascertainment are heterogeneous across studies, including differences in preferred terms, composite categories, grading frameworks, and treatment-related versus all-cause reporting, we emphasize clinically interpretable patterns rather than pooled estimates. EV monotherapy is characterized by cutaneous toxicity, peripheral neuropathy, hyperglycemia, dysgeusia, and ocular events, including early epithelial/metabolic events and cumulative neuropathy. Pembrolizumab monotherapy has a lower overall high-grade toxicity burden but is defined by immune-mediated endocrinopathies, pneumonitis, hepatitis, colitis, and nephritis. Combination therapy produces a predictable overlap of these toxicity domains, creating diagnostic and management challenges for syndromes such as skin toxicity, diarrhea, fatigue, and pulmonary symptoms. We provide comparative visual toxicity signatures, regimen-specific summary tables, temporal toxicity mapping, and a pragmatic attribution framework that classifies events as EV-predominant, immune-predominant, overlap/indeterminate, or high-risk requiring initial interruption of both agents. This review aims to support bedside recognition, provisional attribution, early management, and safer implementation of EV/P in contemporary urothelial carcinoma practice.

Purpose Radioligand therapy (RLT) with [ 177 Lu] Lu-PSMA-617 has shown significant benefits in metastatic castration-resistant prostate cancer (mCRPC), including prolonged overall survival (OS) and progression-free survival (PFS), as well as improved quality of life. For patients previously treated with [ 177 Lu]Lu-PSMA-617 who subsequently experience disease progression, retreatment with [ 177 Lu] Lu-PSMA-617 has emerged as a potential approach, yet data on the outcomes of RLT retreatment remains limited. This study aimed to assess the efficacy and safety of retreatment RLT in mCRPC. Methods Clinical and imaging data of patients who underwent at least two cycles of [ 177 Lu] Lu-PSMA-617, followed by a second course of treatment with [ 177 Lu] Lu-PSMA-617 between March 2018 and December 2024, were retrospectively reviewed. Endpoints included biochemical response, imaging response, toxicity, PSA-PFS, rPFS, and OS. Radiologic and biochemical responses were evaluated using RECIST 1.1 criteria and PSA levels, respectively. Results A total of 589 patients underwent [ 177 Lu] Lu-PSMA-617 RLT, of whom 20 (3.4%, 20/589) received RLT retreatment. The median age was 71.3 years (range: 63.7–95.2), and the median follow-up was 73.3 months (95% CI, 35.7–77.2 months) after the initial treatment and 21.7 months (95% CI, 16.9–26.0 months) after retreatment. The initial treatment involved a median of 4.5 cycles (range: 2–6). Following the first course of RLT, 15 patients (75%, 15/20) had exhibited a >50% decline in PSA levels, including 9 who achieved a >90% decrease. Additionally, 12 patients (60%, 12/20) had demonstrated a complete or partial imaging response, while 3 (15%, 3/20) patients had stable disease, and 5 (25%, 5/20) patients had progressive radiologic disease. Patients received a median of 4 retreatment cycles (range, 1–6), and the median interval between initial RLT and retreatment RLT was 33.1 months (IQR, 16.2–48.9 months; range, 10.7–58.8 months). A PSA decline of ≥50% was observed in 9 out of 20 patients (45%, 9/20). An imaging response was observed in 10 patients (50%, 10/20), with 4 achieving a complete response and 6 achieving a partial response, whereas 10 patients (50%, 10/20) showed progression. The median PSA-PFS was 9.8 months (95% CI, 4.1–17.9 months), and the median rPFS was 8.2 months (95% CI, 3.3–17.9 months). Eight deaths occurred during follow-up. The estimated Kaplan Meier OS rates were 83.6% at 12 months (95% CI, 57.3%–94.4%) and 53.7% at 24 months (95% CI, 28.3%–73.7%). Grade 2 renal toxicity was observed in one patient (5%, 1/20). Three patients (15%, 3/20) developed Grade 2 anemia. Notably, no grade 3 or grade 4 adverse events were observed during either treatment period. Conclusion In our cohort, retreatment with [¹ 77 Lu]Lu-PSMA-617 RLT was associated with biochemical and imaging responses in some patients, with observed survival outcomes that support further investigation. However, given the retrospective single-arm design and small sample size, large prospective studies are needed to more rigorously evaluate the safety, efficacy, and optimal patient selection for retreatment RLT.

Abstract BACKGROUND [177Lu]Lu-PSMA-617 improves survival and quality of life in men with metastatic castration-resistant prostate cancer but requires substantial healthcare involvement. Our analysis evaluated the time toxicity associated with [177Lu]Lu-PSMA-617, representing the first dedicated radioligand time toxicity assessment. MATERIALS AND METHODS We conducted a multi-institutional retrospective study of patients initiating [177Lu]Lu-PSMA-617 between April 2022 and March 2023. Patients were followed from first [177Lu]Lu-PSMA-617 administration until 3 months after the final cycle, initiation of new systemic therapy, or death. Time toxicity was quantified as healthcare contact days during the at-risk interval. Associations with baseline characteristics were evaluated using negative binomial regression models. Univariate and multivariable models were performed. RESULTS Among 135 patients, median age was 69 years and median prior systemic therapies was 4. Patients completed a median of 5 [177Lu]Lu-PSMA-617 cycles over 7.6 months. Median healthcare contact days were 20 (IQR, 15–28), representing 9.5% (IQR, 6.4–13.9) of at-risk days. Fifteen patients (11%) experienced high time toxicity (>1 contact day per 5 days), while 42 (31%) had low time toxicity (≤1 contact day per 14 days). Among the 57 patients who received both cycle 1 and cycle 6, mean per cycle healthcare contact days were 4 and 3.6, respectively (paired Wilcoxon signed-rank test, p = 0.04). Routine oncology visits comprised 32.7% of contact days, compared with 8.8% from hospitalizations. Lower baseline hemoglobin was independently associated with greater time toxicity (RR = 0.87; 95% CI, 0.79–0.96; p = 0.004). CONCLUSION In heavily pretreated patients, [177Lu]Lu-PSMA-617 demonstrated relatively low time toxicity, supporting it as a time-efficient therapy.

Aim: Despite advances with immune checkpoint inhibitor (ICI)-based regimens in the past decade, patients with metastatic urothelial cancer (mUC) face a poor prognosis with few approved options. Platinum-based chemotherapy with paclitaxel and carboplatin (TC) +/– ICI may be a feasible choice. Methods: We generated an IRB-approved, HIPAA-compliant retrospective database of patients at Mayo Clinic Cancer Center with mUC who started TC +/– ICI after disease progression on ICI from January 2018 through December 2024. Baseline demographics, clinicopathologic features, and treatment outcomes were extracted from the electronic health record. Kaplan-Meier method was used to calculate median duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: There were 32 patients who fit inclusion criteria, including 31 patients who had disease progression on ICI in the metastatic setting and 1 patient who developed metastatic disease on adjuvant nivolumab. Patients received a median of 4 cycles (range 1–14) of TC over median 12 weeks (range 3–53). Overall, 81% of patients received TC concurrently with an ICI, and 28% continued maintenance ICI after TC discontinuation (at the treating oncologist’s discretion due to adequate response or toxicity). The best objective response rate was 41% and disease control rate was 75%, with median DOR of 4.8 months (IQR 2.7–10.4), median PFS of 4.6 months (IQR 3.3–10.2), and median OS of 9.4 months (IQR 6.3–15.9). Some patients in this series had very durable responses with PFS > 12 months and OS > 24 months. TC +/– ICI was overall well tolerated with expected type and severity of adverse events. Conclusions: Strategies to overcome ICI resistance are needed, and TC +/– ICI after disease progression on an ICI shows promising tolerability and efficacy in this setting for patients with mUC. Our series was notable for some patients having a durable response. Validation in larger cohorts is warranted.

e23276 Background: More than 50,000 patients with cancers of all stages were enrolled in the E2C2 trial, which captured patient-reported data across 6 symptom domains (SPPADE): sleep, pain, impaired physical function, anxiety, depression, and energy deficit or fatigue. This trial offers a unique opportunity to evaluate the evolution of symptom burden as prostate cancer (PCa) advances and the association of symptom burden with prognosis in the various disease states. Methods: The cohort was derived by cross-referencing participants in the E2C2 study with the Mayo Clinic Cancer Registry for more granular data on disease state and treatment characteristics, focusing on PCa. Symptoms were patient-reported on a 0-10 numerical rating scale, categorized as none/mild (0-3), moderate (4-6), and severe (7-10). We compared the prevalence of symptom burden across disease states, using the first survey completed by patients, in 3 groups: (1) non-metastatic (localized, locally advanced, and biochemically recurrent), (2) metastatic hormone sensitive (mHSPC), and (3) castration resistant (CRPC), using chi square tests. We then used log-rank tests to compare survival distributions based on symptom severity within each disease state. Results: A total of 1,011 patients were included. The distribution of moderate to severe symptoms by disease state is shown in Table 1. Fatigue, impaired physical function, and pain were more prevalent in patients with advanced disease, whereas the prevalence of depression and anxiety was not statistically different by disease state. Greater fatigue and physical impairment were consistently associated with poorer OS across all disease states, including patients with non-metastatic disease (p < 0.001). Pain was most strongly associated with inferior outcomes in the more advanced disease states of mHSPC (p < 0.001) and CRPC (p < 0.001). Anxiety (p < 0.001) and depression (p = 0.001) were only prognostic in CRPC patients. Conclusions: SPPADE symptoms are common in PCa. Physical symptoms are greater in more advanced disease, yet the high burden of unmet psychologic needs is similar across the disease states. Notably, severe patient-reported fatigue and physical dysfunction are strongly prognostic even in early disease, suggesting they are markers of physiologic vulnerability. Structured symptom monitoring may improve the identification of high-risk patients. Clinical trial information: NCT03892967 . Moderate to severe symptoms by disease state. Non-Metastatic (N= 243) mHSPC (N= 479) CRPC (N= 289) P-value Pain, n (%) 51 (21.3) 121 (25.5) 100 (35.1) 0.001 Fatigue, n (%) 92 (38.3) 230 (48.6) 163 (57.2) <0.001 Impaired Physical Function, n (%) 79 (32.5) 180 (37.7) 146 (50.7) <0.001 Sleep Disturbance, n (%) 72 (30.1) 167 (35.2) 104 (36.1) 0.3 Depression, n (%) 47 (19.6) 92 (19.4) 63 (22.0) 0.67 Anxiety, n (%) 56 (23.4) 93 (19.6) 68 (23.9) 0.3

5068 Background: 177 Lu-PSMA-617 (LuPSMA) is a groundbreaking therapy for mPC, but biomarkers are urgently needed to improve patient selection. Plasma-derived EVs are emerging blood-based markers of tumor burden. Here, we analyzed levels of EVs of 123 patients (pts) from 4 cohorts: a pre- and during LuPSMA treatment for a contemporary prospective Mayo Clinic cohort, pre-treatment plasma levels of EVs for a historical Tulane cohort, localized prostate cancer (LPC) after radical prostatectomy (RP), and male healthy donors (HD). Methods: Blood samples were collected from 51 pts pre-cycles (pre-C) 1-3 of LuPSMA at Mayo Clinic from 12/2024-12/2025 and 26 pts pre-C1 at Tulane Cancer Center between 12/2018-1/2025. Small and large EVs were incubated with fluorescently conjugated antibodies (PSMA, STEAP1, CEACAM5, and TROP2) and enumerated using nanoscale flow cytometry. EVs from blood samples of 10 HD and 36 LPC post-RP from 6/2020-8/2024 at Mayo Clinic as controls. AUC-ROC and logistic regression analyses were performed to identify marker signatures associated with PSA50 response. Results: Baseline demographics are shown in the table. Median levels of PSMA, STEAP1, CEACAM5, and TROP2 EV/milliliter (mL) were all significantly higher for pts with mPC (pooled Tulane and Mayo cohorts) compared to LPC post-RP (p<0.001) and HD (p<0.001). In the Mayo cohort, 10 of 51 pts (20%) had undetectable PSA pre-C1. There were no significant differences in median pre-C1 plasma EV levels for these 4 different types of EVs comparing pts with undetectable vs detectable PSA. For 41 Mayo pts with detectable PSA pre-C1, 20 achieved PSA50 response at time of data cutoff (49%), while 7 pts (17%) had persistent PSA rise on LuPSMA. For pts who achieved PSA50, there was a significant decline in both CEACAM5 and TROP2 EVs/mL pre-C1 compared to pre-C3 (19 x 10 6 vs 5.8 x 10 6 , p=0.003 and 16 x 10 6 vs 5.5 x 10 6 , p<0.001, respectively), while no significant changes occurred for the 7 pts with no PSA response. A composite score of pre-C1 CEACAM5 and TROP2 EVs (large- and small-sized EVs) demonstrated the strongest association with PSA50 response (OR=2.96, 95% CI: 1.27-6.44, p=0.038), achieving AUC of 0.73. PSMA and STEAP1 EVs did not show any significant changes from pre-C1 to pre-C3. Conclusions: Plasma-derived EVs are a promising biomarker to identify patients who will benefit from LuPSMA. Longer follow-up and enrolling a larger cohort are underway. Clinical trial information: NCT06200103 . Median values for pre-LuPSMA (Mayo and Tulane), post-RP for LPC, and HD. Mayo mPC (n=51) Tulane mPC (n=26) LPC (n=36) HD (n=10) Age (range) 73 (57-87) 71 (54-83) 66 (56-77) 55 (50-57) Prior lines (range) 1 (1-3) 4 (1-11) - - Gleason score 9 8 7 - PSA (range) 1.0 (0-182) 75 (0.8-503) - - PSMA EV/mL 3.7 x 10 6 14 x 10 6 2.0 x 10 6 1.4 x 10 6 STEAP1 EV/mL 30 x 10 6 45 x 10 6 12 x 10 6 12 x 10 6 CEACAM5 EV/mL 17 x 10 6 5.1 x 10 6 3.7 x 10 6 3.9 x 10 6 TROP2 EV/mL 13 x 10 6 5.2 x 10 6 4.5 x 10 6 3.6 x 10 6

PURPOSE 177Lu-PSMA-617 (LuPSMA) is an approved prostate-specific membrane antigen (PSMA)–targeted radiopharmaceutical therapy for men with metastatic castration-resistant prostate cancer (mCRPC). Older patients, particularly octogenarians, represent a substantial proportion of men with mCRPC but have been traditionally underrepresented in key registrational trials of LuPSMA. METHODS This retrospective multi-institutional study evaluated patients age 80 years and older with mCRPC after chemotherapy treated with ≥1 cycle of LuPSMA from August 2022 to December 2024. Clinical and demographic data were abstracted from electronic medical records. Outcomes included prostate specific antigen (PSA) response (PSA50 and PSA90), progression-free survival (PFS), overall survival (OS), and toxicities. Kaplan-Meier methods estimated PFS/OS; descriptive statistics summarized baseline and safety data. RESULTS Ninety-five patients (median age, 83 years) were included, of whom 36 (38%) and 21 (22%) had a history of cardiac disease or chronic kidney disease, respectively. Median follow-up was 24.1 months (IQR, 6.7-28.1). Patients received a median of five cycles of LuPSMA. Fifty-two (57%) and 21 (23%) patients achieved a PSA50 and PSA90, respectively. Median PFS and OS were 7.3 months (95% CI, 6.4 to 8.7) and 13.5 months (95% CI, 9.7 to 18.8), respectively. Grade ≥3 hematologic toxicities included anemia (n = 19; 20%) and thrombocytopenia (n = 4, 4%); grade ≥3 acute kidney injury occurred in one patient. Fourteen (15%) patients had dose delays, seven (7%) required reductions, and 10 (11%) discontinued therapy due to toxicity. Thirty-seven patients (39%) were hospitalized during therapy, with intensive care unit-level care required in two patients (2%), and there was one treatment-related death. CONCLUSION LuPSMA had comparable outcomes in octogenarians with mCRPC to patients on registrational trials, although 2/5 of patients required hospitalization during therapy. These findings support the feasibility and efficacy of LuPSMA in well-selected older men with mCRPC and suggest a role for closer monitoring of older patients.

142 Background: LuPSMA is a life-prolonging radioligand therapy that is widely considered to have favorable tolerability. SPPADE symptoms (Sleep disturbance, Pain, Physical dysfunction, Anxiety, Depression, low Energy) are common in prostate cancer, yet data on patient-reported outcomes with LuPSMA in real-world settings remain limited. Methods: The E2C2 study (NCT03892967) evaluates the impact of a collaborative care intervention on patient-centered outcomes and healthcare utilization. This analysis includes mCRPC patients who initiated LuPSMA at Mayo Clinic (June 2022-July 2023) and completed at least one symptom survey within 6 weeks before or 2 weeks after the first LuPSMA treatment (baseline survey). SPPADE symptoms were rated on 0-10 scales; scores of 4-6 indicate moderate and 7-10 severe burden. A composite z-score was derived by standardizing each SPPADE domain to the cohort mean and averaging z-scores across domains per patient. Patients were stratified by composite symptom burden using cohort median and upper-tertile cutoffs. Associations with PSA50 response and overall survival (OS, from start of LuPSMA) were assessed using chi-square and Kaplan-Meier methods. In a longitudinal subgroup of patients completing a baseline survey plus at least one additional PRO survey while receiving LuPSMA (≥2 surveys), scores were compared from baseline to best during-treatment using Wilcoxon and Mann-Whitney U tests. Results: Of 373 patients starting LuPSMA, 51 patients met inclusion criteria. Median age was 71 years, 31% had visceral metastases, and median baseline PSA was 42.1 ng/mL. Overall, 85% of patients reported at least one moderate symptom and 46% at least one severe symptom. The most common moderate-to-severe symptoms were low energy (58%), pain (52%), and sleep disturbance (49%). Using an upper-tertile cutoff of the composite SPPADE score, 17 patients had high and 34 had low/moderate symptom burden prior to LuPSMA. PSA50 response was achieved in 17.6% of patients with high vs 47.1% with low/moderate composite symptom scores (p = 0.08). Median OS was 9.2 vs 16.7 months for high vs low symptom groups (p = 0.15, median split). The longitudinal subgroup included 24 patients with serial ePRO assessments while on LuPSMA. Composite SPPADE scores improved from baseline to the best during-treatment assessment in both PSA50 responders (n=10) and non-responders (n=14), with median composite z-score Δ of 0.35 vs 0.20, respectively (p = 0.68). Conclusions: Among patients with mCRPC receiving LuPSMA, baseline SPPADE symptom burden was high. Though not statistically significant in this underpowered cohort, PSA response and OS were numerically inferior in those with higher baseline burden. These findings suggest that ePRO-captured symptom burden may provide prognostic and patient-centered insights beyond traditional clinical variables. Clinical trial information: NCT03892967 .

TPS898 Background: Enfortumab vedotin with pembrolizumab (EV/Pembro) is now first-line therapy for locally advanced or metastatic urothelial carcinoma (la/mUC) following the EV-302/KEYNOTE-A39 trial, which demonstrated a 67.7% response rate and prolonged survival. However, ~35% of cancers exhibited primary resistance and most responders relapse within one year, with post-EV/Pembro therapies achieving < 15% response and median survival < 3 years. We previously showed that therapeutic plasma exchange (TPE) removed soluble PD-L1 and other immune checkpoint inhibitor (ICI) blocking soluble factors from the blood and that this overcame ICI resistance. Combining TPE with EV/Pembro rechallenge may overcome acquired resistance and restore antitumor immunity. Methods: RECIPE-B1 [NCT07087860] is an open-label, randomized phase II trial enrolling 50 patients (1:1) with EV/Pembro-refractory la/mUC and ECOG 0–2. Arm A receives TPE on days 1–3 followed by EV 1.25 mg/kg IV plus pembrolizumab 200 mg IV on day 3 of each 21-day cycle for the first three cycles, then continues EV/Pembro alone from cycle 4. Arm B receives investigator’s-choice next-line standard of care (SOC) per NCCN guidelines. Tumor assessments occur at the end of cycle 4 (±28 days) and every 12 weeks thereafter; safety is monitored each cycle (CTCAE v5.0). The primary endpoint is objective response rate (ORR) by RECIST 1.1, comparing TPE + EV/pembro versus SOC. Secondary endpoints include progression-free survival, overall survival, duration of response, quality of life (EORTC QLQ-CIPN20), and safety. Correlative studies evaluate circulating and urinary tumor DNA and exosomal biomarkers (including exosomal Nectin-4) as predictors of response and resistance. The trial is open at Mayo Clinic; as of September 2025, 2 of 50 patients have been enrolled, with planned accrual of ~2 patients/month and central coordination at Mayo Clinic and affiliates. Clinical trial information: NCT07087860 .

214 Background: 177 Lu-PSMA-617 (LuPSMA) has revolutionized care for patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC), but only half achieves PSA decline ≥50%. Biomarkers are urgently needed to improve pt selection. EVs and ctDNA released by cancer cells into the blood are emerging biomarkers to estimate overall tumor burden and capture tumor heterogeneity in mCRPC. Here, we analyzed pre-treatment plasma levels of tumor EVs and ctDNA in a pilot cohort of 35 pts with mCRPC treated with LuPSMA. Methods: Blood samples were collected pre-cycle 1 of LuPSMA at Tulane Cancer Center between 12/2018-1/2025. Plasma-derived small and large EVs were incubated with fluorescently conjugated antibodies and enumerated using nanoscale flow cytometry. ctDNA fraction was estimated from plasma cfDNA methylation WGS (∼10×) with ichorCNA. We also analyzed EVs from blood samples of male healthy donors (HD) and pts with localized prostate cancer (LPC) collected 1 day to 8 months after radical prostatectomy (post-RP) from 6/2020-8/2024 at Mayo Clinic as controls. Results: Median age at collection for 10 HD was 55 yrs and for 36 pts with LPC post-RP was 65 yrs. Median PSMA+ EV level was 2.0 x 10 6 /mL for post-RP and 1.4 x 10 6 /mL for HD. For 35 pts with mCRPC, 25 pts had complete data for analysis. Median PSMA+ EV level was 1.4 x 10 7 /mL, significantly higher than post-RP (p<0.001) and HD (p<0.001). At LuPSMA start, median age was 69 yrs (range 54-83), PSA was 82 ng/mL (range 0.8-503), median time from CRPC diagnosis to start was 50 months (range 6.9-285), median time from plasma collection to treatment initiation was 0.5 months (range 0-7.3). Median number of prior lines of life-extending therapy was 4 (range 1-11), including 100% androgen receptor pathway inhibitor and 75% docetaxel. Pts received median 4 cycles of LuPSMA. Median ctDNA fraction was 14.0% (range 0-51.1). Median time to reach nadir PSA for pts with any decline was 2.6 months. 15 pts (60%) achieved PSA40 (defined ≥40% decline in PSA from start to nadir) (range -99% to -42%) compared to 10 pts (40%) who did not (range -16% to rise), which predicted better median overall survival (OS) after LuPSMA start (40.7 v 6.0 months; HR 0.23, 95% CI, 0.07-0.71; p=0.0001). Pts were classified as LuPSMA responders using PSA40. Responders had a lower ratio of large to small PSMA+ EVs (0.30 v 0.53, p=0.0042) with an area under the receiver operating characteristic curve (AUC) of 0.83 (95% CI, 0.68-0.99), and a lower median ctDNA fraction (6.1% v 26.2%, p=0.0044) with an AUC of 0.83 (95% CI, 0.68-1.00). Incorporating both PSMA+ EV and ctDNA fraction together predicted PSA40 response with an AUC of 0.93 (95% CI, 0.84-1.00, p=0.0003). Conclusions: Using pre-LuPSMA plasma samples from a heavily pre-treated historical cohort, we integrated non-invasive liquid biopsy methods to successfully predict response to LuPSMA using PSA decline. Prospective validation is underway.