Orme, Jacob J.

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.

Abstract Cellular senescence has been implicated in the pathophysiology of radiotherapy-associated bone loss. Based on our previous work, clearance of senescent cells using genetic and pharmacological tools alleviates the anomalies associated with radiation-associated bone deterioration. The pro-inflammatory senescence associated secretome referred to as senescence associated secretory phenotype (SASP), is a hallmark of cellular senescence. The modulation of SASP by senomorphic drugs, potentially can suppress the pro-inflammatory secretome of senescent cells, irrespective of the underlying senescence mechanism. In this study we tested a senomorphic drug, ruxolitinib, a Janus kinase inhibitor (JAKi), during acute and chronic radiotherapy related effects on the bone. Our clinical data indicate an early increase in several pro-inflammatory SASP proteins following radiotherapy of spinal metastasis in prostate cancer patients. Longitudinal assessment of SASP-related genes confirmed this acute elevation in several SASP markers in systemic circulation following irradiation of male mouse femurs. In studies done in male mice, following three preclinical radiotherapy regimens of 30Gy (5 x 6Gy), 60Gy (5 x 12Gy) and a single dose of 24Gy, suppression of SASP by JAKi was efficacious in suppressing radiation-induced bone damage. In comparison and as shown before, the senolytic combination of D+Q was also able to alleviate radiation-associated bone loss. Early and intermittent suppression of SASP using JAK inhibitors in male mice alleviated chronic bone deterioration, diminished telomere dysfunction, lowered senescence and SASP marker expression and reduced bone-marrow adiposity. Overall, our study shows that early targeting of SASP proteins could be a potential therapeutic to prevent radiotherapy-related chronic bone loss and risk of fractures.

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.

ABSTRACT Management of prostate cancer has improved over the past two decades, driven by innovations in detection of metastatic disease, biomarker characterization, and treatment. This review summarizes the latest progress in managing advanced states of this disease, spanning high risk biochemical recurrence, metastatic hormone sensitive prostate cancer (mHSPC), and metastatic castration resistant prostate cancer (mCRPC). Improved outcomes for patients have been seen with earlier use of androgen receptor pathway inhibitors in the setting of high risk biochemical recurrence and mHSPC. Meanwhile, individuals with mCRPC now represent a more diverse population, differentiated by both their previous treatments and other biological features. Advanced imaging and genomic biomarkers improve patient selection and permit more personalized therapy. Landmark clinical trials and meta-analyses have established and/or refined the role of chemotherapy, poly-ADP ribose polymerase (PARP) inhibitors, and 177 Lu-PSMA-617 in this disease space. Finally, as patients with prostate cancer are living longer, the review focuses on understanding and managing potential adverse events, including cardiac and hematologic toxicity and bone health.

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