Citations

TPS890 Background: Although first-line (1L) EV + pembrolizumab has improved outcomes for patients with la/mUC, most experience disease progression, highlighting an unmet need for novel therapies. TROP2 is a glycoprotein highly expressed in several epithelial tumors, including UC. Dato-DXd is a TROP2-directed antibody–drug conjugate comprising an anti-TROP2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload (DXd), designed to induce selective tumor-cell death and reduce systemic exposure to the payload. Dato-DXd has demonstrated durable efficacy and a manageable safety profile in patients with la/mUC both as monotherapy (TROPION-PanTumor01 [NCT03401385]) and in combination with immunotherapy (TROPION-PanTumor03 [NCT05489211]). We describe a phase 2/3 trial comparing the efficacy and safety of Dato-DXd + platinum CT (carboplatin or cisplatin) vs gemcitabine + platinum CT in participants with la/mUC with disease progression on or after EV + pembrolizumab. Methods: TROPION-Urothelial03 (NCT07129993) is a global, multicenter, randomized, open-label, phase 2/3 trial. In part A (phase 2), ~60 participants will be randomized 1:1 to receive Dato-DXd 4 or 6 mg/kg + platinum CT. In part B (phase 3), ~570 participants will be randomized 1:1 to receive Dato-DXd at the recommended phase 3 dose (determined using part A data) + platinum CT vs gemcitabine + platinum CT. Randomization in part A is stratified by assignment of platinum CT (carboplatin vs cisplatin), and in part B, by assignment of platinum CT, presence vs absence of liver metastasis at screening, and time to progression on 1L EV + pembrolizumab ( < 6 vs ≥6 months). Study treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, death, loss to follow-up, or other reasons per protocol. Radiographic tumor assessments occur every 6 weeks for 54 weeks, then every 12 weeks. The primary endpoint of part A is objective response rate (ORR) by investigator per Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1). The dual primary endpoints of part B are progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1 and overall survival (OS). Secondary endpoints include duration of response by investigator per RECIST 1.1 (part A), and PFS by investigator per RECIST 1.1 and ORR by BICR and investigator per RECIST 1.1 (part B). In part A, ORR will be summarized with 2-sided 95% exact confidence intervals using the Clopper–Pearson method by trial group. In part B, PFS and OS will be compared between trial groups using a log-rank test stratified by randomization stratification factors, with hazard ratios from the stratified Cox regression model. Clinical trial information: NCT07129993 .

TPS290 Background: Landmark randomized trials established the survival benefit of adding D to ADT in mCSPC. Building on this foundation, subsequent trials (PEACE-1 and ARASENS) demonstrated further survival improvements when androgen receptor pathway inhibitors (ARPI) were added to the ADT + D backbone. However, the independent contribution of D within the triplet regimen remains unclear given lack of prospective evaluation. Additionally, tumor suppressor gene (TSG) alterations involving TP53, PTEN, and RB1 are frequently observed in PC and are associated with aggressive biology and poor outcomes, providing an opportunity to enhance prognostic accuracy and optimize selection of candidates for treatment intensification. We hypothesize that adding D to ADT plus A will improve survival compared to ADT + A in mCSPC and stratification by TSG status may identify different treatment effects across molecular subgroups. Methods: ASPIRE is an open-label, two-arm, randomized phase 3 study to assess the benefit of D added to ADT plus A for patients with mCSPC. Eligible patients include those with confirmed adenocarcinoma of the prostate with evidence of distant metastatic disease on conventional imaging and are appropriate to receive D. Patients with metachronous low-volume disease or PSMA-PET only disease are excluded. Candidates must have next-generation sequencing (NGS) results from a CLIA-certified tissue test available for TSG status stratification at registration. Eligible patients will receive ADT plus A (240 mg PO daily) +/- D for up to 6 cycles until progression of disease by PCWG3/RECIST version 1.1 criteria. Prior therapy with ADT (with or without ARPI) initiated within 120 days before registration is permitted. The primary endpoint is overall survival (OS). Secondary endpoints include OS by TSG status; radiographic progression-free survival (rPFS); time to castration resistance; symptomatic skeletal event–free survival; time to worsening of disease-related symptoms (NCCN-FACT FPSI-17); safety and tolerability (CTCAE v5.0); PSA90 response at 6 weeks and 6 months; time to PSA progression; and objective response rate in patients with measurable disease. The study will enroll 1200 patients and is currently actively accruing patients. Clinical trial information: NCT06931340 .

TPS277 Background: Recent advances in genomic sequencing have deepened our understanding of the molecular complexity of metastatic castration-resistant prostate cancer (mCRPC), revealing multiple actionable alterations that now inform biomarker-driven treatment strategies. Accordingly, germline and somatic tumor profiling is recommended for all patients with mCRPC. Beyond DNA aberrations, gene expression profiling can uncover additional therapeutic targets and pathway activations. The phase 2 PREDICT trial is leveraging both DNA and RNA alterations to guide rationally designed, biomarker-based therapeutic approaches for patients with mCRPC. Methods: This multi-center, multi-arm, biomarker-driven phase 2 umbrella trial is evaluating rationally selected therapies for patients with metastatic castration-resistant prostate cancer (mCRPC). The primary endpoint is objective response rate in patients with measurable disease, with secondary endpoints including radiographic progression-free survival, PSA response, time to first symptomatic skeletal event, overall survival, safety, and correlative biomarker analyses. Eligible patients must have progressive mCRPC of any histology, prior treatment with an androgen receptor pathway inhibitor (ARPI), and either prior or declined taxane chemotherapy, with both measurable and non-measurable disease permitted. Enrollment requires standard-of-care next-generation DNA sequencing from tissue or circulating tumor DNA performed in a CLIA-certified laboratory, and RNA-based allocation will use the CLIA-certified Caris MI Tumor Seek assay (whole exome and whole transcriptome sequencing) on tissue obtained within 12 months of study entry, with a real-time molecular tumor board reviewing results to confirm arm assignment. Patients with RB1 loss (DNA), an RB functional loss signature (RNA), or an NEPC signature (RNA) will receive the EZH1/2 inhibitor valemetostat; those with ≥2 of 3 tumor suppressor gene alterations (TP53, RB1, PTEN), FANC alterations (DNA), or SLFN11 overexpression (RNA) will receive cabazitaxel plus carboplatin; and those without study-defined alterations will receive physician’s choice of cabazitaxel, ARPI, or 177Lu-PSMA-617. The design permits incorporation of additional biomarker-defined arms, and up to 158 patients per arm (64 with measurable and 94 with non-measurable disease) will be accrued under a Simon two-stage minimax design, providing a one-sided type I error of 0.05 if the true response rate is 0.20 and 90% power if the response rate is 0.37 (Clinical trial information: NCT06632977). Clinical trial information: NCT06632977 .

696 Background: EVP is the preferred 1st-line therapy for patients (pts) with aUC. Upfront EV dose reductions may be utilized to enhance tolerance and minimize treatment-related toxicities when intolerance is anticipated. Prior studies of EV monotherapy suggest that starting dose 1.25 mg/kg resulted in exposure that maximized chance of response. We hypothesize that upfront EV dose reductions would not compromise EVP efficacy. Methods: Pts with aUC treated with EVP in the multi-site UNITE database were analyzed. Upfront dose reduction was defined as starting dose < 1.25 mg/kg. Correlation between clinical features and EV dose reduction were assessed using Fisher’s Exact test. Endpoints include progression-free survival (PFS) and overall survival (OS) from EVP initiation, assessed by Kaplan-Meier analysis and Cox models. Multivariable Cox analysis (MVA) included age (< 75 vs ≥ 75), ECOG performance status (PS) (0-1 vs 2-3), hemoglobin level (< 10 vs ≥ 10), and liver metastases (present vs absent), chosen in accordance with Bellmunt criteria. Correlation with investigator-assessed observed response rate (ORR) was determined using logistic regressions. All tests were 2-sided with p < 0.05 considered significant. Results: A total of 456 pts across 17 sites were included (median age 72; 77% Caucasian; 75% male; 26% upper tract primary; 66% pure UC; 77% ECOG PS 0-1; 17% with liver metastasis; 89% 1 st line EVP). Upfront dose reduction occurred in 96 pts (21%); 76 pts (79%) started at 1.0 mg/kg and 20 pts (21%) at 0.75 mg/kg. Upfront dose reduction was significantly associated with age ≥ 75 (p = 0.002), ECOG PS 2/3 (p = 0.04), and hemoglobin < 10 (p = 0.01) but not with liver metastasis (p = 0.9). Lower starting EV dose correlated with shorter median PFS (5 vs 6 months) and OS (9 vs 10 months), and lower ORR (28% vs. 60%) when compared to full dose (Table). In MVA adjusting for prognostic factors for PFS and OS, these associations were no longer statistically significant. Conclusions: In this real-world analysis, upfront EV dose reductions were most frequently used in pts with factors associated with frailty and poor prognosis, e.g. older age and ECOG PS 2/3, and were associated with lower ORR. When adjusted for these factors, upfront EV dose reductions were not associated with shorter PFS/OS though a trend towards inferior outcomes persisted. These differences in outcomes may reflect baseline risk factors rather than dose intensity; however, prospective investigation is required to validate our hypothesis-generating results. Association of upfront EV dose reduction with outcomes. Outcome (Upfront dose reduction vs no upfront dose reduction) Univariable analysis Multivariable analysis PFS: HR (95% CI), p 1.50 (1.11 – 2.02), 0.008 1.33 (0.95-1.86), 0.09 OS: HR (95% CI), p 1.56 (1.11-2.20), 0.01 1.41 (0.96-2.06), 0.08 ORR: OR (95% CI), p 0.35 (0.21-0.60), 0.0001 0.38 (0.21-0.67), 0.0009

496 Background: Approximately 10% of patients with renal cell carcinoma (RCC) have an associated venous tumor thrombus (VTT), the presence of which impacts surgical management and increases perioperative risk. Historical systemic therapy regimens had limited success in downsizing VTT; however, the impact of immune checkpoint inhibitors (ICIs) on VTT shrinkage is unknown. Our primary objective is to assess VTT shrinkage comparing responses to ICI versus non-ICI regimens. Methods: This multicenter retrospective cohort study included patients with RCC and VTT from 2006-2024 who received upfront systemic therapy. Patients were evaluated at tertiary referral centers across Mayo Clinic Rochester, Florida, and Arizona. Systemic therapies were categorized as ICI versus non-ICI regimens. VTT length was quantified by distance relative to the superior border of the renal vein ostium. The primary outcome was change in VTT length on serial imaging as measured by absolute length reduction (cm), RECIST version 1.1 criteria, and Mayo VTT level reclassification. Linear mixed-effect models (LMMs) identified associations with VTT shrinkage and clinicopathologic features. Results: A total of 108 patients with median age 65 years (IQR 57-71) were included, of whom 49 (45%) received ICI regimens. ICI regimens were associated with greater VTT shrinkage (1cm vs 0.1 cm, p=0.025), increased RECIST responses (51% vs 32%, p=0.046), and a higher rate downstaging per Mayo VTT level (33% vs 12%, p=0.008) compared to non-ICI regimens. On multivariable LMM analysis, ICI regimens remained more likely to result in VTT shrinkage compared to non-ICI regimens (-0.12 cm/month, 95% CI –0.24-0.00, p=0.046). Absence of abdominal lymphadenopathy was also associated with VTT shrinkage (-0.18cm/month, 95% CI -0.06- -0.30, p=0.004). Initial Mayo VTT level, IMDC risk, and number of metastatic sites were not associated with VTT shrinkage. Conclusions: Treatment with ICI-regimens resulted in VTT shrinkage and Mayo VTT level reduction. This is a particularly important area of exploration as radical nephrectomy and tumor thrombectomy carry up to a 40% risk of peri-operative major complications. These data support using ICI regimens for patients with RCC with VTT who are not candidates for upfront surgery and prioritizing ICI regimens in neoadjuvant clinical trials.

BACKGROUND: Left ventricular (LV) dysfunction is a potential cardioembolic source of ischemic stroke, but its role in recurrent stroke risk and treatment response remains unclear. We explore whether LV injury associates with the risk of recurrent stroke and modifies the association between anticoagulation and stroke recurrence using real-world data. METHODS: We performed a multicenter, retrospective study of Cardiac Abnormalities in Stroke Prevention and Recurrence cohort across 27 US sites. Patients with LV ejection fraction ≥20% were included. LV injury, defined as LV ejection fraction 20% to 40% and wall motion abnormality, was the primary exposure and treatment effect modifier. The treatment of interest was anticoagulant versus antiplatelet therapy. The composite outcome included recurrent stroke, major bleeding, or death. Outcomes were evaluated using unadjusted and inverse probability weighting adjusted Cox proportional hazards models, with treatment effect modification tested by LV injury status. RESULTS: Among 2685 patients enrolled, 2328 with complete data were analyzed (median age, 65 years; 49.8% female; median follow-up, 1.6 years). LV injury was present in 310 patients (13.3%). Overall, 535 events occurred: 258 recurrent ischemic strokes, 28 hemorrhagic strokes, 67 major hemorrhages, and 256 deaths. LV injury was associated with a higher unadjusted risk of the primary outcome (hazard ratio [HR], 1.51 [95% CI, 1.21–1.87]), though nonsignificant after inverse probability weighting adjustment (adjusted HR, 1.29 [95% CI, 0.97–1.70]). In the LV injury subgroup, anticoagulation versus antiplatelet therapy was associated with a lower risk of the primary outcome (adjusted HR, 0.24 [95% CI, 0.10–0.59]), relative to the non-LV injury subgroup (adjusted HR, 1.28 [95% CI, 0.83–1.95]; p[LV-interaction], 0.001). Similar interactions were seen for EF 20% to 40% (versus >40%; adjusted HR, 0.19 [95% CI, 0.04–0.86]; p[LV-interaction], 0.001) and wall motion abnormality (versus no wall motion abnormality; adjusted HR, 0.33 [95% CI, 0.15–0.73]). CONCLUSIONS: After cryptogenic stroke, anticoagulation in those with LV injury was associated with lower rates of recurrent stroke, major bleeding, and death. These findings warrant confirmation in a dedicated randomized controlled trial. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06398366.

PURPOSE The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

Importance There is a need for greater recognition of clinical psychopharmacology endpoints, including instances where specific psychotropic medications may become unnecessary, redundant, contradictory, or otherwise inappropriate and therefore merit deprescribing. Objective To address circumstances warranting psychotropic medication deprescribing. Evidence Review The American Society of Clinical Psychopharmacology convened a panel of 45 international psychopharmacology experts who developed and completed a multiround Delphi survey and conducted a focused literature review between January and May of 2025, in order to identify areas of consensus or disagreement on key aspects of the deprescribing of psychotropic medications. These included collaborative risk-benefit assessments with patients; pharmacokinetic and pharmacodynamic factors; pharmacogenomics; distinguishing redundant or conflictual from complementary mechanisms of action; managing adverse effects; assuring medication adherence; drug tolerance or tachyphylaxis; medication misuse; and the psychological context and ramifications of deprescribing. Findings Consensus was achieved on 44 of 50 final Delphi statements (88%). Panelists unanimously agreed that components of a pharmacotherapy regimen should undergo periodic review to ensure that treatments target relevant symptoms and have favorable risk-benefit ratios. Key points of consensus were that deprescribing: (1) should not occur without first assessing medication adherence; (2) merits consideration if less than partial therapeutic response is apparent, or if treatment goals have been reached and relapse prevention is not a long-term objective; (3) involves psychological ramifications that warrant attention; (4) should be followed by close clinical monitoring; and (5) risk-benefit decisions should ideally involve active patient participation within a shared decision-making model. Conclusions and Relevance Through this Consensus Statement, the Task Force identified circumstances in which the selective elimination of certain psychotropic medications may be clinically indicated. Empirical trials are needed to assess the implementation of deprescribing protocols and gauge their safe, effective, and acceptable outcomes.

Introduction: Congenital preauricular lesions, including skin tags, accessory tragi, and pits, have long been associated with renal anomalies due to their shared embryologic origin. Despite the common practice of recommending routine renal ultrasound screening for these patients, the necessity of this protocol has not been conclusively validated. Methods: A retrospective review was conducted at a single institution from 1996 to 2025. A total of 109 patients presenting with congenital preauricular lesions were identified. Data extracted included demographics, comorbidities, syndromic status, hearing assessments, external ear abnormalities, and renal imaging findings. Statistical analyses (chi-square, Fisher's exact test, and one-sample proportion z-tests) were employed to evaluate the prevalence of renal anomalies compared to the general population and explore associations with other clinical factors. Results: Of the 109 patients with congenital preauricular lesions, 69 underwent renal imaging, and 34.8% (24/69) were found to have abnormal findings, significantly higher ( P = .0011) than the estimated 1.5% prevalence among the general US population. Hydronephrosis was the most frequent abnormality, while no significant differences emerged across syndromic versus nonsyndromic patients, external ear anomalies, or documented hearing loss. Conclusion: These findings indicate a higher-than-expected rate of renal pathology in patients with congenital preauricular lesions and support a low threshold for imaging regardless of syndromic status or other risk factors. Prospective research is needed to further refine screening recommendations.