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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.

129 Background: Androgen receptor pathway inhibitors (ARPIs) improve metastasis-free and overall survival in men with non-metastatic hormone-resistant prostate cancer (nmHRPC). Apalutamide and darolutamide were approved by the Federal Drug Administration in 2018 and 2019, respectively, based on pivotal clinical trials showing similar efficacy. However, no head-to-head comparisons exist in real-world settings. We compared prescription patterns and survival outcomes between apalutamide and darolutamide in men with nmHRPC using the Surveillance, Epidemiology and End Results (SEER)-Medicare data. Methods: We identified men aged ≥66 years with localized or locoregional prostate cancer between 2000 and 2021 using the SEER-Medicare linked database. Eligible patients initiated apalutamide or darolutamide between January 2019 and December 2021, defined by Medicare Part D claims. The index date was the first prescription of either agent. Men with distant metastases, prior malignancies and age ≤65 were excluded. Baseline demographics and clinical characteristics were compared using chi-square and Wilcoxon rank-sum tests. Survival was assessed using Kaplan-Meier analysis with log-rank tests. Cox proportional hazards regression was used to estimate adjusted hazard ratios (HRs) for mortality. Results: Among 582 men with nmHRPC, 435 (74.7%) received apalutamide and 147 (25.3%) received darolutamide. The mean age at diagnosis was 73.8 vs 74.1 years (p=0.95). Most patients were White (84.6% vs 81.0%, p=0.21) and resided in metropolitan areas (85.0% vs 88.4%, p=0.39). Darolutamide use was more frequent in the Northeast (42.9% vs 24.6%, p<0.001), while apalutamide was more common in the South (28.7% vs 15.6%, p<0.001). Patients receiving darolutamide had higher-grade tumors (68.0% grade III vs 51.3%, p=0.002) and a longer median time from diagnosis to prescription (93 vs 64 months, p<0.001). Kaplan-Meier curves and adjusted Cox models showed no significant difference in overall survival (HR 1.00; 95% CI 0.51–1.98; p=1.00). Age was independently associated with mortality (HR 1.05 per year; 95% CI 1.00–1.10; p=0.04). Conclusions: Apalutamide and darolutamide demonstrated comparable real-world survival outcomes in nmHRPC. Geographic and clinical factors influenced prescribing patterns, but survival did not differ between agents. Treatment choice may therefore be guided by patient comorbidities, tolerability, and clinician preference. Variable Comparison HR (95% CI) P-Value Treatment Darolutamide vs Apalutamide 1.00 (0.51,1.98) 1.00 Age at Diagnosis 1.05 (1.00, 1.10) 0.04* Race White vs Non-White 0.71 (0.28, 1.80) 0.47 Marital Status Married vs Unmarried 1.29 (0.60, 2.75) 0.51 Geographic Region -Midwest vs West 1.18 (0.34, 4.15) 0.79 -Northeast vs West 1.92 (0.92, 3.88) 0.07 -South vs West 1.01 (0.43, 2.36) 0.99

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

464 Background: Based on LITESPARK-005 trail, Belzutifan was FDA-approved to treat advanced RCC following ICI and a VEGF-TKI. We conducted a retrospective cohort study to report the real-world outcomes of Belzutifan in pre-treated RCC patients. Methods: A retrospective chart review of all patients who received Belzutifan at the Mayo Clinic Comprehensive Cancer Center between Dec 2023 and Sep 2025 was conducted. Patients treated for sporadic RCC were eligible; those with von Hippel–Lindau disease, non-RCC pathologies (e.g., Pheochromocytoma, ovarian cancer) were excluded. Radiologic response was assessed by trained curators using RECIST-defined criteria, approximated through systematic review of radiology reports with clinician adjudication when needed. Progression-free survival (PFS), defined as the time from treatment initiation to radiographic progression or death, was estimated using the Kaplan–Meier method. Non-progressors were censored at the last radiology assessment. Patients who discontinued therapy for non-progression reasons were censored at the last radiology assessment prior to discontinuation. Any-cause hypoxia and anemia were reported using CTCAEv5 definitions. Results: A total of 158 patients were identified; 83 (52.5%) who received Belzutifan for sporadic RCC were included. The remaining were excluded for VHL disease (68, 43%) or other pathologies (7, 4.4%). Median follow up was 12 months, 67% were male, median age was 70 (range 39, 94) with 57 patients (69%) were ≥ 65. 28 patients (34%) had a poor IMDC score at baseline. The cohort received a median of 3 previous lines of therapy (range 1,8). Median treatment duration was 3 months (IQR: 1-9.5). Median PFS was 5.7 months (95% CI, 3.8–8.7). At 12 and 18 months, 23.1% and 13.9% of patients, respectively, remained alive and progression-free. Corresponding OS rates at these time points were 60.2% and 51.5%. A confirmed ORR occurred in 12 patients (14.4%). Hypoxia occurred in 44 (53%) patients, median onset 31 days (range 1–270) and 29 (34.9%) required hospitalizations. Median hemoglobin (Hb) levels at baseline were 12.65 g/dl (range, 7.2-15.5), and 68 (82%) patients developed Hb decline on Belzutifan, 27 (32.5%) required transfusions. Conclusions: In an older, high-risk cohort with higher number of prior lines of therapy, Belzutifan yielded PFS/OS and ORR landmarks comparable to the trial supporting its effectiveness in the real world. Outcomes compared with LITESPARK-005 trial. Variable Real world cohort (Mayo Clinic) LITESPARK-005, Belzutifan arm Median PFS (months, 95% CI) 5.7 (3.8-8.7) 5.6 (3.9-7) 12-month PFS rate (%, 95% CI) 23.1% (14.4-33.4) 33.4% (28.4-33.5) 18-month PFS rate (%, 95% CI) 13.9% (7.7-23.9) 24% (19-29.4) 12-month OS rate (%, 95% CI) 60.2% (48.9-70.8) 67.9% (62.9-72.4) 18-month OS rate (%, 95% CI) 51.5% (40.6-62.9) 55.2% (50-60.1) ORR (%, 95% CI) 14.4% (7.7-23.9) 21.9% (17.8-26.5)

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.

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.

Sudden cardiac arrest (CA) is a leading cause of death in the United States, with coexisting chronic obstructive pulmonary disease (COPD) recognized as an independent risk factor. National trends in mortality among individuals with both conditions remain unclear. Using Centers for Disease Control and Prevention’s Wide-ranging Online Data for Epidemiologic Research (multiple cause-of-death data, we conducted a retrospective cross-sectional analysis of deaths with International Classification of Diseases, Tenth Revision codes for COPD (J41–J44) and CA (I46). Age-adjusted mortality rates (AAMRs) were calculated and stratified by race, sex, age group, census region, urbanization level, and place of death. Temporal trends were assessed using Joinpoint regression, reporting annual percent change (APC), and average annual percent change. From 1999 to 2023, a total of 853,773 deaths were recorded, with AAMRs declining from 35.48 to 22.77. The decline was steepest from 1999 to 2006 (APC: –2.77), followed by a more gradual reduction through 2021 (APC: –0.84), and a marked acceleration between 2021 and 2023 (APC: –5.52). Males consistently had higher AAMRs than females (35.41 vs 23.32). Racial disparities persisted, with non-Hispanic (NH) White (29.5) and NH Black individuals (28.16) experiencing the highest rates, followed by NH American Indians (26.17), Hispanics (22.2), and NH Asian/Pacific Islanders (17.82). Mortality was also highest in nonmetropolitan areas (31.37) and the Western region (39.68). Notably, home deaths increased following the coronavirus disease 2019 pandemic. Overall, CA-related mortality in individuals with COPD has declined over the past 25 years, with sharper reductions observed in the post-coronavirus disease period. Despite these improvements, persistent and widening disparities underscore the need for targeted interventions in high-risk populations.

ABSTRACT Background Optimal management of direct oral anticoagulants (DOAC) prior to implantation of cardiac implantable electronic devices (CIED) remains controversial. Objective To determine whether a strategy of minimal interruption of DOAC before cardiac CIED implantation is associated with improved clinical outcomes compared to uninterrupted DOAC use. Methods The electronic clinical records of 310 patients who were on DOAC and underwent CIED implantation were evaluated. The patients were separated into 2 groups: patients in Group 1 had minimal DOAC interruption (DOAC held < 24 h before procedure), while patients in Group 2 continued DOAC before procedure. Resumption of DOAC in both groups was on the same day of the procedure or the next morning at the operator's discretion. Clinically significant pocket hematoma and thromboembolic events were compared. Results Among the 310 patients, 71 (22.9%) of them had DOAC held < 24 h before procedure, while DOAC was continued without interruption in 239 (77.1%) in the periprocedural period. Clinically significant pocket hematomas were found in 1 patient (1.4%) in the DOAC interrupted group and 24 (10.0%) in the DOAC continuous group ( p = 0.046). Low thromboembolic events were observed in both groups: 0 in the minimally interrupted group and 1 (0.4%) in the un‐interrupted group ( p > 0.05). Conclusion The bleeding risk in our cohort of patients who underwent CIED implantation with the uninterrupted DOAC approach is higher than previously reported in the literature. A minimally interrupted approach appears to mitigate this risk without significantly increasing the risk of thromboembolism.