Singh, Parminder

703 Background: The association of circulating tumor DNA (ctDNA) reduction with treatment response has been investigated across multiple malignancies. This study aims to assess the impact of ctDNA response on survival outcomes in patients receiving enfortumab-pembrolizumab (EV-P). Methods: We identified 32 patients with advanced urothelial carcinoma who received EV-P and had ≥2 ctDNA assessments with ≥1 detectable level. Deep molecular response was defined as >2-log reduction from highest ctDNA detection. Radiographic progression was determined from radiology reports documenting progression by RECIST criteria. Kaplan Meier analyses were performed to compute Hazard Ratios (HR) with 95% confidence intervals (CI) for radiographic progression free survival (rPFS), defined as time from treatment start to radiographic progression or death and overall survival (OS) defined as time from treatment start to death were computed. Log-rank tests were performed to compare PFS and OS in patients with deep molecular response to those without response. A p-value <0.05 indicated a statistically significant association with response. Results: Thirty-two patients were included (median age 71 years; range 39–90). Median follow-up was 10.6 months. At cutoff (10/1/2025), 26 patients were alive and 6 had died. Seventeen (53%) achieved a ≥2-log ctDNA reduction (responders), while 15 (47%) did not (non-responders). Progression-free survival was significantly longer in responders (log-rank P < 0.001); median PFS was 5.9 months (95% CI 2.4–NR) in non-responders and not reached in responders (HR 0.09, 95% CI 0.02–0.44; P = 0.0026). Median overall survival was 12.7 months (95% CI 10.0–NR) in non-responders versus not reached in responders (log-rank P = 0.011; HR 0.11, 95% CI 0.01–0.88; P = 0.037). At cutoff, 94% of responders and 67% of non-responders were alive. Conclusions: Achieving a >2-log decrease in ctDNA during EV + Pembrolizumab therapy was significantly associated with improved progression free and overall survival. These findings support ctDNA kinetics as a potential early biomarker of response warranting prospective validation. Clinical outcomes by >2-log ctDNA reduction status. Endpoint > 2-log drop (n = 17 ≤ 2-log drop (n = 15) Log-rank p Median (mo) ≤ 2-log > 2-log HR (95% CI) P C-index PFS 2 events (12%) 10 events (67%) 0.0002 5.9 (2.4–NA) NR 0.09 (0.02–0.44) 0.0026 0.77 OS 1 event (6%) 6 events (40%) 0.011 12.7 (10.0–NA) NR 0.11 (0.01–0.88) 0.037 0.73

360 Background: Adding NHT to androgen deprivation therapy (ADT) improves survival in mCSPC, but their comparative impact on patient-reported QoL and time to deterioration (TTD) across FACT-P domains remains underexplored. Methods: MEDLINE and Embase were systematically searched from each database’s inception through August 21, 2025, to identify Phase III trials assessing NHT treatment in mCSPC. Time to FACT-P (total, physical, emotional, functional, and social/family well-being) deterioration across trials with the latest follow up were extracted. Hazards ratios (HRs) and 95% confidence intervals (CIs) were pooled and mixed treatment comparisons were made using network meta-analysis. P-scores were computed; a higher score indicated better QoL. Results: A total of 4 trials (12 references) with 4,037 patients met the inclusion criteria with median follow up ranging from 14.4 months to 30 months. Median time to QoL deterioration ranged from 11.4 to 12.9 months. In terms of FACT-P overall, darolutamide (DARO)+ADT (HR: 0.76; 95% CI: 0.62-0.93), abiraterone acetate (AAP)+ADT (0.85; 0.73-0.98) significantly improved TTD as compared to ADT alone. DARO+ADT was associated with significant improvement in TTD when compared to APA+ADT (0.75; 0.56-0.98). In terms of FACT-P social/family wellbeing, DARO+ADT significantly improved TTD when compared to AAP+ADT (0.75; 0.57-0.96), and ADT (0.79; 0.64-0.98). Likewise, ENZA+ADT significantly improved TTD when compared to AAP+ADT (0.77; 0.63-0.95), APA+ADT (0.88; 0.61-0.99) and ADT (0.82; 0.70-0.95). However, there was no statistically significant difference between DARO+ADT and ENZA+ADT. In terms of FACT-P physical wellbeing, AAP+ADT was associated with statistically significant improvement in TTD when compared to APA+ADT (0.66; 0.52-0.83), ENZA+ADT (0.74; 0.61-0.90), and ADT (0.75; 0.65-0.87). In terms of FACT-P functional wellbeing, DARO+ADT was associated with statistically significant improvement in TTD when compared to ADT (0.78; 0.63-0.96). The ranking analysis is showed in Table. Conclusions: Novel hormonal therapies significantly delay QoL deterioration in mCSPC, particularly across overall, emotional, and functional domains. Domain-specific analyses suggest darolutamide may preserve social/family and functional well-being, while abiraterone favors physical well-being. Rank table. Rank (P-score) FACT-Ptotal FACT-Psocial/family FACT-Pphysical FACT-Pfunctional FACT-Pemotional AAP+ADT 2 (0.73) 5 (0.18) 1 (0.98) 2 (0.62) 3 (0.52) APA+ADT 5 (0.17) 4 (0.22) 5 (0.07) 4 (0.33) 4 (0.52) DARO+ADT 1 (0.90) 1 (0.88) 2 (0.68) 1 (0.92) 2 (0.66) ENZA+ADT 3 (0.50) 2 (0.84) 4 (0.36) 3 (0.52) 1 (0.67) ADT 4 (0.18) 3 (0.38) 3 (0.42) 5 (0.11) 5 (0.13)

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