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Background Grade group 5 (GG5) prostate cancer (PCa) carries a less favorable prognosis after standard-of-care (SOC) therapy, necessitating novel therapeutic approaches. High-dose rate brachytherapy (HDRBT) and androgen deprivation therapy (ADT) may modulate immune response in GG5 PCa, particularly in tumors with increased immune content. This study evaluated whether the addition of nivolumab to SOC was associated with improved disease control in patients with high-volume GG5 PCa, including those with oligometastatic disease. Methods In this non-randomized phase II trial, 31 patients with localized or oligometastatic GG5 PCa and >30% positive biopsy cores were evaluated between September 2018 and April 2021. Patients received four doses of nivolumab (240 mg every 2 weeks) beginning 4 weeks prior to HDRBT, alongside ADT, HDRBT, and external beam radiation. The primary endpoint was to evaluate whether the 2-year freedom from biochemical recurrence (FFBR) rate would exceed a prespecified historical control rate of 75%. Results Among the 31 patients, the median follow-up was 38.8 months (IQR 31.0–46.5 months). The addition of nivolumab to SOC RT with ADT was associated with a 2-year FFBR rate of 90.3% (95% CI 74.3% to 98.0%) (median FFBR not reached), exceeding the prespecified historical control rate of 75% (one-sided p value from binomial test=0.024). Definitive and probable nivolumab-related toxicity included 6.3% acute grade 2 and 6.3% acute grade 3 adverse events (AEs), with no grade 4+ AEs observed. A higher Decipher immunosuppression score at diagnosis correlated with early pathologic response (p=0.005) and was independently associated with time to metastatic failure (p=0.044). Conclusions Nivolumab combined with SOC was associated with encouraging FFBR in this high-risk GG5 PCa population and may represent a promising therapeutic intensification strategy. The Decipher immunosuppression score may serve as a predictive biomarker for response. These findings warrant further investigation in randomized trials.

Background: MELAS is a rare mitochondrial disorder characterized by multisystem involvement, including stroke-like episodes, seizures, and cardiomyopathy. Cardiac involvement in MELAS may include left ventricular dysfunction, arrhythmias, and structural abnormalities, yet the occurrence of cardioembolic stroke as a direct consequence of these manifestations is exceedingly rare. To date, no literature has clearly described this association. Case Presentation: A male in his twenties with known MELAS syndrome, epilepsy, and heart failure with reduced ejection fraction (EF 25%) presented with acute right hemiparesis and aphasia. Investigations: CT angiography and CT perfusion revealed reduced opacification in the left MCA bifurcation and a left M2 thrombus (Figure 1A). The contrast echocardiogram showed a normal-sized left ventricle with severely reduced ejection fraction (25%, down from 30% six months prior), diffuse hypokinesis, grade III diastolic dysfunction, and a left ventricular thrombus, with no patent foramen ovale. Treatment: Given the high suspicion for cardioembolic stroke, the patient received intravenous tenecteplase within the 3-hour window. Mechanical thrombectomy was planned but aborted due to spontaneous recanalization. Post-thrombolytic angiography confirmed reperfusion of the left MCA with residual distal M3 thrombus (Figure 1B).MRI confirmed infarcts in the left MCA distribution and right precentral gyrus, with no evidence of hemorrhagic transformation. Anticoagulation was initiated for secondary prevention. Statins were withheld due to concerns about mitochondrial toxicity. Follow-up: On a 3-month follow-up, the patient remained neurologically stable and continued oral anticoagulation without recurrent events. Discussion: The clinical scenario posed a diagnostic challenge—stroke-like episodes in MELAS are metabolic and typically non-territorial. However, an LV thrombus, territorial infarction, and perfusion mismatch pointed to an ischemic etiology. Timely thrombolysis led to significant neurological recovery. This case highlights the importance of distinguishing cardioembolic stroke from mitochondrial stroke-like events, especially in patients with known cardiac involvement. Conclusion: In MELAS patients with cardiac dysfunction, cardioembolic stroke must be considered when clinical and imaging findings suggest a vascular event. Early recognition and intervention, including thrombolysis, can lead to favorable outcomes.

Objectives To evaluate outcomes of patients achieving a post‐treatment pathological stage of <ypT2N0 at radical cystectomy (RC) following neoadjuvant chemotherapy (NAC) for muscle‐invasive bladder cancer (MIBC) to identify an optimal definition of pathological response. Patients and Methods Patients from 10 international centres who underwent NAC for cT2–4aN0–1 MIBC and achieved <ypT2N0 disease at RC were included. The primary outcome was time to recurrence, either local or distant. Kaplan–Meier and Cox proportional hazards regression were used to evaluate associations between clinicopathological variables and outcomes. Results A total of 625 patients were included. The median age was 66 years and 80% were male. Gemcitabine and cisplatin (GC, 56%) and methotrexate, vinblastine, doxorubicin and cisplatin (MVAC)/dose‐dense (dd)MVAC (32%) were the most common NAC regimens. ypT0, pure ypTis, ypTa ±ypTis and ypT1 ± ypTis were attained in 58.1%, 20.0%, 7.6% and 14.2% of patients, respectively. The cumulative incidence of recurrence at 5 years was 9%, 16%, 29% and 30%, respectively. Pathological stage was prognostic for recurrence, with ypTa ± Tis (hazard ratio [HR] 3.20, 95% confidence interval [CI] 1.40–7.30) and ypT1 ± Tis disease (HR 4.03, 95% CI 2.13–7.63) associated with a significantly higher recurrence risk. Pure ypTis (HR 1.66, 95% CI 0.82–3.38) and the type of NAC regimen (ddMVAC: HR 1.59, 95% CI 0.55–4.56; MVAC: HR 1.18, 9%% CI 0.25–5.54; reference: GC) were not associated with recurrence. Conclusion We propose that optimal pathological response after NAC be defined as attainment of ypT0N0/ypTisN0 at RC. Patients with ypTaN0 or ypT1N0 disease (with or without Tis) at RC displayed a significantly higher risk of recurrence and may be candidates for trials investigating adjuvant therapy.

472 Background: Enfortumab Vedotin (EV), an antibody-drug conjugate that targets nectin-4, is approved for metastatic urothelial carcinoma (mUC) progressing post-platinum and PD1/L1 inhibitor therapy. Erdafitinib is approved in patients for post-platinum mUC with activating genomic alterations in FGFR2/3, but the activity of EV in this subset is unclear. We investigated the activity of EV in patients (pts) with mUC based on FGFR2/3 genotype to inform management. Methods: In this multi-center, retrospective analysis, we assessed the objective response rate (ORR) to EV in mUC pts with and without FGFR2/3 genomic alterations detected by targeted panel next-generation sequencing. Activating gene fusions and known hotspots mutations in the two genes were considered. Descriptive analysis of ORR and patient characteristics was performed. Fisher’s exact test and binomial test with two-tailed p-value were used. Results: 40 pts were available from 4 institutions. Most pts were male (31/40, 78%) and the median age at start of EV was 74.1 (range 49 – 90) years. Ten patients (25%) had upper tract urothelial carcinoma (UTUC), and 33 (82%) had baseline ECOG performance status of 0-1. 31 of 39 patients had received both platinum-based chemotherapy and PD1/L1 inhibitors. Seven patients had confirmed activating hotspot FGFR3 mutations (p.S249C or p.Y373C). One pt had FGFR2 high-level amplification (HA), and one had FGFR3 HA. Of 36 patients evaluable for ORR, 18 had partial response (PR), 12 had stable disease (SD) and 6 had progressive disease (PD). Patients with FGFR2/3 activating mutations exhibited an ORR that was not statistically different compared to patients without no mutations: 2/7 (29%; 90% CI: 5 – 66%) vs. 16/29 (55%; 90% CI: 38 – 71%) respectively ( p-value = 0.4). 3/7 patients with FGFR3 hotspot mutations received an FGFR2/3 inhibitor and none responded; one of them had a sequential response to EV. Conclusions: In this multi-center retrospective cohort, FGFR2/3 activating genomic alterations did not appear to compromise response to EV in mUC. Larger studies are required to confirm our findings and optimal sequencing of EV and erdafitinib in mUC pts with FGFR2/3 genomic alterations requires further assessment.

5043 Background: Pathologic complete response (pCR) after NAC for MIBC is strongly correlated with long-term overall survival. However, there are sparse data on the risk of recurrence based on depth of pathologic response (pT0, pTa, pTis, pT1), and the differential impact of clinicopathologic factors and NAC regimen on recurrence. Methods: Baseline data on all pts with cT2-4N0-1 MIBC receiving NAC and who achieved < ypT2N0 disease at radical cystectomy (RC) from 9 international centers were obtained. The key outcome was time to recurrence (TTR) – defined as the time to any recurrence in the urinary tract or regional/distant metastasis, with death (in the absence of recurrence) considered a competing risk. Cox regression analysis was used to analyze the impact of clinical factors on recurrence. Results: A total of 506 pts were available. Median age was 66 years (range 33-86) and 78% (n = 396) were male; median follow-up after RC was 2.6 years. The majority of patients had pure urothelial histology (n = 371, 73%), and baseline stage was cT2N0 (n = 368, 73%), cT3-4N0 (n = 95, 19%) and TanyN1 (n = 43, 9%). NAC regimens were gemcitabine-cisplatin (GC, n = 296, 59%), dose-dense methotrexate-vinblastine-doxorubicin-cisplatin (ddMVAC, n = 141, 28%), split-dose GC (n = 29, 6%), MVAC (n = 29, 6%) and non-cisplatin based regimens (n = 11, 2%). At RC, 304 patients (60%) had ypT0N0 disease, 32 (6%) had ypTaN0, 107 (21%) had ypTisN0 and 63 (13%) had ypT1N0. Overall, 43 patients (8%) recurred with a median TTR of 56 weeks (range 7-251); 5-year freedom from recurrence was 87% (95% CI 83-91). The majority (n = 38) recurred outside the urinary tract. On multivariable analysis, ypTa (HR = 3.36 [1.24-9.11]) and ypT1 (HR = 2.88 [1.33-6.22], p = 0.013) disease at RC were predictors of shorter TTR, while female sex was associated with longer TTR (HR = 0.52 [0.27-0.98], p = 0.043). The type of NAC was not predictive of TTR (GC vs. other, HR = 1.49 [0.75-2.97], p = 0.26). Conclusions: To our knowledge, this is the largest study to quantify the risk of recurrence in pts achieving pathologic response after NAC and RC for MIBC. 8% of patients undergoing NAC and achieving < ypT2N0 at RC recurred. Residual ypTa and ypT1 disease conferred a significantly higher risk of recurrence, while ypTis did not; female sex was associated with a lower risk of recurrence. Importantly, the type of cisplatin-based NAC regimen used was not an independent predictor of recurrence.