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27 Background: Validated homozygous loss detection is becoming increasingly important in clinical practice, with prostate NCCN guideline inclusion of BRCA1/2 loss (often portending durable PARP inhibitor benefit) and multi-tumor trials of PRMT5 and MAT2A inhibitors ongoing (biomarker: MTAP loss). Homozygous losses are challenging to detect and require intentional NGS assay design and validations. Using an FDA-approved NGS assay, we evaluated the most frequent losses identified in metastatic prostate cancer, evaluated prognostic associations on ARPI, and prevalence before and after ARPI treatments. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine Prostate Cancer clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (~800 sites of care). Patients with metastatic prostate cancer and tissue tumor genomic testing by FoundationOne CDx were eligible for analysis. Alteration prevalence was compared between non-sequential groups of specimens obtained from patients naïve to ADT and ARPI, naïve to ARPI but not ADT, or exposed to any ARPI. Outcome analyses adjusted for: ECOG performance score, age, baseline PSA, and socioeconomic status. To limit immortal time confounding, outcome analyses were restricted to patients with specimens tested prior to initiation of ARPI. Results: 1990 specimens from 1984 unique patients met criteria for assessment. The most common losses and respective ADT & ARPI naïve vs ADT exposed & ARPI-naïve vs ARPI-exposed prevalence were PTEN (17.1% vs 24.8% vs. 33.5%, p < 0.001), FAS (2.4% vs 5.0% vs 5.8%, p = 0.003), BRCA2 (4.2% vs 3.2% vs. 2.8%, p = 0.36), RB1 (1.6% vs 3.0% vs 3.5%, p = 0.062), and TP53 (2.3% vs 2.3% vs 4.4%, p = 0.064). 227 patients had tissue specimens obtained and NGS results reported prior to initiation of ARPI. Sufficient patients with PTEN loss were present for nominal outcome associations, observing less favorable time to next treatment (HR: 1.81, 95%CI: 1.24 – 2.65, p = 0.002) and overall survival (HR: 1.65, 95%CI: 1.02 – 2.65, p = 0.040) from the initiation of ARPI. In the mHSPC (ADT and ARPI naïve) setting, 17.1% had PTEN loss, 32.8% had an HRR gene alteration, and 2.8% had both. Conclusions: Our results are consistent with homozygous losses of certain genes, notably PTEN , potentially being acquired resistance alterations to ARPI. Prostate cancer trials often do not specify timing of specimen acquisition relative to treatment initiation. For trials like IPATential-150 or CAPItello-280 that evaluate AKT inhibitors in post-ARPI setting, patients with PTEN status determined by archival tissue could be false negatives and reduce power of analysis in biomarker(+) group. Our results underscore the importance of clinical context, especially prior treatment exposures, when interpreting biomarker prevalence.

TPS898 Background: Enfortumab vedotin with pembrolizumab (EV/Pembro) is now first-line therapy for locally advanced or metastatic urothelial carcinoma (la/mUC) following the EV-302/KEYNOTE-A39 trial, which demonstrated a 67.7% response rate and prolonged survival. However, ~35% of cancers exhibited primary resistance and most responders relapse within one year, with post-EV/Pembro therapies achieving < 15% response and median survival < 3 years. We previously showed that therapeutic plasma exchange (TPE) removed soluble PD-L1 and other immune checkpoint inhibitor (ICI) blocking soluble factors from the blood and that this overcame ICI resistance. Combining TPE with EV/Pembro rechallenge may overcome acquired resistance and restore antitumor immunity. Methods: RECIPE-B1 [NCT07087860] is an open-label, randomized phase II trial enrolling 50 patients (1:1) with EV/Pembro-refractory la/mUC and ECOG 0–2. Arm A receives TPE on days 1–3 followed by EV 1.25 mg/kg IV plus pembrolizumab 200 mg IV on day 3 of each 21-day cycle for the first three cycles, then continues EV/Pembro alone from cycle 4. Arm B receives investigator’s-choice next-line standard of care (SOC) per NCCN guidelines. Tumor assessments occur at the end of cycle 4 (±28 days) and every 12 weeks thereafter; safety is monitored each cycle (CTCAE v5.0). The primary endpoint is objective response rate (ORR) by RECIST 1.1, comparing TPE + EV/pembro versus SOC. Secondary endpoints include progression-free survival, overall survival, duration of response, quality of life (EORTC QLQ-CIPN20), and safety. Correlative studies evaluate circulating and urinary tumor DNA and exosomal biomarkers (including exosomal Nectin-4) as predictors of response and resistance. The trial is open at Mayo Clinic; as of September 2025, 2 of 50 patients have been enrolled, with planned accrual of ~2 patients/month and central coordination at Mayo Clinic and affiliates. Clinical trial information: NCT07087860 .

TPS892 Background: Enfortumab Vedotin (EV) plus pembrolizumab (Pembro) is now first-line therapy for advanced urothelial carcinoma (UC), yielding ~30% complete response (CR) rates; nevertheless, most patients (pts) progress within 1 year and median overall survival (OS) remains < 3 years. In muscle invasive bladder cancer, local consolidation after systemic therapy improves outcomes, suggesting that residual, treatment-refractory intravesical disease drives relapse. We hypothesize that cytoreductive cystectomy/nephroureterectomy (CC/U)—with metastasis-directed therapy (MDT) as needed—can consolidate responses to EV/Pembro and extend benefit in regionally advanced or metastatic UC. CAST-AI prospectively evaluates this multimodal strategy and integrates correlative studies of exosomal Nectin-4 and circulating tumor DNA (ctDNA) from blood and urine as predictive/MRD biomarkers. Methods: CAST-AI is a phase II, decentralized single-arm trial enrolling pts with histologically confirmed UC of the bladder or upper urinary tract with ≥N1 and/or M1 disease and ECOG PS 0–2 who are potential surgical candidates (planned n = 75). Treatment: EV 1.25 mg/kg IV D1 & D8 + Pembro 200 mg IV D1 q21d, ≥4 cycles; MDT permitted any time pre-surgery. Response assessments occur q9 weeks (±4) to 18 months, then q12 weeks (±4). Surgical eligibility requires: (A) fitness for surgery; (B) complete or partial response (CR/PR) or, for select low-burden/unmeasurable disease, urologist-adjudicated candidacy; (C) all distant sites addressed; and (D) procedure in pt’s best interest. Post-CC/U maintenance EV/Pembro is encouraged per clinical discretion and guided by definitive surgical pathology results, which provide true pathologic staging often unattainable through imaging after systemic therapy. Primary endpoint: 12-month progression-free survival (PFS). Secondary endpoints: Objective response rate (ORR), CR rate, down-staging at CC/U, PFS, OS, and safety (using CTCAE). Exploratory endpoints: longitudinal exosomal Nectin-4 and ctDNA dynamics as MRD and early relapse indicators; tissue–blood–urine Nectin-4 concordance; pt-reported tolerability (using CIPN20). Key exclusions: > 20% variant histology or disallowed subtypes (e.g., micropapillary, plasmacytoid, sarcomatoid, neuroendocrine); prior chemotherapy for UC; contraindications to surgery/EV/ICI; or active uncontrolled comorbidities/infections. Status: Enrollment is open and ongoing, with 25 of 75 pts enrolled as of September 2025. The trial uses a decentralized model, allowing pts to receive EV/Pembro at their local facility, with central coordination, biospecimen shipping, and surgical evaluation at Mayo Clinic or affiliated sites. ClinicalTrials.gov: NCT06764095. Clinical trial information: NCT06764095 .

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

454 Background: Immune checkpoint inhibitor (ICI)-based combination therapy has become the standard of care for advanced renal cell carcinoma (RCC). A pathologic complete response (pCR) in the primary tumor may be observed in up to one-third of patients; however, data on the outcomes of these patients remain limited. This study aimed to evaluate the clinical outcomes of patients who achieved a pCR following ICI therapy. Methods: Patients with advanced RCC who underwent nephrectomy following ICI therapy were evaluated across five high-volume U.S. academic centers between 2015 and 2023. Clinical characteristics and outcomes were compared between those with and without a pCR in the primary tumor (ypT0N0/Nx). Multivariable logistic regression models were used to identify factors associated with pCR. Recurrence-free (RFS) and overall survival (OS) rates were estimated using the Kaplan-Meier (KM) method. Results: A total of 182 patients were included (Table 1). Among all patients, downstaging to ≤ypT1N0/Nx was observed in 45 patients (25%), of whom 21 (11%) achieved a pCR. In multivariable analysis, the presence of clinical thrombus was marginally associated with a lower likelihood of achieving pCR (odds ratio [95% CI]: 0.39 [0.15–1.00], p=0.06). During a median follow-up of 25 months, 70 patients (38%) experienced recurrence, including 4 (2%) in the pCR group. Median time to recurrence was 7.5 months. KM analysis demonstrated a higher estimated 5-year RFS in the pCR group compared to those with residual disease; however, the difference was not statistically significant (68% vs. 54%, p=0.2). In addition, OS rates were comparable between the two groups. Conclusions: In our cohort, 11% of patients who underwent nephrectomy following ICI therapy for advanced RCC showed pCR, which correlated with improved oncologic outcomes. Despite the lower recurrence rates observed in the pCR group, sustained long-term surveillance remains necessary due to the continued, albeit reduced, risk of disease recurrence. Clinical characteristics of patients who underwent post-ICI nephrectomy, stratified by their pathologic complete response (pCR). Variable pCR (n=21) No pCR (n=161) p-value Median (IQR) age, year 61 (56 – 70) 64 (56 – 71) 0.46 Gender (male), n (%) 15 (71) 118 (73) 0.8 Tumor advancement, n (%) Locally advanced Metastatic 2 (10)19 (90) 36 (22)125 (78) 0.26 Risk group (for metastatic), n (%) Favorable Intermediate Poor 3 (25)6 (50)3 (25) 38 (34)59 (54)13 (12) 0.42 ICI regimen, n (%) ICI monotherapy ICI+ICI ICI+TKI 4 (19)9 (43)8 (38) 46 (28)64 (40)51 (32) 0.64 Immunotherapy cycles (>4), n (%) 8 (50) 49 (37) 0.42 Median (IQR) clinical tumor size, cm 9.3 (6.7 – 11.9) 8.4 (6.6 – 12) 0.68 Clinical nodal involvement, n (%) 8 (38) 53 (33) 0.63 Clinical thrombus, n (%) 12 (57) 60 (37) 0.1 ICI: immune checkpoint inhibitor; TKI: tyrosine kinase inhibitor.

PURPOSE BRCA carriers face high risks of developing both breast and ovarian/fallopian tube cancers (hereafter referred to as ovarian ). Among BRCA carriers with ovarian cancer, it is not clear whether the risk of breast cancer is sufficiently high that risk-reducing mastectomy should be offered. This study aimed to assess the risk of breast cancer BRCA carriers after a diagnosis of ovarian cancer. METHODS We included women with a pathogenic/likely pathogenic variant in BRCA1 or BRCA2 , a diagnosis of ovarian cancer, and no other cancer history and no risk-reducing bilateral mastectomy. Women were followed for incident breast cancer from the date of ovarian cancer diagnosis or the date of baseline questionnaire, whichever came last. The 5-, 10-, and 15-year cumulative risks of breast cancer were compared for women with ovarian cancer and an age-matched set of control women without ovarian cancer. RESULTS A total of 960 participants with ovarian cancer were identified (814 BRCA1 and 146 BRCA2 carriers). After a mean follow-up of 4.9 years, 41 women (4.3%) developed breast cancer, at a mean age at diagnosis of 57.5 years (range, 39-74). Actuarial cumulative breast cancer risks after ovarian cancer were 4.4%, 8.9%, and 11.5% at 5, 10, and 15 years, respectively. Only three breast cancer–related deaths occurred. Among 741 age-matched BRCA carriers without ovarian cancer, actuarial cumulative risks of breast cancer were 20.9%, 38.6%, and 47.2% at 5, 10, and 15 years, respectively. The hazard ratio for breast cancer, after an ovarian cancer diagnosis, compared with no ovarian cancer, was 0.18 ([95% CI, 0.12 to 0.27]; P < .0001). CONCLUSION After ovarian cancer, BRCA carriers have a relatively low risk of breast cancer. Risk-reducing mastectomy should not be recommended routinely, but might be considered for long-term survivors. Magnetic resonance imaging surveillance and/or mammography is a realistic alternative.

Abstract Natural killer (NK) cells represent key effectors of antitumor immunity, yet emerging evidence highlights populations with distinct roles in cancer. Despite such expanded diversity within the NK cell repertoire, we lack an understanding of how this heterogeneity affects immune responses and downstream clinical outcomes. Using single-cell RNA sequencing, we systematically profiled NK cells across cancer and uncovered a dichotomous phenotypic and functional landscape of tumor-infiltrating NK cells shaped by opposing intrinsic signaling programs that drive the expression of IFNG or TGFB1. These divergent programs are associated with distinct transcription factor circuits that integrate cues within the tumor microenvironment and skew NK cells toward proinflammatory or suppressive functions. We found that the capacity for NK cells to engage in either functional direction is intrinsically linked to their phenotypic identity. Canonical NK cells recruited from circulation predominantly directed suppressive TGFB1 signals toward effector CD8+ T cells in tumors. Of note, these subsets exhibited higher TGFB1 expression than intratumoral myeloid cells across tumor types. In contrast, a tissue-resident (TR) adaptive subset exhibited exclusively proinflammatory IFNG-driven profiles and was associated with prolonged survival in both primary and metastatic tumor settings. Moreover, these TR adaptive NK cells, but not other subsets, were linked to response to immune checkpoint blockade. Collectively, our study reveals a previously unrecognized regulatory axis in NK cells that shapes NK cell diversity and augments broader antitumor immune responses.

Background Cardiovascular disease is linked to mental health conditions. Patients with cardiovascular disease and comorbid psychiatric illnesses such as major depressive disorder or generalized anxiety disorder often experience greater physical limitations and decreased overall health. Objective To determine if proactive psychiatric interventions improve staff satisfaction and patient outcomes, such as reducing length of stay and decreasing the 30-day readmission rate, for patients hospitalized on cardiac units with psychiatric comorbidities. Methods The implementation of a proactive psychiatric consultation-liaison service, which included proactive screening of psychiatric needs among patients hospitalized on cardiac units, targeted support for cardiovascular staff, and supportive interactions for patients. Results Comparison between preintervention and postintervention periods indicated a 21% reduction in the 30-day readmission rate for patients hospitalized on cardiac inpatient units with psychiatric comorbidities without adversely affecting hospital length of stay. Staff satisfaction significantly increased with the availability of psychiatric resources. Conclusion The implementation of a multi-disciplinary proactive psychiatric consultation-liaison service on inpatient cardiac units was associated with an increase in cardiovascular staff satisfaction with psychiatric services and a decrease in the 30-day readmission rate of patients with psychiatric comorbidities who were hospitalized for cardiovascular services without significantly affecting length of stay.