Mendiratta, Prateek

815 Background: EV, alone or combined with pembrolizumab (EVP), is a standard of care for patients (pts) with aUC. Markers predictive of early or durable treatment response in aUC remain limited. Here, we investigate serial ctDNA monitoring and TP53 VAF as complementary predictors of early EV/EVP response. Methods: This single-institution IRB-approved study included pts with aUC treated with EV/EVP between 1/2021 and 9/2025. Pt demographics, clinicopathologic features, serial Signatera ctDNA results, and somatic tissue next-generation sequencing (NGS) data were abstracted from medical records. Primary refractory disease (PRD) was defined as progressive disease on first restaging scan or earlier clinical progression resulting in death from disease. PRD and progression-free survival (PFS) were assessed using Fisher’s exact and log-rank tests. Results: Out of 158 pts, 67 pts were included in study cohort. Median follow-up was 13.2 months, with 52% of pts alive at time of data cutoff. Clinical characteristics at EV start include median age 69 years (range 41-99), 78% male, 91% white, 15% variant-predominant histologic subtype, 15% upper tract disease, 43% with visceral metastasis (24 lung, 7 liver), 66% frontline treatment (42 EVP, 2 EV), and 34% refractory setting (6 EVP, 17 EV). At first restaging scan, observed response rate was 50%; 23% had PRD. TP53 alterations on NGS were identified in 39 pts (58%); TP53 VAF was available for 36 pts (92%), with median VAF 50.7% (range 8-82%). While TP53 mutation presence did not significantly associate with PFS (hazard ratio [HR] 1.28, 95% CI 0.68-2.42; log-rank p = 0.45), pts with TP53 VAF ≥ 50% had significantly longer PFS compared with TP53 VAF < 50% (HR 0.44, 95% CI 0.18-1.04; log-rank p = 0.03). PRD was more commonly observed with TP53 VAF < 50% than with TP53 VAF ≥ 50% (odds ratio [OR] 0.06, 95% CI 0.01-0.48, p = 0.01). 23 pts (21 EVP, 2 EV) had ≥ 2 serial ctDNA draws ≤ 120 days apart, including baseline draw within 2 months of EV start. Median time between 1 st and 2 nd ctDNA draws was 43 days. 70% (16 pts) had ≥ 90% ctDNA decline and 17% (4 pts) had ctDNA rise. The 2 pts with PRD exhibited ctDNA rise, whereas no pts with ctDNA decline had PRD (p = 0.04). 10 of these pts (43%) had TP53 mutations with available VAF. Of those 5 pts with TP53 VAF ≥ 50%, 3 had ctDNA clearance over 90%, 1 had 0-90% ctDNA clearance, and 1 had ctDNA rise. Of those 5 pts with TP53 VAF < 50%, 2 had ctDNA clearance over 90%, 1 had 0-90% ctDNA clearance, and 2 had ctDNA rise. Conclusions: Integrated serial ctDNA monitoring and tumor TP53 VAF may capture early treatment sensitivity to EV/EVP. Limitations include retrospective analysis, small sample size/power, combined EV/EVP cohort, and lack of centralized imaging review. Further validation in large, prospective cohorts is warranted.

Importance The ideal duration of androgen deprivation therapy (ADT) for treating localized prostate cancer is unknown due to variable adherence and treatment durations tested in clinical trials. Objective To determine the ideal duration of ADT for patients with prostate cancer treated with radiotherapy. Data Sources This individual patient data meta-analysis of 13 randomized phase 3 clinical trials evaluated the use of radiotherapy alone or with ADT. It included patients with a median follow-up of 11.3 (IQR, 9.5-14.5) years and ADT duration of 0 to 36 months. Most patients (7392 [72%]) included had National Comprehensive Cancer Network high-risk or very high-risk disease. Study Selection For this meta-analysis, a systematic literature search from 1980 to 2020 was performed in trial registries (Cochrane Central Register of Controlled Trials and ClinicalTrials.gov), MEDLINE (1966-2020), Embase (1982-2020), Web of Science, and Scopus to identify trials. Data Extraction and Synthesis Intention-to-treat and as-treated analyses were performed. The number needed to treat to prevent 1 distant metastasis at 10 years was calculated based on prognostic risk group. The analyses were conducted from January 5 to August 15, 2023. Main Outcomes and Measures The primary end point for this study was overall survival, defined as time to death or last follow-up from randomization. Secondary end points included biochemical recurrence, distant metastasis (DM), prostate cancer–specific mortality, and other-cause mortality. Results The median (IQR) age among the 10 266 male patients was 70 (65-74) years. Longer durations of ADT were associated with nonlinear improvement in relative benefits of DM, prostate cancer–specific mortality, and overall survival, with reduced estimated benefits beyond 9 to 12 months of ADT based on the end point. There was a near-linear increase in other-cause mortality associated with long-term ADT use (hazard ratio, 1.28; 95% CI, 1.09-1.50; P = .002 for 28 vs 0 months of ADT). The optimal ADT duration based on 10-year DM was 0, 6, 12 months, and undefined for patients with 1 intermediate-risk factor, 2 or more intermediate-risk factors, and National Comprehensive Cancer Network high-risk and very high-risk disease, respectively. Conclusions and Relevance The results of this meta-analysis suggest that, for men with localized prostate cancer treated with definitive radiotherapy and ADT, there are relative and absolute benefits from increasing durations of ADT that help provide individualized risk estimates.

Abstract The combination of enfortumab vedotin and pembrolizumab (EVP) has recently revolutionized care for patients with previously untreated locally advanced and metastatic urothelial carcinoma. However, predictive biomarkers of response, the optimal duration of EVP for patients who respond well to therapy, and the role of circulating tumor DNA to monitor treatment response have not yet been fully elucidated. In this molecular tumor board, we summarize 6 patients from 4 different academic institutions with unresectable or oligometastatic urothelial carcinoma who achieved long-term remission on surveillance after a short duration of EVP treatment that resulted in complete response on follow-up imaging followed by consolidative radical cystectomy. We discuss potential predictive biomarkers for patients with exceptional response to EVP. These findings highlight the need to determine an optimal duration of EVP to maximize efficacy while minimizing adverse events. We aim to further define and explore the value of local therapy with consolidative cystectomy in the setting of unresectable, locally advanced, oligometastatic disease, or those with metastatic disease who achieve complete response of disease outside of the bladder. Identifying this subset of patients who may be candidates for this type of multidisciplinary management may result in durable treatment-free remission.

387 Background: Level 1 evidence supports treatment of high-risk and node positive PCa using 4-9 weeks of radiotherapy (RT) combined with 18-36 months of androgen deprivation therapy (ADT) with or without abiraterone acetate plus prednisone (AAP). While effective, some cancers recur, and this prolonged treatment is associated with inconvenience and variable morbidity. We aimed to determine whether the biological synergy of stereotactic body radiotherapy (SBRT) with a 6-month combination of ADT, AAP, and the PARP inhibitor niraparib, could enable a shorter intensified, yet safe and effective, therapeutic alternative. Methods: ASCLEPIuS (NCT04194554) is a multicenter investigator-initiated phase I/II trial in high-risk or node positive, homologous recombination unselected, PCa. Patients received 6 months of ADT, AAP, niraparib and SBRT to the prostate (37.5-40 Gy) +/- pelvic lymph nodes (25 Gy). Focal prostate/nodal boosting was permitted. The phase I primary endpoint was the maximum tolerated dose (MTD) of niraparib using the time-to-event continuous reassessment method (3 dose levels: 100 mg and 200 mg held during SBRT, or 200 mg concurrent with SBRT). Dose limiting toxicities (DLT) were any persistent grade 4+ hematologic toxicity or any grade 3+ rectal/urinary toxicity at least possibly related to treatment as assessed by CTCAE v5.0. Patient reported quality of life (QOL) was assessed with the EPIC-26 short form. Linear mixed models were used to compare scores over time. Results: Accrual began in Nov. 2020 with a transition from phase I to phase II in May 2023 after enrolling 54 men. Median follow-up of the phase I cohort is 12.1 months (IQR 9.4-18.9), 80% (n=43) had Grade Group 4-5, median PSA was 17 ng/mL (range, 1-73), 15% (n=8) had cN+ disease, and 76% (n=41) received nodal RT. There were 0 DLTs to date, no grade 3+ rectal or urinary toxicities, and 5 serious adverse events at least possibly attributable to study treatment (anemia, non-rectal gastrointestinal, syncope, infection, musculoskeletal). The most common grade 3 toxicities were hypertension (n = 11, 21%) and leukopenia (n=6, 11%). Transient dose reductions or holds of AAP or niraparib occurred in 10 and 11 patients, respectively. There were no statistically significant declines in patient reported urinary QOL at 6- or 12-months post-treatment compared to baseline (all p >0.15). A transient decline in bowel QOL at 6-months occurred (p<0.01), which improved by 12-months (p=0.16). Conclusions: Our phase I findings support the short-term safety and tolerability of the combination of SBRT to the prostate and nodes, ADT, AAP, and niraparib at an MTD of 200 mg in men with high-risk or node positive PCa. Our trial completed phase II enrollment in May 2024, and longer-term safety, efficacy, and genomic correlations will be presented in the future. Clinical trial information: NCT04194554 .