A phase III randomized trial of pembrolizumab in combination with sacituzumab govitecan vs standard of care in anti–PD-(L)1–resistant advanced urothelial cancer: ECOG-ACRIN EA8231.

TPS4641 Background: Patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC) who progress after anti-PD-(L)1 therapy (CPI-R) and enfortumab vedotin (EV) have relatively limited treatment options and poor outcomes. SG, a TROP-2–directed antibody–drug conjugate (ADC), has meaningful efficacy in previously treated la/mUC, while SG plus pembro achieved 41% overall response rate (ORR; 20% complete response rate) in platinum-refractory la/mUC. With rapidly evolving treatment paradigms and earlier use of EV and anti-PD(L)1, the frequency of CPI-R la/mUC is expected to increase; therefore, newer combinations and the role of anti-PD(L)1 re-challenge should be prospectively evaluated in previously treated la/mUC. We hypothesized that SG/pembro combination would improve outcomes over standard chemotherapy (SOC) in pts previously treated with anti-PD(L)1. Methods: EA8231 is an open-label, multicenter, randomized phase III trial enrolling adults with unresectable la/mUC. Key eligibility criteria: a) ECOG PS 0-2 b) Prior anti-PD(L)1 given in any disease setting but no cancer progression within 12 weeks from starting prior anti-PD(L)1initiation c) Prior exposure to EV unless contraindicated d) ≥1 lines of systemic therapy for la/mUC FGFR3 altered tumors must have received prior FGFR inhibitor unless contraindicated e) Bellmunt score 0-2 f) No prior exposure to SG or other TROP-2 directed therapies or drugs containing topo-isomerase I inhibitor. Treatment: Pts are randomized 1:1 to Arm A SOC (platinum-gemcitabine or taxane Q3 week cycle) OR Arm B pembro/SG (Pembro 200mg on day 1 + SG 10mg/kg on days 1, 8 of a 21-day cycle with G-CSF support). Pts are stratified by Bellmunt score (0-1 vs 2), prior lines of therapy (≤2 vs >2), prior exposure to platinum-based chemotherapy (yes vs no prior exposure and platinum-eligible vs no prior exposure and platinum-ineligible), duration of prior anti PD-(L)1 therapy (≤6 vs >6 months). G-CSF primary prophylaxis is strongly recommended, esp. with SG. Endpoints : Primary endpoint: overall survival (OS); secondary endpoints: progression-free survival, ORR, clinical benefit rate, duration of response, safety/tolerability, health related QOL (NFBlSI-18; FACIT-Fatigue; EQ-5D-5L). Statistical plan: Trial is designed to demonstrate 42.5% improvement in median OS platinum-ineligible cohort: median OS increase from 9 to 12.8 months; platinum-eligible cohort: median OS increase from 10.3 to 14.7 months; 80% power with 1-sided 0.025 type I error rate; HR (pembro+SG/SOC) 0.70, N=320. Trial Status: Activation date: 10/23/2025 (1 patient accrued as of Jan 6, 2026; 28 approved sites, additional sites pending). Clinical trial information: NCT06524544 .