(UroToday.com) The 2026 American Society of Clinical Oncology Genitourinary (ASCO) Annual Meeting held in Chicago, IL, will host the Kidney and Bladder Cancer - Posters Session. Dr. Monika Joshi will present Abstract TPS4641: A phase III randomized trial of pembrolizumab in combination with sactizumab govitecan vs standard of care in ant-PD-(L)1-resistant aUC: ECOG ACRIN EA8231.
Patients with locally advanced or metastatic urothelial carcinoma who progress following anti–PD-(L)1 therapy and enfortumab vedotin currently face limited treatment options and poor outcomes. She noted that sacituzumab govitecan (SG), a TROP-2–directed antibody-drug conjugate, has previously demonstrated meaningful activity in heavily pretreated urothelial carcinoma, while the combination of SG plus pembrolizumab achieved encouraging response rates in platinum-refractory disease. Given the increasing use of both anti–PD-(L)1 therapy and enfortumab vedotin in earlier disease settings, the number of patients with CPI-refractory disease is expected to rise substantially, underscoring the need for prospective evaluation of novel combination strategies and immune checkpoint inhibitor rechallenge.
The design of EA8231, an ongoing open-label, multicenter, randomized phase III trial evaluating sacituzumab govitecan plus pembrolizumab versus standard chemotherapy in patients with previously treated unresectable locally advanced or metastatic urothelial carcinoma.
Eligible patients must have:
- ECOG performance status 0–2
- Prior anti–PD-(L)1 exposure in any disease setting
- No progression within 12 weeks of initiating prior anti–PD-(L)1 therapy
- Prior exposure to enfortumab vedotin unless contraindicated
- At least one prior systemic therapy for metastatic disease
- Prior FGFR inhibitor exposure for FGFR3-altered tumors unless contraindicated
- Bellmunt score 0–2
Patients previously treated with sacituzumab govitecan, other TROP-2–directed therapies, or topoisomerase I inhibitor–containing agents are excluded.
Patients are randomized 1:1 to:
- Standard-of-care chemotherapy consisting of platinum-gemcitabine or taxane-based therapy every 3 weeks
- Pembrolizumab 200 mg Day 1 plus sacituzumab govitecan 10 mg/kg on Days 1 and 8 of a 21-day cycle with G-CSF support
Randomization is stratified according to:
- Bellmunt score (0–1 vs 2)
- Number of prior therapy lines (≤2 vs >2)
- Prior platinum exposure and platinum eligibility
- Duration of prior anti–PD-(L)1 therapy (≤6 vs >6 months)
G-CSF primary prophylaxis is strongly recommended, particularly in patients receiving sacituzumab govitecan.
The primary endpoint is overall survival. Secondary endpoints include progression-free survival, objective response rate, clinical benefit rate, duration of response, safety, tolerability, and health-related quality-of-life measures utilizing NFBlSI-18, FACIT-Fatigue, and EQ-5D-5L instruments.
The study is powered to detect a 42.5% improvement in median overall survival, with a target hazard ratio of 0.70 and planned enrollment of 320 patients. The trial officially activated in October 2025, with enrollment ongoing across multiple participating sites.
EA8231 addresses a growing unmet need in patients with CPI-refractory metastatic urothelial carcinoma and may help define the role of sacituzumab govitecan plus pembrolizumab as a potential treatment strategy following prior anti–PD-(L)1 therapy and enfortumab vedotin exposure.
Presented by: Monika Joshi, MD, MRCP, Professor of Medicine, Endowed Professorship in Cancer Clinical Care, Division of Hematology-Oncology, Penn State Cancer Institute, State College, PA
Written by: Julian Chavarriaga, MD, Clinical Assistant Professor, Urologic Oncologist, Department of Urology at Penn State Health @chavarriagaj on X during the American Society of Clinical Oncology Genitourinary (ASCO) Annual Meeting held in Chicago, IL between May 29th and June 1st, 2026