ASCO GU 2026: HCRN GU 20-444: Phase 2 Trial of Pembrolizumab with Response-Guided Bladder-Sparing in Patients with MIBC

(UroToday.com) The 2026 GU ASCO annual meeting featured a urothelial carcinoma session and a presentation by Dr. Jonathan F. Anker discussing results of HCRN GU 20-444, a phase 2 trial of pembrolizumab with response-guided bladder-sparing in patients with muscle-invasive bladder cancer.

Many patients with muscle-invasive bladder cancer are not candidates for radical cystectomy and/or favor bladder-sparing alternatives. Neoadjuvant chemotherapy following TURBT leads to a pathologic complete response in a subset of patients, suggesting that radical cystectomy is not universally required to achieve cure. Dr. Anker and colleagues previously showed that TURBT followed by cisplatin-based neoadjuvant chemotherapy plus PD-1 blockade yielded a stringently defined clinical complete response in 43% of patients, and ~2/3 of such patients, omitting upfront radical cystectomy, experienced durable bladder-intact survival.¹ However, ~50% of patients with muscle-invasive bladder cancer are ineligible for cisplatin, and neoadjuvant PD-1 blockade monotherapy can produce pathologic complete response rates of 30-40%. HCRN GU 20-444 evaluated TURBT followed by pembrolizumab monotherapy with response-guided bladder-sparing for patients with muscle-invasive bladder cancer.

Eligible patients had cT2-3N0M0 urothelial cancer and were cisplatin-declining or ineligible. Following maximal TURBT, patients received 2 cycles of pembrolizumab (q6 week dosing) followed by clinical restaging with MRI/CT, urine cytology, and cystoscopy with biopsies. Patients with a clinical complete response omitted definitive local therapy and received up to 7 additional cycles of pembrolizumab. Patients without a clinical complete response received definitive local therapy (radical cystectomy or chemoradiation): 

 
ctDNA was serially evaluated through whole genome sequencing of tumor and plasma coupled with artificial intelligence-based pattern recognition for ultrasensitive detection of residual disease (TrueMRD, Veracyte). The primary endpoint was the clinical complete response rate. Key secondary and exploratory endpoints included 2-year metastasis-free survival, overall survival, and ctDNA status.

 From July 2022 to December 2024, 46 patients were enrolled with a median age of 74 years (range: 41-91; 24% were ≥80): 

The median follow-up was 11 months (range: 2.4-33.5), with a clinical complete response achieved in 43% (95% CI 29%-59%) of patients. Among patients achieving a clinical complete response, all proceeded without upfront radical cystectomy, and none developed metastatic disease; 1/20 had a delayed cystoprostatectomy due to a new prostate cancer (bladder cancer pT0N0), and 2/20 died due to non-cancer causes:

Adverse events were consistent with the toxicity profile of pembrolizumab:

Cycle 1 ctDNA was undetectable in 90% and 55% of patients with and without a clinical complete response, respectively (Mann-Whitney p = 0.01). Undetectable cycle 1 ctDNA was associated with improved metastasis-free survival (HR 11.2, 95% CI 2.2-57, log-rank p = 0.0003) and overall survival (HR 11.4, 95% CI 1.3-103, p = 0.007): 

Cycle 2 ctDNA was undetectable in 100% patients with a clinical complete response. Among patients without a clinical complete response, undetectable cycle 2 ctDNA was associated with improved metastasis-free survival (HR 14.8, 95% CI 1.4-2000, p = 0.02). The following Swimmer plot highlights the outcomes in patients achieving a clinical complete response: 

Dr. Anker concluded his presentation discussing the results of HCRN GU 20-444 with the following take-home points:

• A uniformly assessed and stringently defined clinical complete response was achieved in 43% of patients treated with pembrolizumab monotherapy after TURBT, and facilitated a response-guided bladder-sparing approach
• Undetectable ctDNA using an ultrasensitive whole genome sequencing-based approach identified patients at extremely low risk for metastatic recurrence
• All patients achieving a clinical complete response had undetectable ctDNA by cycle 2, day 1
• Follow-up for long-term outcomes in patients achieving a clinical complete response is ongoing

Presented by: Jonathan F. Anker, MD, PhD, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY

Reference:

1. Galsky MD, Daneshmand S, Izadmehr S, et al. Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: A phase 2 trial. Nat Med. 2023 Nov;29(11):2825-2834.