Clinical trials corner issue 12(1)

Dear Readers,

In this issue, we highlight recently presented and published trials from the 2025 ESMO Annual Meeting. In the future, please reach out to us directly in order to highlight any specific clinical trials at pkagarwal@bsd.uchicago.edu or cns9006@med.cornell.edu and/or at blc.pra@sagepub.com

Sincerely,

OPEN IN VIEWER

Piyush K. Agarwal, MD	Cora N. Sternberg, MD, FACP
Associate Editor, Bladder Cancer	Associate Editor, Bladder Cancer
Professor of Surgery and Vice-Chief of Urology	Clinical Director, Englander Institute for
Director, Bladder Cancer Program	Precision Medicine
The University of Chicago	Weill Cornell Medicine
Chicago, Illinois	New York, New York

Study Title: KEYNOTE-905/EV-303: A Phase 3, randomized study of perioperative Pembrolizumab plus Enfortumab Vedotin (EV) for muscle-invasive bladder cancer (MIBC) in cisplatin-ineligible patients.

Clinicaltrials.gov identifier: NCT03924895

Sponsor: Merck Sharp & Dohme Corp./Astellas Pharma/Seagen Inc. (Pfizer)

Enrollment: 359 (Randomized population for efficacy analysis in presented cohorts)

Rationale: There is a critical unmet need for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for or decline cisplatin-based chemotherapy. Approximately half of patients are ineligible for cisplatin-based chemotherapy due to comorbidities or impaired renal function. The current standard of care for this population is radical cystectomy (RC) alone, which is associated with high recurrence rates and poor long-term survival. Enfortumab vedotin (EV) plus pembrolizumab (Pembro) has previously demonstrated profound efficacy and a survival benefit in the metastatic setting (EV-302). KEYNOTE-905 evaluates whether this potent combination, given perioperatively (neoadjuvant and adjuvant), can improve outcomes compared to surgery alone in this high-risk, cisplatin-ineligible population.

Study Design: This is a randomized, open-label, Phase 3 study. Patients with MIBC (T2-T4aN0M0 or T1-T4aN1M0) who were cisplatin-ineligible (per Galsky criteria) or declined cisplatin were randomized to treatment. The presented data focused on the comparison between Arm C (Perioperative Combination) and Arm B (Surgery Alone).

Arm C (Experimental): Neoadjuvant EV (1.25 mg/kg Days 1, 8) + Pembrolizumab (200 mg Day 1) Q3 W for 3 cycles, followed by Radical cystectomy (RC)+ pelvic lymph node dissection (PLND), followed by Adjuvant EV (6 cycles) + Pembrolizumab (up to 14 cycles).

Endpoints: The primary endpoint was Event-Free Survival (EFS) by blinded independent central review. Secondary endpoints included Overall Survival (OS), Pathological Complete Response (pCR) rate, and safety.

Results: Overall, 344 patients were randomized (170 to the combination arm and 174 to the control arm). Results from the interim analysis presented at ESMO 2025 showed a statistically significant and clinically meaningful benefit for the combination arm.

Event-Free Survival (EFS): The median EFS was Not Reached in the combination arm vs. 15.7 months in the control arm. This corresponded to a Hazard Ratio (HR) of 0.40 (95% CI: 0.28–0.57; p < 0.0001), representing a 60% reduction in the risk of progression or death.

Comments: KEYNOTE-905 represents a practice-changing milestone, being the first phase III trial to show an overall survival (OS) and event-free survival (EFS) benefit with perioperative systemic therapy in cisplatin-ineligible MIBC patients.The pCR rate of 57.1% is the highest ever reported in a Phase 3 MIBC trial, significantly outperforming historical controls. In addition, this was a generally older population than other perioperative MIBC trials, with a median age of 74 years in the combination arm as compared to 72.5 years in the cystectomy arm. Notably, adjuvant immunotherapy was largely absent in the control arm, with only 16.7% of patients receiving adjuvant immune checkpoint therapy. While the toxicity is higher in the combination arm than surgery alone, it was reported as manageable and did not preclude curative-intent surgery. These results established the EV + Pembro regimen as a new standard of care for cisplatin-ineligible patients, leading to FDA approval in November 2025.

Reference: Presented by Christof Vulsteke, MD, PhD, ESMO Annual Congress 2025, Berlin, Germany. Abstract LBA2.

Study Title: IMvigor011: A Phase 3 trial of circulating tumour (ct)DNA-guided adjuvant atezolizumab vs placebo in muscle-invasive bladder cancer (MIBC).

Clinicaltrials.gov identifier: NCT04660344

Sponsor: F. Hoffmann-La Roche Ltd/Genentech, Inc.

Enrollment: 761 (Surveillance Phase); 250 (Randomized Treatment Phase)

Rationale: High-risk muscle-invasive bladder cancer (MIBC) patients often face recurrence after radical cystectomy (RC). Previous trials (e.g., IMvigor010) failed to show a benefit for adjuvant atezolizumab in an unselected population, but retrospective analyses suggested that only patients with detectable circulating tumor DNA (ctDNA) derived benefit. IMvigor011 was designed to prospectively validate whether serial ctDNA testing could identify patients with molecular residual disease (MRD) who would benefit from adjuvant therapy, while sparing ctDNA-negative patients from unnecessary treatment.

Study Design: This was a global, double-blind, randomized Phase 3 study. Patients with high-risk MIBC (pT2-4aN0M0 or pT1-4aN1-3M0) post-cystectomy were enrolled in a surveillance phase with serial ctDNA testing (Signatera™) performed every 6 weeks for up to 12 months. Prior neoadjuvant chemotherapy was allowed.

ctDNA-Positive: Patients who tested positive for ctDNA (either at baseline or during surveillance) were randomized 2:1 to receive Atezolizumab (1200 mg q3w for up to 1 year) or Placebo.

Endpoints: The primary endpoint was investigator-assessed Disease-Free Survival (DFS) in the intent-to-treat (ITT) population of randomized (ctDNA+) patients. Secondary endpoints include Overall Survival (OS), Distant Metastasis-Free Survival (DMFS), and Safety.

Results: At the ESMO 2025 interim analysis, data was presented on 607 patients (250 patients with ctDNA positivity (167 randomized to atezolizumab and 83 to placebo) and 357 patients with ctDNA negativity) as the study met its primary and key secondary endpoints:

Disease-Free Survival (DFS): In the randomized ctDNA + population, the median DFS was 9.9 months with Atezolizumab vs. 4.8 months with Placebo. This resulted in a Hazard Ratio (HR) of 0.64 (95% CI: 0.47–0.87; p = 0.0047). The 12-month DFS rate was 44.7% vs 30.0%.

Comments: IMvigor011 is a landmark, practice-changing study providing the first Level 1 evidence for ctDNA-guided intervention in MIBC post cystectomy. It fundamentally shifts the treatment paradigm from treating “risk” (pathological stage) to treating “disease” (molecular presence). The authors concluded that the data confirmed that ctDNA + patients derive significant survival benefit from immunotherapy, while ctDNA-negative patients can be safely spared the toxicity and cost of treatment, as their recurrence risk is exceptionally low. However, in the ctDNA-negative cohort, 102 patients (22%) subsequently converted to ctDNA-positive status, and 39 (8%) experienced clinical recurrence before ctDNA positivity. Thus, approximately 30% of patients had unfavorable outcomes. Importantly, the question of treatment versus placebo at the time of molecular recurrence is conceptually distinct from whether treatment at molecular recurrence is non-inferior to conventional adjuvant therapy. This study validates the use of serial ctDNA monitoring as a standard of care for post-cystectomy management.

Reference: Presented by Thomas Powles, MD, ESMO Annual Congress 2025, Berlin, Germany. Abstract LBA8 and Powles T et al., N Engl J Med. 2025 Dec 18;393(24):2395–2408.

Study Title: POTOMAC: A Phase 3, randomized study of Durvalumab in combination with Bacillus Calmette-Guérin (BCG) for BCG-naive, high-risk, non-muscle-invasive bladder cancer (NMIBC).

Clinicaltrials.gov identifier: NCT03528694

Sponsor: AstraZeneca

Enrollment: 1018

Rationale: Standard treatment for high-risk non-muscle-invasive bladder cancer (NMIBC) involves transurethral resection followed by intravesical BCG. However, recurrence and progression rates remain high. Durvalumab (an anti-PD-L1 antibody) has shown efficacy in advanced urothelial carcinoma. The POTOMAC trial hypothesized that combining systemic checkpoint inhibition with local BCG immunotherapy could enhance the antitumor immune response and improve disease control in the BCG-naive, high-risk setting.

Study Design: This was a randomized, open-label, global Phase 3 study. Patients with histologically confirmed, BCG-naive, high-risk NMIBC (including CIS, T1, or high-grade Ta) were randomized 1:1:1 to three arms:

Arm A (Experimental): Durvalumab (1500 mg IV q4w for 13 cycles/1 year) + BCG Induction (6 weeks) + BCG Maintenance (Standard SWOG protocol for 24 months).

Endpoints: The primary endpoint was Disease-Free Survival (DFS), defined as the time to recurrence of high-grade NMIBC, progression to muscle-invasive or metastatic disease, or death. Secondary endpoints include Overall Survival (OS) and safety.

Results: Data was presented on 1018 patients at a median follow-up of 60.7 months as the study met its primary endpoint for the combination maintenance arm.

Disease-Free Survival (DFS): Durvalumab + BCG (Induction + Maintenance) reduced the risk of recurrence or progression by 32% compared to BCG alone (Hazard Ratio 0.68; 95% CI: 0.50–0.93; p = 0.0154).

Comments: POTOMAC is a significant positive trial in the NMIBC space, demonstrating that adding systemic durvalumab to full BCG maintenance improves outcomes for high-risk patients. Crucially, the failure of the “Induction only” arm reinforces that systemic therapy cannot simply replace local BCG maintenance; rather, they work synergistically. These results are in line with the CREST trial (sasanlimab + BCG) presented earlier in the year at the AUA 2025 Annual Meeting. However, these results contrast with the ALBAN trial (also presented at ESMO 2025), which failed to show a benefit with atezolizumab + BCG, potentially due to differences in study population risk or BCG dosing schedules. Durvalumab + BCG represents a potential new standard of care for patients at the highest risk of recurrence.

Reference: Presented by Maria De Santis M, MD, ESMO Annual Congress 2025, Berlin, Germany. Abstract LBA108 and De Santis M et al., Lancet 2025 Nov 8;406(10516):2221–223.

Study Title: ALBAN (GETUG-AFU 37): A Phase 3, randomized, open-label trial of intravenous Atezolizumab and intravesical Bacillus Calmette-Guérin (BCG) versus BCG alone in BCG-naive high-risk, non-muscle invasive bladder cancer (NMIBC).

Clinicaltrials.gov identifier: NCT03799835

Sponsor: Unicancer (GETUG-AFU)

Enrollment: 517

Rationale: Intravesical BCG is the standard of care for high-risk NMIBC, but treatment failure occurs in 30–40% of patients. Preclinical data suggests that PD-L1 expression is associated with BCG resistance and that combining immune checkpoint inhibition with BCG could overcome this resistance. The ALBAN trial was designed to evaluate whether adding systemic atezolizumab (anti-PD-L1) to standard BCG therapy could improve event-free survival in patients who had not previously received BCG.

Study Design: This was a randomized, open-label, international Phase 3 study. Patients with histologically confirmed, BCG-naive, high-risk NMIBC (High-grade Ta, T1, or CIS) were randomized 1:1 to two arms:

Arm A (Control): Intravesical BCG induction (6 weekly instillations) + BCG Maintenance (3 weekly instillations at months 3, 6, and 12). Note: This represents a 1-year maintenance schedule, shorter than the 3-year SWOG protocol used in POTOMAC.

Endpoints: The primary endpoint was investigator-assessed Event-Free Survival (EFS), defined as the time to high-grade recurrence, progression to muscle-invasive or metastatic disease, or death. Secondary endpoints include High-Grade Recurrence-Free Survival (RFS), Overall Survival (OS), and Safety.

Results: At a median follow-up of 35.3 months, the study failed to meet its primary endpoint.

Event-Free Survival (EFS): There was no statistically significant difference in EFS between the combination arm and the BCG-only arm. The Hazard Ratio (HR) was 0.98 (95% CI: 0.71–1.36; p = 0.9106).

Comments: The ALBAN trial is a negative study, standing in stark contrast to the positive POTOMAC trial (Durvalumab + BCG). Several factors may explain the discrepancy:

BCG Schedule: ALBAN used a 1-year BCG maintenance protocol, whereas POTOMAC used the standard 3-year SWOG protocol.

However, both trials also demonstrate how effective BCG induction and maintenance therapy is as a single agent for BCG-naïve high NMIBC.

Reference: Presented by Morgan Rouprêt, MD, PhD, ESMO Annual Congress 2025, Berlin, Germany. Abstract LBA107.

Authorship

All authors were involved in the conceptualisation and writing of the manuscript.

Disclosures

Cora N. Sternberg

Advisory Board or Consultant: Pfizer, Merck Ga, MSD, AstraZeneca, Astellas Pharma, Roche/Genentech, Gilead, Amgen, Bayer, Bristol Myers Squibb, Seattle Genetics, Janssen, Lilly, Foundation Medicine, Bicycle Therapeutics, Tolmar, Duality Biotherapeutics, UroToday

Piyush K. Agarwal

Advisory Board or Consultant (paid): Janssen, ImmunityBio, Ferring; Investigator: CG oncology (PIVOT6 trial); Speaker (paid): Ferring, Janssen (Johnson and Johnson); Spouse (employee): Pfizer