End Points for the Next-Generation Bladder-Sparing Perioperative Trials for Patients With Muscle-Invasive Bladder Cancer

Andrea Necchi^{1

2}, Matthew D Galsky³, Nazli Dizman⁴, David H Aggen⁵, Neeraj Agarwal⁶, Hikmat Al-Ahmadie⁷, Andrea B Apolo⁸, Leslie Ballas⁹, Rick Bangs¹⁰, Peter C Black¹¹, Maurizio Brausi¹², Giorgio Brembilla¹³, Liang Cheng^{14

15}, Arturo Chiti^{1

16}, Alessia Cimadamore¹⁷, Maurizio Colecchia^{1

18}, Siamak Daneshmand¹⁹, Savino Di Stasi^{20

21}, Jason A Efstathiou²², Alex Filicevas²³, Daniel M Geynisman²⁴, Petros Grivas²⁵, Shilpa Gupta²⁶, Alexia Iasonos²⁷, Nick D James^{28

29}, Seth P Lerner³⁰, Yohann Loriot³¹, Lydia E Makaroff²³, Fernando Maluf^{32

33}, Marco Moschini³⁴, Irina Ostrovnaya²⁷, Sumanta K Pal³⁵, Elizabeth R Plimack²⁴, Gagan Prakash³⁶, Sarah P Psutka³⁷, Jonathan E Rosenberg⁵, Sarmad Sadeghi³⁸, Bogdana Schmidt³⁹, Lawrence H Schwartz⁴⁰, Guru P Sonpavde^{41

42}, Marie-Pier St Laurent¹¹, Dingwei Ye⁴³, Philippe E Spiess⁴⁴, Ashish M Kamat⁴⁵

Affiliations

¹ Vita-Salute San Raffaele University, Milan, Italy.
² Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy.
³ Icahn School of Medicine at Mount Sinai, New York, NY.
⁴ The University of Texas MD Anderson Cancer Center, Houston, TX.
⁵ Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY.
⁶ Huntsman Cancer Institute (NCI-CCC), University of Utah, Salt Lake City, UT.
⁷ Department of Pathology, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY.
⁸ Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
⁹ Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA.
¹⁰ Bladder Cancer Advocacy Network, Bethesda, MD.
¹¹ Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
¹² Department of Urology, Hesperia Hospital, Modena, Italy.
¹³ Department of Radiology, IRCCS San Raffaele Hospital, Milan, Italy.
¹⁴ Department of Surgery (Urology), Brown University Warren Alpert Medical School, Providence, RI.
¹⁵ Department of Pathology and Laboratory Medicine, Brown University Health, Providence, RI.
¹⁶ Department of Nuclear Medicine, IRCCS San Raffaele Hospital, Milan, Italy.
¹⁷ Department of Medicine, Institute of Pathological Anatomy, University of Udine, Udine, Italy.
¹⁸ Department of Pathology, IRCCS San Raffaele Hospital, Milan, Italy.
¹⁹ Department of Urology, USC/Norris Comprehensive Cancer Center, Los Angeles, CA.
²⁰ Catholic University "Our Lady of Good Counsel", Tirana, Albania.
²¹ Tor Vergata University, Rome, Italy.
²² Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
²³ World Bladder Cancer Patient Coalition, Brussels, Belgium.
²⁴ Fox Chase Cancer Center-Temple University Health System, Philadelphia, PA.
²⁵ University of Washington, Fred Hutchinson Cancer Center, Seattle, WA.
²⁶ Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH.
²⁷ Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY.
²⁸ Institute of Cancer Research, London, United Kingdom.
²⁹ Royal Marsden NHS Foundation Trust, London, United Kingdom.
³⁰ Baylor College of Medicine, Houston, TX.
³¹ Early Drug Development Department, Gustave Roussy, Villejuif, France.
³² Hospital Israelita Albert Einstein, São Paulo, Brazil.
³³ Hospital Beneficência Portuguesa de São Paulo, São Paulo, Brazil.
³⁴ Department of Urology, IRCCS San Raffaele Hospital, Milan, Italy.
³⁵ Division of Medical Oncology, City of Hope Cancer Center, Duarte, CA.
³⁶ Department of Surgical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India.
³⁷ Department of Urology, University of Washington, Fred Hutchinson Cancer Center, Seattle, WA.
³⁸ Department of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA.
³⁹ University of Utah, Salt Lake City, UT.
⁴⁰ Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY.
⁴¹ AdventHealth Cancer Institute, Orlando, FL.
⁴² College of Medicine, University of Central Florida, Orlando, FL.
⁴³ Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, PR China.
⁴⁴ Department of GU Oncology, Moffitt Cancer Center, Tampa, FL.
⁴⁵ Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX.

PMID: 40934451
PMCID: PMC12431632
DOI: 10.1200/JCO-25-01608

End Points for the Next-Generation Bladder-Sparing Perioperative Trials for Patients With Muscle-Invasive Bladder Cancer

Andrea Necchi et al. J Clin Oncol. 2025.

. 2025 Sep 11:JCO2501608.

doi: 10.1200/JCO-25-01608. Online ahead of print.

Authors

Affiliations

¹ Vita-Salute San Raffaele University, Milan, Italy.
² Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy.
³ Icahn School of Medicine at Mount Sinai, New York, NY.
⁴ The University of Texas MD Anderson Cancer Center, Houston, TX.
⁵ Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY.
⁶ Huntsman Cancer Institute (NCI-CCC), University of Utah, Salt Lake City, UT.
⁷ Department of Pathology, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY.
⁸ Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
⁹ Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA.
¹⁰ Bladder Cancer Advocacy Network, Bethesda, MD.
¹¹ Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
¹² Department of Urology, Hesperia Hospital, Modena, Italy.
¹³ Department of Radiology, IRCCS San Raffaele Hospital, Milan, Italy.
¹⁴ Department of Surgery (Urology), Brown University Warren Alpert Medical School, Providence, RI.
¹⁵ Department of Pathology and Laboratory Medicine, Brown University Health, Providence, RI.
¹⁶ Department of Nuclear Medicine, IRCCS San Raffaele Hospital, Milan, Italy.
¹⁷ Department of Medicine, Institute of Pathological Anatomy, University of Udine, Udine, Italy.
¹⁸ Department of Pathology, IRCCS San Raffaele Hospital, Milan, Italy.
¹⁹ Department of Urology, USC/Norris Comprehensive Cancer Center, Los Angeles, CA.
²⁰ Catholic University "Our Lady of Good Counsel", Tirana, Albania.
²¹ Tor Vergata University, Rome, Italy.
²² Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
²³ World Bladder Cancer Patient Coalition, Brussels, Belgium.
²⁴ Fox Chase Cancer Center-Temple University Health System, Philadelphia, PA.
²⁵ University of Washington, Fred Hutchinson Cancer Center, Seattle, WA.
²⁶ Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH.
²⁷ Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY.
²⁸ Institute of Cancer Research, London, United Kingdom.
²⁹ Royal Marsden NHS Foundation Trust, London, United Kingdom.
³⁰ Baylor College of Medicine, Houston, TX.
³¹ Early Drug Development Department, Gustave Roussy, Villejuif, France.
³² Hospital Israelita Albert Einstein, São Paulo, Brazil.
³³ Hospital Beneficência Portuguesa de São Paulo, São Paulo, Brazil.
³⁴ Department of Urology, IRCCS San Raffaele Hospital, Milan, Italy.
³⁵ Division of Medical Oncology, City of Hope Cancer Center, Duarte, CA.
³⁶ Department of Surgical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India.
³⁷ Department of Urology, University of Washington, Fred Hutchinson Cancer Center, Seattle, WA.
³⁸ Department of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA.
³⁹ University of Utah, Salt Lake City, UT.
⁴⁰ Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY.
⁴¹ AdventHealth Cancer Institute, Orlando, FL.
⁴² College of Medicine, University of Central Florida, Orlando, FL.
⁴³ Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, PR China.
⁴⁴ Department of GU Oncology, Moffitt Cancer Center, Tampa, FL.
⁴⁵ Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX.

PMID: 40934451
PMCID: PMC12431632
DOI: 10.1200/JCO-25-01608

Abstract

Purpose: The evolving treatment landscape of muscle-invasive bladder cancer (MIBC) increasingly warrants novel trial design to evaluate perioperative strategies aimed at bladder preservation. To establish standardized outcome measures for evaluating organ preservation strategies in MIBC, the International Bladder Cancer Group (IBCG) and the Global Society of Rare Genitourinary Tumors (GSRGT) assembled an international, multidisciplinary consensus panel.

Methods: The IBCG and GSRGT gathered global bladder cancer experts and patient advocates to establish a framework for risk-adapted bladder-sparing treatment approaches for MIBC. Working groups reviewed the literature and developed draft recommendations, which were discussed at a live meeting in December 2024 in Milan. This was followed by voting by the members using a modified Delphi process. Recommendations achieving ≥75% agreement during the meeting were further refined and presented.

Results: Clinical complete response (cCR) definition should encompass the absence of high-grade malignancy on pathology and malignant cells on urine cytology and no evidence of local or metastatic disease on cross-sectional imaging. Although cCR remains immature as a primary or coprimary end point in registrational trials, it could serve as a suitable end point in early-phase studies and risk-adapted investigations. Event-free survival (EFS) remains the preferred primary end point as it could reliably capture the durability of clinically meaningful benefit after omittance of surgical consolidation or chemoradiation. Given the composite nature of EFS, events should be prespecified, evaluated in an intention-to-treat approach, and meticulously collected. Continuous assessment of individual patient preferences should begin at the outset of perioperative therapy discussions, with informed decision making prioritized throughout.

Conclusion: The consensus definition of cCR and the framework presented in this study can serve as a foundation for thorough testing of risk-adapted bladder-sparing treatment paradigms for MIBC.

PubMed Disclaimer

Conflict of interest statement

Panelists, all of whom are co-authors of this manuscript, have individually declared all potential and actual financial relationships and competing interests relevant to the topics discussed as part of the development of this manuscript. Those with industry employment or significant financial interests that may impair unbiased contributions were recused from discussions and development of this consensus report. Guideline development procedures, including in-person and virtual attendance, were funded solely by IBCG and GSRGT. No for-profit or industry funding was involved.

Figures

**Figure 1.**
A simplified overview of standard-of-care treatment for surgically fit and systemic treatment eligible patients with muscle invasive bladder cancer and next generation bladder preservation strategies. *Abbreviations*: cCR: clinical response; ctDNA: circulating tumor DNA; EFS: event-free survival; MRI: magnetic resonance imaging; PROs: patient reported outcomes; TURBT: Transurethral resection of bladder tumor; utDNA: urinary tumor DNA. Created by Biorender.com *Currently being tested prospectively

See this image and copyright information in PMC

References

1. Flaig TW, Tangen CM, Daneshmand S, et al. A Randomized Phase II Study of Coexpression Extrapolation (COXEN) with Neoadjuvant Chemotherapy for Bladder Cancer (SWOG S1314; NCT02177695). Clin Cancer Res. 2021. May 1;27(9):2435–2441. - PMC - PubMed
1. Pfister C, Gravis G, Flechin A, et al. Perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin in muscle-invasive bladder cancer (VESPER): survival endpoints at 5 years in an open-label, randomised, phase 3 study. Lancet Oncol. 2024. Feb;25(2):255–264. - PubMed
1. Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol. 2018. Dec 1;36(34):3353–3360. - PubMed
1. Powles T, Kockx M, Rodriguez-Vida A, et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med. 2019. Nov;25(11):1706–1714. - PubMed
1. van Dijk N, Gil-Jimenez A, Silina K, et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat Med. 2020. Dec;26(12):1839–1844. - PubMed

Grants and funding

ZIA BC011351/ImNIH/Intramural NIH HHS/United States

LinkOut - more resources

Full Text Sources

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

End Points for the Next-Generation Bladder-Sparing Perioperative Trials for Patients With Muscle-Invasive Bladder Cancer

Affiliations

End Points for the Next-Generation Bladder-Sparing Perioperative Trials for Patients With Muscle-Invasive Bladder Cancer

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources