PURPOSE OF REVIEW: This review explores the design and endpoints of perioperative platforms in clinical trials for muscle-invasive bladder cancer (MIBC). RECENT FINDINGS: The choice of clinical trial design in perioperative platforms for MIBC must align with specific research objectives to ensure robust and meaningful outcomes. Novel designs in perioperative platforms for MIBC integrate bladder-sparing approaches. Primary endpoints such as pathological complete response and disease-free survival are highlighted for their role in expediting trial results in perioperative setting. Incorporating patient-reported outcomes is important to inform healthcare decision makers about the outcomes most meaningful to patients. Given the growing body of evidence, potential biomarkers, predictive and prognostic tools should be considered and implemented when designing trials in perioperative platforms for MIBC. SUMMARY: Effective perioperative platforms for MIBC trials are critical in enhancing patient outcomes. The careful selection and standardization of study designs and endpoints in the perioperative platform are essential for the successful implementation of new therapies and the advancement of personalized treatment approaches in MIBC.

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Urology IRCCS San Raffaele Hospital and Vita Salute San Raffaele University Milan Italy

Department of Urology University of Texas Southwestern Dallas Texas USA

Department of Urology Weill Cornell Medical College New York New York

Hourani Center for Applied Scientific Research Al Ahliyya Amman University Amman Jordan

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

S H Ho Urology Centre Department of Surgery The Chinese University of Hong Kong Hong Kong China

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Alfred Witjes J, Max Bruins H, Carrión A, et al. European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: summary of the 2023 guidelines. Eur Urol 2024; 85:17–31.

Ploussard G, Shariat SF, Dragomir A, et al. Conditional survival after radical cystectomy for bladder cancer: evidence for a patient changing risk profile over time. Eur Urol 2014; 66:361–370.

Isbarn H, Jeldres C, Zini L, et al. A population based assessment of perioperative mortality after cystectomy for bladder cancer. J Urol 2009; 182:70–77.

Esteban-Villarrubia J, Torres-Jiménez J, Bueno-Bravo C, et al. Current and future landscape of perioperative treatment for muscle-invasive bladder cancer. Cancers (Basel) 2023; 15:566.

Kamat AM, Apolo AB, Babjuk M, et al. Definitions, end points, and clinical trial designs for bladder cancer: recommendations from the Society for Immunotherapy of Cancer and the International Bladder Cancer Group. J Clin Oncol 2023; 41:5437–5447.

Ceelen W, Soreide K. Randomized controlled trials and alternative study designs in surgical oncology. Eur J Surg Oncol 2023; 49:1331–1340.

Kendall JM. Designing a research project: randomised controlled trials and their principles. Emerg Med J 2003; 20:164–168.

Griffiths G, Hall R, Sylvester R, et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 2011; 29:2171–2177.

Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003; 349:859–866.

Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med 2021; 384:2102–2114.

Simon GE, Shortreed SM, DeBar LL. Zelen design clinical trials: why, when, and how. Trials 2021; 22:541.

Pallmann P, Bedding AW, Choodari-Oskooei B, et al. Adaptive designs in clinical trials: why use them, and how to run and report them. BMC Med 2018; 16:29.

Ford I, Norrie J. Pragmatic trials. N Engl J Med 2016; 375:454–463.

Zolin SJ, Petro CC, Prabhu AS, et al. Registry-based randomized controlled trials: a new paradigm for surgical research. J Surg Res 2020; 255:428–435.

Geynisman DM, Abbosh P, Ross EA, et al. A phase II trial of risk-enabled therapy after initiating neoadjuvant chemotherapy for bladder cancer (RETAIN). J Clin Oncol 2023; 41:438.

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; 29:2825–2834.

Iyer G, Ballman KV, Atherton PJ, et al. A phase II study of gemcitabine plus cisplatin chemotherapy in patients with muscle-invasive bladder cancer with bladder preservation for those patients whose tumors harbor deleterious DNA damage response (DDR) gene alterations (Alliance A031701). J Clin Oncol 2022; 40:TS4615–TS4615.

Weissfeld LA. Multiple endpoints in clinical trials. Wiley StatsRef Stat Ref Online 2014. https://doi.org/10.1002/9781118445112.stat04948 .

Sherry AD, Msaouel P, Lin TA, et al. Postprogression therapy and confounding for the estimated treatment effect on overall survival in phase III oncology trials. BMJ Oncol 2024; 3:e000322.

Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med 1996; 125:605–613.

Martini A, Gandaglia G, Briganti A. Evidence-based urology: surrogate endpoints. Eur Urol Focus 2021; 7:1217–1218.

Fontanella C, Loibl S, von Minckwitz G. Clinical usefulness and relevance of intermediate endpoints for cytotoxic neoadjuvant therapy. Breast 2015; 24:S84–S87.

Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med 1989; 8:431–440.

Martini A, Fallara G, Ploussard G, Pradere B. Progression-free survival is an adequate endpoint for clinical trials of locally advanced and metastatic urothelial carcinoma. Curr Opin Urol 2022; 32:500–503.

Teramukai S, Nishiyama H, Matsui Y, et al. Evaluation for surrogacy of end points by using data from observational studies: tumor downstaging for evaluating neoadjuvant chemotherapy in invasive bladder cancer. Clin Cancer Res 2006; 12:139–143.

Schober JP, Plimack E, Geynisman DM, Zibelman M. The past, present, and future of pT0 in bladder cancer clinical trials. Curr Opin Urol 2022; 32:495–499.

Petrelli F, Coinu A, Cabiddu M, et al. Correlation of pathologic complete response with survival after neoadjuvant chemotherapy in bladder cancer treated with cystectomy: a meta-analysis. Eur Urol 2014; 65:350–357.

Martini A, Jia R, Ferket BS, et al. Tumor downstaging as an intermediate endpoint to assess the activity of neoadjuvant systemic therapy in patients with muscle-invasive bladder cancer. Cancer 2019; 125:3155–3163.

Shariat SF, Palapattu GS, Karakiewicz PI, et al. Discrepancy between clinical and pathologic stage: impact on prognosis after radical cystectomy. Eur Urol 2007; 51:137–151.

deVere White RW, Lara PNJ, Goldman B, et al. A sequential treatment approach to myoinvasive urothelial cancer: a phase II Southwest Oncology Group trial (S0219). J Urol 2009; 181:2471–2476.

Sternberg C, Squifflet P, Burdett S, et al. 1746P disease-free survival (DFS) and distant metastasis-free survival (DMFS) as surrogates for overall survival (OS) in adjuvant treatment of muscle-invasive bladder cancer (MIBC). Ann Oncol 2022; 33:S1335–S1336.

Zimmermann K, Mostafaei H, Heidenreich A, et al. Health-related quality of life in bladder cancer patients: bladder cancer-specific instruments and domains. Part 2. Curr Opin Urol 2021; 31:304–314.

Zimmermann K, Mostafaei H, Heidenreich A, et al. Health-related quality of life in bladder cancer patients: general and cancer-specific instruments. Part 1. Curr Opin Urol 2021; 31:297–303.

Kordecka A, Walkiewicz-Żarek E, Łapa J, et al. Selection of endpoints in clinical trials: trends in european marketing authorization practice in oncological indications. Value Heal 2019; 22:884–890.

Panebianco V, Briganti A, Boellaard TN, et al. Clinical application of bladder MRI and the vesical imaging-reporting and data system. Nat Rev Urol 2024; 21:243–251.

Sevcenco S, Ponhold L, Heinz-Peer G, et al. Prospective evaluation of diffusion-weighted MRI of the bladder as a biomarker for prediction of bladder cancer aggressiveness. Urol Oncol 2014; 32:1166–1171.

Pecoraro M, Del Giudice F, Magliocca F, et al. Vesical imaging-reporting and data system (VI-RADS) for assessment of response to systemic therapy for bladder cancer: preliminary report. Abdom Radiol (NY) 2022; 47:763–770.

Muin D, Laukhtina E, Hacker M, Shariat SF. PET in bladder cancer imaging. Curr Opin Urol 2023; 33:206–210.

Hensley PJ, Panebianco V, Pietzak E, et al. Contemporary staging for muscle-invasive bladder cancer: accuracy and limitations. Eur Urol Oncol 2022; 5:403–411.

Lindskrog SV, Birkenkamp-Demtröder K, Nordentoft I, et al. Circulating tumor DNA analysis in advanced urothelial carcinoma: insights from biological analysis and extended clinical follow-up. Clin Cancer Res 2023; 29:4797–4807.

Christensen E, Birkenkamp-Demtröder K, Sethi H, et al. Early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing of plasma cell-free DNA in patients with urothelial bladder carcinoma. J Clin Oncol 2019; 37:1547–1557.

Advancements in systemic therapy for muscle-invasive bladder cancer: A systematic review from the beginning to the latest updates