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Refining neoadjuvant therapy clinical trial design for muscle-invasive bladder cancer before cystectomy: a joint US Food and Drug Administration and Bladder Cancer Advocacy Network workshop

Nature Reviews Urology volume 19, pages 37–46 (2022)Cite this article

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Abstract

The success of the use of novel therapies in the treatment of advanced urothelial carcinoma has contributed to growing interest in evaluating these therapies at earlier stages of the disease. However, trials evaluating these therapies in the neoadjuvant setting must have clearly defined study elements and appropriately selected end points to ensure the applicability of the trial and enable interpretation of the study results. To advance the development of rational trial design, a public workshop jointly sponsored by the US Food and Drug Administration and the Bladder Cancer Advocacy Network convened in August 2019. Clinicians, clinical trialists, radiologists, biostatisticians, patients, advocates and other stakeholders discussed key elements and end points when designing trials of neoadjuvant therapy for muscle-invasive bladder cancer (MIBC), identifying opportunities to refine eligibility, design and end points for neoadjuvant trials in MIBC. Although pathological complete response (pCR) is already being used as a co-primary end point, both individual-level and trial-level surrogacy for time-to-event end points, such as event-free survival or overall survival, remain incompletely characterized in MIBC. Additionally, use of pCR is limited by heterogeneity in pathological evaluation and the fact that the magnitude of pCR improvement that might translate into a meaningful clinical benefit remains unclear. Given existing knowledge gaps, capture of highly granular patient-related, tumour-related and treatment-related characteristics in the current generation of neoadjuvant MIBC trials will be critical to informing the design of future trials.

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Fig. 1: Current treatment paradigm incorporating cystectomy ± neoadjuvant cisplatin-based chemotherapy for clinically localized muscle-invasive bladder cancer.

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References

  1. Griffiths, G., Hall, R., Sylvester, R., Raghavan, D. & Parmar, M. K. 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. 29, 2171–2177 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Grossman, H. B. et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder. Cancer 349, 859–866 (2003). This was the first randomized trial in MIBC that included pCR as a key end point, reported pCR results in neoadjuvant chemotherapy and control arms, and also survival results according to pCR status.

    CAS  Google Scholar 

  3. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur. Urol. 48, 202–205; discussion 205–206 (2005).

  4. Thompson, R. H. et al. Eligibility for neoadjuvant/adjuvant cisplatin-based chemotherapy among radical cystectomy patients. BJU Int. 113, E17–E21 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. Jiang, D. M. et al. Defining cisplatin eligibility in patients with muscle-invasive bladder cancer. Nat. Rev. Urol. 18, 104–114 (2021).

    Article  PubMed  Google Scholar 

  6. Powles, T. et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N. Engl. J. Med. 384, 1125–1135 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Loriot, Y. et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N. Engl. J. Med. 381, 338–348 (2019).

    Article  CAS  PubMed  Google Scholar 

  8. Dietrich, B., Siefker-Radtke, A. O., Srinivas, S. & Yu, E. Y. Systemic therapy for advanced urothelial carcinoma: current standards and treatment considerations. Am. Soc. Clin. Oncol. Educ. Book 38, 342–353 (2018).

    Article  PubMed  Google Scholar 

  9. Donat, S. M. et al. Potential impact of postoperative early complications on the timing of adjuvant chemotherapy in patients undergoing radical cystectomy: a high-volume tertiary cancer center experience. Eur. Urol. 55, 177–185 (2009).

    Article  PubMed  Google Scholar 

  10. Fisher, B., Gunduz, N. & Saffer, E. A. Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastases. Cancer Res. 43, 1488–1492 (1983).

    CAS  PubMed  Google Scholar 

  11. Petrelli, F. et al. Correlation of pathologic complete response with survival after neoadjuvant chemotherapy in bladder cancer treated with cystectomy: a meta-analysis. Eur. Urol. 65, 350–357 (2014). This meta-analysis of 13 trials demonstrates a correlation between pCR after neoadjuvant chemotherapy and improved long-term outcomes in MIBC.

    Article  PubMed  Google Scholar 

  12. FDA. Surrogate endpoint resources for drug and biologic development. Surrogate Endpoint Resources for Drug and Biologic Development. FDA https://www.fda.gov/drugs/development-resources/surrogate-endpoint-resources-drug-and-biologic-development (2018).

  13. Korn, E. L., Sachs, M. C. & McShane, L. M. Statistical controversies in clinical research: assessing pathologic complete response as a trial-level surrogate end point for early-stage breast cancer. Ann. Oncol. 27, 10–15 (2016). The authors explain the difference between a trial-level surrogate and individual-level surrogate and reanalyse previous meta-analyses evaluating pCR as a trial-level surrogate for EFS and OS in breast cancer, finding no evidence that pCR is a trial-level surrogate in breast cancer or that it should be used to discourage further drug development of a new agent based on negative results for pCR.

    Article  CAS  PubMed  Google Scholar 

  14. Korn, E. L. & Freidlin, B. Surrogate and intermediate endpoints in randomized trials: what’s the goal? Clin. Cancer Res. 24, 2239–2240 (2018).

    Article  PubMed  Google Scholar 

  15. Prentice, R. L. Surrogate endpoints in clinical trials: definition and operational criteria. Stat. Med. 8, 431–440 (1989).

    Article  CAS  PubMed  Google Scholar 

  16. De Gruttola, V. G. et al. Considerations in the evaluation of surrogate endpoints in clinical trials. summary of a National Institutes of Health workshop. Control. Clin. Trials 22, 485–502 (2001).

    Article  PubMed  Google Scholar 

  17. Teramukai, S., Nishiyama, H., Matsui, Y., Ogawa, O. & Fukushima, M. 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. 12, 139–143 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Molenberghs, G. et al. Statistical challenges in the evaluation of surrogate endpoints in randomized trials. Control. Clin. Trials 23, 607–625 (2002).

    Article  PubMed  Google Scholar 

  19. Burzykowski, T., Molenberghs, G. & Buyse, M. The validation of surrogate end points by using data from randomized clinical trials: a case-study in advanced colorectal cancer. J. R. Stat. Soc. Ser. A 167, 103–124 (2004). The authors describe a method of validating a binary end point as a surrogate end point for a time-to-event true end point, which has subsequently been used in several pooled analyses, including in Cortazar et al.22, which evaluated the relationship between pCR and EFS/OS in breast cancer.

    Article  Google Scholar 

  20. Fleming, T. R. & Powers, J. H. Biomarkers and surrogate endpoints in clinical trials. Stat. Med. 31, 2973–2984 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Broglio, K. R. et al. Association of pathologic complete response to neoadjuvant therapy in HER2-positive breast cancer with long-term outcomes: a meta-analysis. JAMA Oncol. 2, 751–760 (2016).

    Article  PubMed  Google Scholar 

  22. Cortazar, P. et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384, 164–172 (2014).

    Article  PubMed  Google Scholar 

  23. Minckwitz, G. V. et al. Correlation of various pathologic complete response (pCR) definitions with long-term outcome and the prognostic value of pCR in various breast cancer subtypes: results from the German neoadjuvant meta-analysis. J. Clin. Oncol. 29, 1028–1028 (2011).

    Article  Google Scholar 

  24. Spring, L. M. et al. Pathologic complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: a comprehensive meta-analysis. Clin. Cancer Res. 26, 2838–2848 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Mieog, J. S., van der Hage, J. A. & van de Velde, C. J. Preoperative chemotherapy for women with operable breast cancer. Cochrane Database Syst. Rev. 2007, CD005002 (2007).

    PubMed Central  Google Scholar 

  26. FDA. BLA 125409Orig1s051 Summary Review. Drugs@FDA https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/125409Orig1s051SumR.pdf (2013).

  27. Baselga, J. et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N. Engl. J. Med. 366, 109–119 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. von Minckwitz, G. et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N. Engl. J. Med. 377, 122–131 (2017).

    Article  Google Scholar 

  29. FDA. BLA 125409Orig1s113s118 letter. Supplement approval fulfillment of postmarketing requirement and commitment. FDA https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/125409Orig1s113s118ltr.pdf (2017).

  30. Schmid, P. et al. Pembrolizumab for early triple-negative breast cancer. N. Engl. J. Med. 382, 810–821 (2020).

    Article  CAS  PubMed  Google Scholar 

  31. FDA. Combined FDA and Merck Sharp & Dohme Briefing Document for the February 9, 2021 Meeting of the Oncologic Drugs Advisory Committee. FDA https://www.fda.gov/media/145654/download (2021).

  32. FDA. Oncologic Drugs Advisory Committee (ODAC) Meeting: Tuesday, February 9, 2021 (transcript). FDA https://fda.report/media/149022/ODAC-20210209-Transcript_0.pdf (2021).

  33. Prowell, T. M., Beaver, J. A. & Pazdur, R. Residual disease after neoadjuvant therapy — developing drugs for high-risk early breast cancer. N. Engl. J. Med. 380, 612–615 (2019). This FDA’s perspective article summarizes the history of pCR in breast cancer trials and highlights the advantages of an approach enrolling patients without pCR in trials evaluating adjuvant therapy.

    Article  PubMed  Google Scholar 

  34. FDA. BLA 125409Orig1s051 cross discipline team leader review. FDA https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/125409Orig1s051CrossR.pdf (2013).

  35. Berry, D. A. & Hudis, C. A. Neoadjuvant therapy in breast cancer as a basis for drug approval. JAMA Oncol. 1, 875–876 (2015).

    Article  PubMed  Google Scholar 

  36. Rosenblatt, R. et al. Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer. Eur. Urol. 61, 1229–1238 (2012).

    Article  PubMed  Google Scholar 

  37. No authors listed. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. Lancet 354, 533–540 (1999).

    Article  Google Scholar 

  38. Apolo, A. B. et al. Eligibility and radiologic assessment in adjuvant clinical trials in bladder cancer. JAMA Oncol. 5, 1790–1798 (2019). The leaders of an FDA and National Cancer Institute workshop in 2017 summarized the workshop discussion in this paper, identifying areas where a uniform approach to eligibility and radiological assessment in adjuvant clinical trials in bladder was needed.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Galsky, M. D. et al. Treatment of patients with metastatic urothelial cancer “unfit” for cisplatin-based chemotherapy. J. Clin. Oncol. 29, 2432–2438 (2011).

    Article  PubMed  Google Scholar 

  40. Ge, P. et al. Oncological outcome of primary and secondary muscle-invasive bladder cancer: a systematic review and meta-analysis. Sci. Rep. 8, 7543 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Pietzak, E. J. et al. Genomic differences between “primary” and “secondary” muscle-invasive bladder cancer as a basis for disparate outcomes to cisplatin-based neoadjuvant chemotherapy. Eur. Urol. 75, 231–239 (2019).

    Article  PubMed  Google Scholar 

  42. Chang, S. S. et al. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO Guideline. J. Urol. 198, 552–559 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  43. NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Bladder Cancer. NCCN https://www.nccn.org/professionals/physician_gls/PDF/bladder.pdf (2021).

  44. Kim, L. H. C. & Patel, M. I. Transurethral resection of bladder tumour (TURBT). Transl. Androl. Urol. 9, 3056–3072 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Shinagare, A. B. et al. Metastatic pattern of bladder cancer: correlation with the characteristics of the primary tumor. AJR Am. J. Radiol. 196, 117–122 (2011).

    Google Scholar 

  46. Metwally, M. I. et al. The validity, reliability, and reviewer acceptance of VI-RADS in assessing muscle invasion by bladder cancer: a multicenter prospective study. Eur. Radiol. 31, 6949–6961 (2021).

    Article  PubMed  Google Scholar 

  47. Panebianco, V. et al. Multiparametric magnetic resonance imaging for bladder cancer: development of VI-RADS (Vesical Imaging-Reporting And Data System). Eur. Urol. 74, 294–306 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Witjes, J. A. et al. EAU-ESTRO-SIOG guidelines on muscle-invasive and metastatic bladder cancer. Eur. Urol. 64, 778–792 (2014).

    Article  Google Scholar 

  49. van der Pol C. B. et al. ACR Appropriateness Criteria: pretreatment staging of muscle-invasive bladder cancer. ACR https://acsearch.acr.org/docs/69370/Narrative/ (2017).

  50. Einerhand, S. M. H. et al. 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in muscle-invasive bladder cancer. Curr. Opin. Urol. 30, 654–664 (2020).

    PubMed  Google Scholar 

  51. Goodfellow, H. et al. Role of fluorodeoxyglucose positron emission tomography (FDG PET)-computed tomography (CT) in the staging of bladder cancer. BJU Int. 114, 389–395 (2014).

    CAS  PubMed  Google Scholar 

  52. Apolo, A. B. et al. Clinical value of fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in bladder cancer. J. Clin. Oncol. 28, 3973–3978 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Dason, S. et al. Utility of routine preoperative 18f-fluorodeoxyglucose positron emission tomography-computerized tomography in identifying pathological lymph node metastases at radical cystectomy. J. Urol. 204, 254–259 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Al-Daghmin, A. et al. External validation of preoperative and postoperative nomograms for prediction of cancer-specific survival, overall survival and recurrence after robot-assisted radical cystectomy for urothelial carcinoma of the bladder. BJU Int. 114, 253–260 (2014).

    Article  PubMed  Google Scholar 

  55. Galsky, M. D. et al. Web-based tool to facilitate shared decision making with regard to neoadjuvant chemotherapy use in muscle-invasive bladder cancer. JCO Clin. Cancer Inform. 1, 1–12 (2017).

    PubMed  Google Scholar 

  56. Cahn, D. et al. MP58-12 clinical destiny of indeterminate pulmonary nodules in patients undergoing radical cystectomy for urothelial carcinoma of the bladder. J. Urol. 197, e776–e777 (2017).

    Article  Google Scholar 

  57. Galsky, M. D. et al. Comparative effectiveness of treatment strategies for bladder cancer with clinical evidence of regional lymph node involvement. J. Clin. Oncol. 34, 2627–2635 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Galsky, M. D. et al. Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer. Cancer 121, 2586–2593 (2015).

    Article  CAS  PubMed  Google Scholar 

  59. Peyton, C. C. et al. Downstaging and survival outcomes associated with neoadjuvant chemotherapy regimens among patients treated with cystectomy for muscle-invasive bladder cancer. JAMA Oncol. 4, 1535–1542 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Flaig, T. W. et al. SWOG S1314: a randomized phase II study of co-expression extrapolation (COXEN) with neoadjuvant chemotherapy for localized, muscle-invasive bladder cancer. J. Clin. Oncol. 37, 4506 (2019).

    Article  Google Scholar 

  61. Koshkin, V. S. et al. Feasibility of cisplatin-based neoadjuvant chemotherapy in muscle-invasive bladder cancer patients with diminished renal function. Clin. Genitourin. Cancer 16, e879–e892 (2018).

    Article  PubMed  Google Scholar 

  62. Dash, A. et al. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder. Cancer 113, 2471–2477 (2008).

    Article  PubMed  Google Scholar 

  63. Osterman, C. K. et al. Efficacy of split schedule versus conventional schedule neoadjuvant cisplatin-based chemotherapy for muscle-invasive bladder cancer. Oncologist 24, 688–690 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Powles, T. et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat. Med. 25, 1706–1714 (2019).

    Article  CAS  PubMed  Google Scholar 

  65. Necchi, A. 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. 36, 3353–3360 (2018).

    Article  CAS  PubMed  Google Scholar 

  66. Bajorin, D. F. et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N. Engl. J. Med. 384, 2102–2114 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Becker, R. E. N. et al. Clinical restaging and tumor sequencing are inaccurate indicators of response to neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur. Urol. 79, 364–371 (2021).

    Article  CAS  PubMed  Google Scholar 

  68. Herr, H., Lee, C., Chang, S. & Lerner, S. Standardization of radical cystectomy and pelvic lymph node dissection for bladder cancer: a collaborative group report. J. Urol. 171, 1823–1828 (2004).

    Article  PubMed  Google Scholar 

  69. Herr, H. W. Outcome of patients who refuse cystectomy after receiving neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur. Urol. 54, 126–132 (2008).

    Article  PubMed  Google Scholar 

  70. Robins, D. et al. Outcomes following clinical complete response to neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma of the bladder in patients refusing radical cystectomy. Urology 111, 116–121 (2018).

    Article  PubMed  Google Scholar 

  71. Sternberg, C. N. et al. Can patient selection for bladder preservation be based on response to chemotherapy? Cancer 97, 1644–1652 (2003).

    Article  PubMed  Google Scholar 

  72. van der Pol, C. B. et al. Update on multiparametric MRI of urinary bladder cancer. J. Magn. Reson. Imaging 48, 882–896 (2018).

    Article  PubMed  Google Scholar 

  73. Necchi, A. et al. Multiparametric magnetic resonance imaging as a noninvasive assessment of tumor response to neoadjuvant pembrolizumab in muscle-invasive bladder cancer: preliminary findings from the PURE-01 study. Eur. Urol. 77, 636–643 (2020).

    Article  CAS  PubMed  Google Scholar 

  74. Choueiri, T. K. et al. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J. Clin. Oncol. 32, 1889–1894 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Choi, S. J. et al. Urothelial phase CT for assessment of pathologic complete response after neoadjuvant chemotherapy in muscle-invasive bladder cancer. Eur. J. Radiol. 126, 108902 (2020).

    Article  PubMed  Google Scholar 

  76. Metser, U. et al. Detection of urothelial tumors: comparison of urothelial phase with excretory phase CT urography — a prospective study. Radiology 264, 110–118 (2012).

    Article  PubMed  Google Scholar 

  77. Zheng, J. et al. Development of a noninvasive tool to preoperatively evaluate the muscular invasiveness of bladder cancer using a radiomics approach. Cancer 125, 4388–4398 (2019).

    Article  PubMed  Google Scholar 

  78. Avulova, S. & Chang, S. S. Role and indications of organ-sparing “radical” cystectomy: the importance of careful patient selection and counseling. Urol. Clin. North Am. 45, 199–214 (2018).

    Article  PubMed  Google Scholar 

  79. Chang, S. S., Cole, E., Cookson, M. S., Peterson, M. & Smith, J. A. Jr. Preservation of the anterior vaginal wall during female radical cystectomy with orthotopic urinary diversion: technique and results. J. Urol. 168, 1442–1445 (2002).

    Article  PubMed  Google Scholar 

  80. Gschwend, J. E. et al. Extended versus limited lymph node dissection in bladder cancer patients undergoing radical cystectomy: survival results from a prospective, randomized trial. Eur. Urol. 75, 604–611 (2019).

    Article  PubMed  Google Scholar 

  81. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01224665 (2021).

  82. Sonpavde, G. et al. Quality of pathologic response and surgery correlate with survival for patients with completely resected bladder cancer after neoadjuvant chemotherapy. Cancer 115, 4104–4109 (2009).

    Article  PubMed  Google Scholar 

  83. Splinter, T. A. et al. The prognostic value of the pathological response to combination chemotherapy before cystectomy in patients with invasive bladder cancer. European Organization for Research on Treatment of Cancer–Genitourinary Group. J. Urol. 147, 606–608 (1992).

    Article  CAS  PubMed  Google Scholar 

  84. Dash, A. et al. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer 113, 2471–2477 (2008).

    Article  PubMed  Google Scholar 

  85. Gress D. M. Principles of cancer staging. In AJCC Cancer Staging Manual 8th Edn (eds Amin, M. B. et al.) (Springer, 2021).

  86. Martini, A. et al. Tumor downstaging as an intermediate endpoint to assess the activity of neoadjuvant systemic therapy in patients with muscle-invasive bladder cancer. Cancer 125, 3155–3163 (2019).

    Article  CAS  PubMed  Google Scholar 

  87. FDA. Pathologic complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval. Guidance document: pathologic complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval. FDA https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pathologic-complete-response-neoadjuvant-treatment-high-risk-early-stage-breast-cancer-use-endpoint (2020). This guidance is intended to assist investigators in designing trials with the use of pCR as an early end point to support accelerated approval, and discusses accepted definitions of pCR in breast cancer, describes trial designs and patient populations in which pCR may be accepted as reasonably likely to predict clinical benefit, and provides guidance on potential trial designs to verify clinical benefit for traditional approval.

  88. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03661320 (2021).

  89. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03732677 (2021).

  90. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03924856 (2021).

  91. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03924895 (2021).

  92. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04209114 (2021).

  93. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04700124 (2021).

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Acknowledgements

The authors thank F. Cross and D. Spillman for project management assistance; D. Zipursky Quale, L. Amiri-Kordestani and A. Ibrahim for support.

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Author notes

  1. These authors contributed equally: Chana Weinstock, Matthew D. Galsky.

Authors and Affiliations

  1. Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, MD, USA

    Elaine Chang, Tatiana Prowell, Harpreet Singh, Daniel Suzman, Hui Zhang & Chana Weinstock

  2. Genitourinary Malignancies Branch, National Cancer Institute, Center for Cancer Research, Bethesda, MD, USA

    Andrea B. Apolo & Rick Bangs

  3. Bladder Cancer Advocacy Network, Education & Research, Bethesda, MD, USA

    Stephanie Chisolm

  4. Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Vinay Duddalwar

  5. Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA

    Jason A. Efstathiou

  6. Oncology Center of Excellence, US Food and Drug Administration, Silver Spring, MD, USA

    Kirsten B. Goldberg, Paul G. Kluetz, Julia A. Beaver & Richard Pazdur

  7. Department of Pathology, Oregon Health & Science University, Portland, OR, USA

    Donna E. Hansel

  8. Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Ashish M. Kamat

  9. Department of Urology, Baylor College of Medicine, Houston, TX, USA

    Seth P. Lerner

  10. Departments of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA

    Elizabeth Plimack

  11. Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA

    Evan Y. Yu

  12. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Matthew D. Galsky

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E.C., A.B.A., V.D., A.M.K., S.P.L., E.P., E.Y.Y, C.W. and M.D.G. researched data for article. E.C., A.B.A., R.B., S.C., V.D., J.A.E., D.E.H., A.M.K., P.G.K., S.P.L., E.P., T.P., H.S., D.S., E.Y.Y., H.Z., J.A.B., R.P., C.W. and M.D.G. made substantial contributions to discussions of content. E.C., A.B.A., V.D., D.E.H., A.M.K., S.P.L., E.Y.Y., J.A.B., C.W. and M.D.G. wrote the article. E.C., A.B.A., V.D., K.B.G., P.G.K., E.P., J.A.B., C.W. and M.D.G. reviewed and edited the manuscript before submission

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Correspondence to Elaine Chang.

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Competing interests

E.C., A.B.A., K.B.G., P.G.K., T.P., H.S., D.S., H.Z., J.A.B., R.P. and C.W. are employees of the US government. R.B. receives honoraria from SWOG, the National Cancer Institute, the NCRA Working Group on Clinical Trials Enrollment and Retention, the Patient Advocate Steering Committee, the Cancer Care Delivery Research Steering Committee; he serves on committees with the National Comprehensive Cancer Network, the Bladder Cancer Advocacy Network, Stand Up to Cancer, Bladder Cancer (Editorial Board). V.D. receives funding from Samsung Healthcare; he serves on the advisory board for Deeptek and is a consultant for Radmetrix. J.A.E. has served as a consultant for Blue Earth Diagnostics, Boston Scientific, AstraZeneca, Taris Biomedical; and on advisory boards for Merck, Roivant Pharma, Myovant Sciences, Janssen, Bayer Healthcare, Progenics, Genentech and EMD Serono. A.M.K. receives funding from Adolor, Bristol-Myers Squibb (BMS), FKD Industries, FerGene, Heat Biologics, Merck, Photocure, SWOG, NIH/GU SPORE, AIBCCR, holds a patent for Cytokine Predictors of Response to Intravesical Therapy; he serves/served as a consultant or on the advisory board for Abbott Molecular, Arquer Diagnostics, ArTara, Asieris, AstraZeneca, BioClin Therapeutics, Biological Dynamics, BMS, Cepheid, CG Oncology, Cold Genesys, H3 Biomedicine/Eisai, Engene, FerGene, Ferring, Imagin Medical, Janssen, MdDxHealth, Medac, Merck, Pfizer, Photocure, ProTara, Roviant, Seattle Genetics, Sessen Bio, Theralase, TMC Innovation, US Biotest, and is a board member of the International Bladder Cancer Group. S.P.L. receives honoraria from UroToday, holds a patent for a TCGA classifier, is involved in clinical trials sponsored by Endo, FKD, JBL, Genentech, SWOG, URoGen, Vaxiion and Viventia; he serves as a consultant or on the advisory board for Ferring, Genentech, Merck, Pfizer, QED, UroGen, Vaxiion, Verity. E.P. receives institutional funding from Astellas, AstraZeneca, BMS, Genentech, Merck, Peloton, Pfizer; she serves as a consultant for BMS, Genentech, Incyte, Janssen, Merck, AstraZeneca, Pfizer. E.Y.Y. receives institutional funding from Bayer, Blue Earth, Daiichi-Sankyo, Dendreon, Merck, Pharmacyclics, Seattle Genetics, Taiho; he serves as a consultant or on the advisory board for Bayer, Clovis, Merck. M.D.G. holds stock/ownership in Rappta Therapeutics, receives institutional funding from Janssen Oncology, Dendreon, Novartis, BMS, Merck, AstraZeneca, Genentech/Roche; he serves as a consultant for BioMotiv, Janssen, Dendreon, Merck, GlaxoSmithKline, Lilly, Astellas Pharma, Genentech, EMD Serono, AstraZeneca, Seattle Genetics, Incyte, Aileron Therapeutics, Dracen, Inovio Pharmaceuticals, NuMab, Dragonfly Therapeutics. His institution holds a patent in Methods and Compositions for Treating Cancer and Related Methods.

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Nature Reviews Urology thanks E. Kikuchi, S. Sridhar and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

FDA–BCAN workshop: https://www.fda.gov/drugs/news-events-human-drugs/fda-bcan-workshop-endpoints-development-neoadjuvant-systemic-therapy-regimens-muscle-invasive

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Chang, E., Apolo, A.B., Bangs, R. et al. Refining neoadjuvant therapy clinical trial design for muscle-invasive bladder cancer before cystectomy: a joint US Food and Drug Administration and Bladder Cancer Advocacy Network workshop. Nat Rev Urol 19, 37–46 (2022). https://doi.org/10.1038/s41585-021-00505-w

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