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A Golden Age of Bladder Cancer Drug Development

Recent years have seen an explosive rate of transformative advances in both pre-clinical and clinical urothelial carcinoma research.  With the public dissemination of comprehensive molecular data from The Cancer Genome Atlas (TCGA) urothelial carcinoma cohort, the global urothelial carcinoma research community now has the initial road map of the key biological themes that drive carcinogenesis, growth, invasion, and metastasis.1   In the clinic, durable tumor responses in a minority of post-platinum metastatic urothelial carcinoma patients treated with PD-1/PD-L1 targeting immune checkpoint inhibitors (CPIs) has resulted in the FDA approval of 5 new CPI agents (atezolizumab, nivolumab, pembrolizumab, durvalumab, avelumab) since 2016.2-6  Furthermore, promising clinical activity has been demonstrated with fibroblast growth factor receptor (FGFR) inhibitors (erdafitinib) in metastatic patients with tumors harboring activating tumor FGFR alterations and with anti-body drug conjugates (enfortumab vedotin) regardless of tumor genomic alterations.7,8  These new drug approvals and breakthrough designations depicted in Figure 1 have provided much-needed additional therapy options and improved outcomes for metastatic urothelial carcinoma patients.
1 Regulatory Approval Timeline advanced bladder therapies V3
The impact of these rapid advances for both urothelial carcinoma patients and the research community is difficult to overstate.  Prior to this recent renaissance, investment in urothelial carcinoma drug development was scant from both the private and public sectors.  The belief that urothelial carcinoma patients were too frail to be treated safely, that urothelial carcinoma trials could not accrue well, and that urothelial carcinoma did not possess therapeutically exploitable biology or targets was a widely held dogma.  Besides achieving their primary goal of improving the lives of patients with urothelial carcinoma, the FDA approvals shown in Figure 1 resoundingly demonstrated to the world that urothelial carcinoma is a fertile ground for new drug registration strategies.  This point has forever changed urothelial carcinoma from a patient population with few clinical trial options to a population with an abundance of trials to choose from across all stages of the disease.  Shown in Figure 2 is a snapshot of recently completed, ongoing, and planned FDA registration trials in urothelial carcinoma.  With multiple registration trials anticipated to read out in the next few years in the front-line metastatic, adjuvant, and BCG-unresponsive non-muscle invasive populations, continued rapid evolution in standards of care and scientific discovery are anticipated.  While change can evoke fear of the unknown, in the case of urothelial carcinoma this should not be the case.  Indeed, our biggest unknown about the changes that will follow is how far further we will improve the outlook for patients with urothelial carcinoma.  For this fact, urothelial carcinoma patients, families, and physician providers are justifiably hopeful and tremendously thankful. 
2 advanced UC registration trials V32 advanced UC registration trials V3

Published Date: July 12th, 2019

Written by: Noah M. Hahn, MD
References:
  1. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507:315-22, 2014
  2. Bellmunt J, de Wit R, Vaughn DJ, et al: Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 376:1015-1026, 2017
  3. Patel MR, Ellerton J, Infante JR, et al: Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 19:51-64, 2018
  4. Powles T, O'Donnell PH, Massard C, et al: Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: Updated results from a phase 1/2 open-label study. JAMA Oncology 3:e172411, 2017
  5. Rosenberg JE, Hoffman-Censits J, Powles T, et al: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. The Lancet 387:1909-1920, 2016
  6. Sharma P, Retz M, Siefker-Radtke A, et al: Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. The Lancet Oncology 18:312-322, 2017
  7. Rosenberg JE, Sridhar SS, Zhang J, et al: Updated results from the enfortumab vedotin phase 1 (EV-101) study in patients with metastatic urothelial cancer (mUC). Journal of Clinical Oncology 36:4504-4504, 2018
  8. Siefker-Radtke AO, Necchi A, Park SH, et al: First results from the primary analysis population of the phase 2 study of erdafitinib (ERDA; JNJ-42756493) in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt). J Clin Oncol 36, 2018
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