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The Latest Research on Advanced Bladder Cancer

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From the Desk of the Editor

Petros Grivas | June 16, 2019

Bladder cancer is common and challenging to treat. A thorough assessment of the molecular biology and immunology background has pinpointed potential biomarkers, “drivers” and promising therapeutic targets. The advent of immune checkpoint inhibitors (ICI) has heralded a new era after approximately two decades of a “stagnant landscape”.  As single agents in patients with advanced urothelial carcinoma, ICI can induce rapid and durable responses, with a very small proportion of patients achieving long term remission. However, most patients do not achieve response, while a proportion may have immune-related adverse events. Therefore, there is an urgent need for additional therapies that raise the bar, improve quality of life, and prolong the life of our patients.

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Petros Grivas, MD

Petros Grivas, MD, Ph.D. is an Associate Professor and the Clinical Director of the Genitourinary Cancers Program at the University of Washington, and an Associate Member of the Clinical Research Division at the Fred Hutchinson Cancer Research Center with expertise in genitourinary cancers such as bladder cancer, prostate cancer, and testis cancer.
Dr. Grivas is dedicated to efficient, personalized and outstanding patient care. He believes in an optimal patient-physician relationship and community outreach. Dr. Petros Grivas was recruited from the Cleveland Clinic where he was leading the bladder/urothelial cancer program and was seeing numerous patients with bladder/urothelial cancer, prostate cancer and testis cancer. Prior to Cleveland Clinic, Dr. Grivas was seeing patients with similar diseases at the University of Michigan, Ann Arbor. He played an important role in clinical trials that led to the FDA approval of new drugs for bladder/urothelial cancer, and he is considered a thought leader and international expert, giving lectures in several countries, educating other oncologists and trainees, leading clinical trials and publishing novel and important research.

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Clinical Conversations by Experts
Everyday Urology - Oncology Insights
Publications focusing on urologic cancer treatments through original manuscripts
By Neal Shore
Published Date: March 2020

In 2015, cisplatin-ineligible patients with metastatic urothelial carcinoma could not be offered a first-line treatment option capable of prolonging their survival. Also, a paucity of second-line treatments resulted in these same patients usually surviving for only 3 to 6 months after progressing on platinum-treatment.
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By Noah Hahn, MD
Published Date: March 2019

This is an extraordinary time in urology. After decades of relative stagnation, patients with urothelial carcinoma are receiving approved immuno-oncologic drugs that significantly extend survival and are safer and more tolerable than chemotherapy.  The success of these treatments in metastatic bladder cancer has generated strong interest and promising early results for their use in localized disease.
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By Neal Shore, MD, FACS
Published Date: June 2018

Initial Considerations
From BCG to interferon gene therapy, physicians have treated bladder cancer with immunotherapy for decades. Treatment particulars generally depend on whether bladder cancer is non-muscle invasive, muscle-invasive, or metastatic. About 75% of patients have non-muscle invasive bladder cancer (NMIBC),1 which is considered high-risk if it consists of non-invasive papillary carcinoma (TaHG),ins
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Library Resources
The State-of-the-Evidence in Brief Reviews by Experts
Written by Janet Baack Kukreja, MD, MPH and Ashish Kamat, MD, MBBS
April 16, 2019
Bladder cancer was one of the top five leading causes of cancer death in 2015.1 Most of these cases are of urothelial histologic origin. For about 35% of patients, bladder cancer is either muscle-invasive or metastatic at disease presentation.
April 16, 2019
BALVERSA is a kinase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma that has 

  • susceptible FGFR3 or FGFR2 genetic alterations and
  • progressed during or following at least one line of prior platinum-containing chemotherapy including within 12 months of neoadjuvant 
Expert Commentary
The State-of-the-Evidence in Brief Reviews by Experts
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
The introduction of immune checkpoint inhibitors (ICIs) has improved the outcomes for a subset of metastatic urothelial carcinoma (mUCC) patients. There is a need for a predictive tool to identify
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Nivolumab is an FDA-approved immune checkpoint for treating platinum-resistant metastatic or surgically unresectable urothelial carcinoma (mUC). The development of predictive biomarkers
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
A significant number of patients with locally advanced and metastatic urothelial cancer (aUC) are not eligible for cisplatin-based chemotherapy.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
The optimal treatment for cisplatin-ineligible patients with metastatic urothelial cancer is unknown.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Patients who achieved a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) have a better prognosis compared to patients with pathologic residual disease (pRD).
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
The optimal treatment for patients with metastatic urothelial carcinoma (mUC) patients who are unfit to receive the standard cisplatin-based chemotherapy is uncertain.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
FGFR3 mutations are common in urothelial carcinoma. The APOBEC mutational process is the dominant mutational mechanism in bladder cancer.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
A shortage of the Bacillus Calmette-Guérin (BCG) Connaught strain occurred between 2013-2016. 
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Perioperative chemotherapy is frequently underutilized. Understanding the trends in the utilization of neoadjuvant or adjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer (MIBC) undergoing cystectomy is critical.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Neoadjuvant chemotherapy followed by radical cystectomy (RC) with lymph node dissection is the standard of care in patients with muscle-invasive urothelial bladder carcinoma (MIBC).
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Immune checkpoints inhibitors (ICIs) are approved as a second line of treatment for metastatic urothelial carcinoma (mUC) patients with progression on cisplatin-based chemotherapy.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Patients with muscle-invasive bladder cancer  (MIBC) who are treated with neoadjuvant chemotherapy (NAC) before cystectomy have a survival advantage.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Downstaging of muscle-invasive bladder cancer (MIBC) following neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) has been correlated with higher survival rates.  
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Platinum-resistant urothelial carcinoma is a lethal disease. After a long period of therapeutic stagnation, the last two years have witnessed an explosion in the development of new second-line therapies.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Neoadjuvant chemotherapy is a standard of care for patients with urothelial muscle-invasive bladder cancer.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) neoadjuvant chemotherapy is a standard of care for muscle-invasive urothelial bladder cancer.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Neoadjuvant chemotherapy is a standard of care for muscle-invasive bladder cancer (MIBC).
Conference Coverage
Conference Highlights from Recent Conference Coverage
Presented by Thomas Powles, MD, MBBS, MRCP
In this presentation during the thematic session at the 2021 European Association of Urology (EAU) annual meeting, focusing on immunotherapy in urothelial cancer, Dr. Thomas Powles reviews predictive markers for response in urothelial cancer. 
Presented by Nick Beije, MD, Ph.D and Morgan Roupret, MD, Ph.D
Dr. Nick Beije of Rotterdam, presented the final results of the CirGuidance Study, which focused on the use of the circulating tumor cells (CTCs) to drive neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC). This was followed by a discussion and summary from Dr. Morgan Roupret.
Presented by  Shilpa Gupta, MD
Previous studies have suggested that gemcitabine-cisplatin + drug X is not better than gemcitabine-cisplatin alone in phase 3 trials to date. This includes the EORTC 30987 trial assessing gemcitabine-cisplatin + paclitaxel versus gemcitabine-cisplatin and the recently published CALGB 90601 trial assessing gemcitabine-cisplatin + bevacizumab versus gemcitabine-cisplatin + placebo.
Presented by Bishoy M. Faltas, MD
The bladder cancer poster discussion session at American Society of Clinical Oncology (ASCO) 2021 featured a discussant presentation by Dr. Bishoy Faltas examining novel immunotherapy approaches across the spectrum of urothelial cancer stages.
Presented by Jason Efstathiou, MD, DPhil

Closing this course on TMT, Dr. Efstathiou presented on Biomarkers, Immunotherapy and Future Directions in TMT. He began by emphasizing, as many of the prior presentations in the course had done, that clinical-pathologic features affect TMT decisions, including tumor size, T stage, hydronephrosis, renal function, and bladder function. The question then is whether genomic factors may be able to inform bladder sparing therapy.

 

Presented by Alex Kutikov, MD, FACS
The State of the Art lecture at the 2021 virtual annual meeting of the Southeastern Section of the AUA was provided by Dr. Alex Kutikov who discussed the current applications for radical cystectomy and perhaps to spare certain bladders while minimizing risk of disease progression.
Presented by Petros Grivas, MD, PhD
In Best of Podium presentation at this year’s Southeast Section of the American Urologic Association Virtual Annual Meeting, Dr. Grivas presented pre-specified subgroup analyses of the JAVELIN Bladder 100 trial.
Presented by Dean F. Bajorin, MD
For patients with muscle-invasive bladder cancer who are eligible for curative-intent treatment, cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is a standard of care with improved pathologic response and overall survival (OS) compared to RC alone.
Presented by Arlene O. Siefker-Radtke, MD
In this presentation, Arlene O. Siefker-Radtke, MD provided a discussion on two presentations on Enfortumab Vedotin (EV)  in previously treated urothelial cancer. Primary results of EV-301 and EV-201 Cohort 2: Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors.
Presented by Andrea Necchi, MD
Muscle-invasive bladder cancer is a systemic disease as >40% of patients ultimately develop recurrence after radical cystectomy. For patients who cannot receive or refuse cisplatin-based chemotherapy, there is no standard-of-care neoadjuvant therapy.
Presented by Thomas Powles, MBBS, MRCP, MD
Cisplatin chemotherapy is the standard of care for medically fit patients in advanced urothelial carcinoma. Up to 50% of these patients are medically ineligible for cisplatin due to low performance status, renal dysfunction, or other medical comorbidities.
Presented by Yohann Loriot, MD, PhD
Avelumab first-line maintenance therapy is approved in the United States for patients with advanced urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy based on significantly prolonged overall survival versus best supportive care alone (median 21.4 months versus 14.3 months; HR 0.69, 95% CI 0.56-0.86) as reported in the phase III JAVELIN Bladder 100 trial.
Presented by Petros Grivas, MD, Ph.D.
In a presentation at the 2021 ASCO GU, Dr. Grivas described the design of the confirmatory phase III trial, TROPiCS-04. TROPiCS-04 is a global, multicenter, open-label, randomized controlled trial, performed among patients with locally advanced unresectable or metastatic urothelial carcinoma.
Presented by Neal Shore, MD, FACS, and Robert Dreicer, MD
At the 2020 Society of Urologic Oncology (SUO) Annual Virtual Meeting, Dr. Neal Shore chaired a session examining the use of newer and emerging agents in bladder cancer, which highlighted a presentation by medical oncologist Dr. Robert Dreicer discussing novel treatment options for patients with advanced bladder cancer.
Presented by Andrea Necchi, MD,
In an oral presentation in a session examining neoadjuvant versus adjuvant strategies in locally advanced bladder cancer at the 12th European Multidisciplinary Congress on Urological Cancers (EMUC), Dr. Andrea Necchi led a discussion of neoadjuvant strategies in advanced bladder cancer.
Presented by Matthew Galsky, MD
In an oral presentation in the Refining the Treatment of Bladder Cancer session at the 12th European Multidisciplinary Congress on Urological Cancers (EMUC), Dr. Matthew Glasky presented an overview of optimal first-line approaches to the treatment of metastatic bladder cancer. Dr. Galsky began by highlighting the treatment approach in what he called the “not too distant past:
Presented by Michiel S. van der Heijden, MD, PhD
Platinum-based chemotherapy is the mainstay of first-line treatment for medically eligible patients with advanced urothelial carcinoma (UC). Unfortunately, up to 50% of patients are unable to receive cisplatin, and disease progression often develops even for patients who receive cisplatin.
Presented by Yohann Loriot, MD, MSc
Treatment options for advanced urothelial cancer that has progressed through platinum chemotherapy and immune checkpoint blockade consist of (1) single agent chemotherapy, (2) FGFR inhibitor therapyfor tumors harboring susceptible alterations, and (3) the antibody-drug conjugate enfortumab vedotin.
Presented by Thomas B. Powles, MBBS, MRCP, MD
Urothelial carcinoma has a substantial impact on patient qualify of life. Patients may experience a multitude of disease-related symptoms, including pain, urinary frequency, physical changes, and mental health issues, with all affect quality of life. 
Presented by Petros Grivas, MD, Ph.D.
Advanced urothelial carcinoma has among the worst prognosis for tumors treated by genitourinary oncologists. Standard of care dictates that patients receive platinum-based induction chemotherapy.
Presented by Bishoy M. Faltas, MD
(UroToday.com) At the Society of Urologic Oncology (SUO) Summer Virtual Webcast, Bishoy Faltas, MD, from Weill Cornell compared the genetic components of the bladder and upper tract urothelial carcinoma. Upper tract urothelial carcinoma comprises 5-10% of all urothelial carcinomas with a unique epidemiologic association with Arsenic exposure and aristolochic acid.
Presented by Yohann Loriot, MD, PhD
(UroToday.com) Outcomes of immunotherapy have been the highlight of meetings over the last decade. At the 2020 European Association of Urology (EAU) Virtual Meeting, Yohann Loriot, MD, PhD, discussed novel treatment options beyond immunotherapy. As noted by Dr. Loriot, the vast majority of trials with new drugs are investigating immunotherapy, but a better understanding of the tumor biology is identifying new targets.
Presented by Cora N. Sternberg, MD, FACP
San Francisco, California (UroToday.com) To close the session entitled “Risk stratification and management of high-risk muscle invasive urothelial carcinoma,” Cora N. Sternberg
Presented by Wassim Kassouf, MD, FRCS
San Francisco, California (UroToday.com) Treatment of patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) remains a significant
Presented by Jonathan E. Rosenberg, MD
San Francisco, CA (UroToday.com) There are limited effective treatments for patients with metastatic bladder cancer who are platinum ineligible. Single-agent immunotherapy
Presented by Karen M. Wheeler, MD
Washington, DC (UroToday.com) As part of the Research Scholars Update at the 20th Annual Meeting of the Society of Urologic Oncology, Dr. Karen Wheeler presented her work on
Presented by Robert Huddart, MA, MBBS, MRCP, FRCR
Washington, DC (UroToday.com) Organ preservation in bladder cancer has been a widely debated topic with polarizing views from different centers and researchers worldwide.
Presented by Roland Seiler, PhD
Athens, Greece (UroToday.com) Dr. Roland Seiler presented after Dr. Andrea Necchi, supporting the role of chemotherapy in the neoadjuvant setting of treating muscle invasive bladder cancer
Presented by Kelly Stratton, MD
Athens, Greece (Urotoday.com) Neoadjuvant chemotherapy (NAC) in bladder cancer has been proven to improve overall survival in patients with muscle-invasive bladder cancer
Presented by Joep J. de Jong
Aarhus, Denmark (UroToday.com) Joep J. de Jong from the Erasmus MC Cancer Institute in Rotterdam discussed efforts at developing a genomic classifier to predict clinically
Presented by Thomas Powles, MBBS
Barcelona, Spain (UroToday.com) Atezolizumab has received regulatory approval for patients with locally advanced or metastatic urothelial carcinoma. 
Presented by Enrique Grande, MD
Barcelona, Spain (UroToday.com) First-line metastatic urothelial carcinoma treatment includes cisplatin or carboplatin-based chemotherapy or checkpoint inhibitors, depending on patient eligibility and PD-L1 status.
Presented by Scott T. Tagawa, MD, MS
Barcelona, Spain (UroToday.com) Platinum-based chemotherapy has been the standard first-line therapy for patients with metastatic urothelial cancer (mUC). Historically, response to standard of care second-line chemotherapy regimens is < 15%.
Presented by Christopher J. Hoimes, DO
Barcelona, Spain (UroToday.com) Platinum-based chemotherapy remains the standard of care for patients with locally advanced or metastatic urothelial carcinoma. Despite the use of first-line PD-1/PD-1L inhibitors, 71–76% of patients who are cisplatin-ineligible do not respond to treatment.
Presented by Daniel Peter Petrylak, MD
Chicago, IL (UroToday.com) After cisplatin-based chemotherapy and immune checkpoint inhibitors, there exist a paucity of effective therapies for patients with metastatic urothelial carcinoma (mUC). Enfortumab vedotin (EV) is an antibody-drug
Presented by Arlene O. Siefker-Radtke, MD
Chicago, IL (UroToday.com) FGF receptor 3 (FGFR3) alterations are frequently encountered in urothelial carcinoma, both in non-muscle invasive and muscle-invasive disease.1 For patients with muscle-invasive disease, FGFR3 mutations have been observed in 2% of primary tumors and 9% of metastases.2
Presented by Bradley Alexander McGregor, MD
Chicago, IL (UroToday.com) Combination ipilimumab/nivolumab (ipi/nivo) has seen success in melanoma, MSI high colorectal cancer, and renal cell carcinoma (RCC).1 In urothelial carcinoma, CheckMate 032 evaluated the efficacy of ipi/nivo in an open-label, multicenter, phase I/II
Presented by Xinan Sheng, MD
Antibody-drug conjugates (ADCs) have made significant progress in several tumor types over the past few years, including brentuximab vedotin for Hodgkin lymphoma, TDM1 for breast cancer, and inotuzumab ozogamicin for non-Hodgkin lymphoma.1 Linking a targeted monoclonal 

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