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Bladder Cancer: FAQs
Current Guideline Management of Patients With Bladder Cancer: Highlights and Answers to Your Frequently Asked Questions

Released: January 22, 2025

Expiration: January 21, 2026

Fed Ghali
Fed Ghali, MD
Tian Zhang
Tian Zhang, MD, MHS
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Key Takeaways
  • Treatment options are expanding for all stages of bladder cancer. These include novel intravesical vaccine strategies for non-muscle-invasive bladder cancer (NMIBC) and combination antibody–drug conjugates with immunotherapy (eg, enfortumab vedotin) for metastatic bladder cancer.
  • In patients with Bacillus Calmette-Guerin–unresponsive NMIBC who refuse or are not candidates for radical cystectomy, clinical trials remain a very important option.
  • As treatment paradigms change in bladder cancer, ongoing trials are being completed to move effective strategies for metastatic disease to the localized/perioperative settings

The management of non-muscle-invasive bladder cancer (NMIBC) and metastatic bladder cancer (mBC) is rapidly evolving. Recent guideline updates and emerging data provide new information that healthcare professionals (HCPs) need to incorporate into their practice to optimize the care of patients with bladder cancer while considering patient preferences and goals. This commentary highlights topics and questions posed by a live audience of HCPs during a symposium on bladder cancer held at the Society of Urologic Oncology meeting, in Dallas, Texas, in December 2024.

Non-Muscle-Invasive Bladder Cancer

Expert Case Guidance: A Patient Case

A 67-year-old man presents 1 year after transurethral resection of a bladder tumor with high-grade Ta/T1 M0N0, NMIBC; he had Bacillus Calmette-Guerin (BCG) (6 doses of induction BCG and 3 doses of maintenance BCG). What would you recommend as the next treatment? Any comments about his prognosis and/or the potential for recurrence?

Fed Ghali, MD:
This patient presents with BCG-refractory NMIBC, meeting the criteria that were established by the FDA and widely adopted in clinical trials as well as National Comprehensive Cancer Network (NCCN) practice guidelines. Although it is challenging to pin down a precise prognosis because of the wide range of reported figures across retrospective publications, his prognosis would be expected to be poor compared with BCG-naive NMIBC—this patient has the potential for higher upstaging at the time of cystectomy, a higher rate of lymph node involvement, and worse overall survival.

Various treatment options can be considered but it should be noted that, by a wide margin, radical cystectomy offers the best disease control for patients with BCG-refractory NMIBC such as our patient case. For a 67-year-old patient who is otherwise fit, radical cystectomy would be the gold-standard treatment modality. In patients who refuse radical cystectomy or are unfit, clinical trials should be considered because this remains an area of active investigation.

At this time, we have no head-to-head comparisons of the various agents available in this disease setting, which include intravesical chemotherapies, nadofaragene firadenovec (Adstiladrin), BCG plus nogapendekin alfa inbakicept (NAI), intravenous pembrolizumab, and others. Indeed, many of the studies supporting these agents are single-arm trials without a comparator arm. In my practice, we favor sequential intravesical gemcitabine and docetaxel as an initial treatment in this patient group. Following that, several of the above agents are also options, with nadofaragene firadenovec remaining my go-to therapy.

What are your thoughts on the potential for novel options in patients with high-risk, BCG-unresponsive NMIBC?

Fed Ghali, MD:
In patients with BCG-unresponsive disease, there is a tremendous need for basic science and clinical research for novel treatment options. We can do better and our patients with BCG-refractory NMIBC would benefit from trials with proper control arms and study of combination therapy, and so on.

We have several agents for BCG-unresponsive carcinoma in situ including for papillary disease (gemcitabine + docetaxel; nadofaragene firadenovec; NAI + BCG, and pembrolizumab) and for Ta/T1 disease (gemcitabine + docetaxel; hyperthermic mitomycin C; single-agent chemotherapy [eg, gemcitabine, docetaxel, mitomycin C, and valrubicin]; NAI + BCG; and pembrolizumab). We also have some interesting ongoing studies such as the phase II SunRISe-1 trial exploring intravesical monotherapy with TAR-200, a novel investigational targeted release system that enables extended release of gemcitabine into the bladder. The SunRISe-1 trial has shown an overall complete response rate of 83.5%. Other phase II studies in this setting are exploring the use of erdafitinib, an agent we see used in the more-advanced setting, but in this case for patients with recurrent FGFR3-altered NMIBC, and the phase II ABLE-22 study evaluating nadofaragene firadenovec either alone or in combination with intravesical chemotherapy or systemic pembrolizumab. The hope with these ongoing trials is that in addition to seeing some signal of efficacy we will see better outcomes for these patients.

I would also highlight that for patients who insist on or are only candidates for bladder-sparing therapy and have met the definition of being BCG unresponsive, if they will not have radical cystectomy, a clinical trial really should be considered. This is a group of patients that needs to be studied further.

Metastatic Bladder Cancer

Any current studies for radical cystectomy of mBC that has had a good response to pembrolizumab plus enfortumab vedotin (EV)?Fed Ghali, MD:

This is a fantastic question. Unfortunately, I am not aware of any studies at this time exploring this question. Several retrospective series in the cisplatin era of mBC have suggested that there may be a role in consolidative surgery for those with good response, yet this remains hypothesis generating.

In the pembrolizumab-plus-EV era, we are grateful to see many more patients who have robust clinical responses, and this question will continue to be important. In our practice, we are currently preparing a trial that we hope will explore this question, but clinical evidence is pending.

Are there contraindications for the use of immunotherapy in patients with bladder cancer?

Tian Zhang, MD, MHS:
Risks and potential adverse effects of immune checkpoint inhibitors should be discussed when patients are considering immunotherapy treatments (including EV-pembrolizumab). Relative contraindications include clinically significant autoimmune disease, which may worsen during immunotherapy treatments, particularly those that require otherwise-immunosuppressive medications (eg, methotrexate, cyclosporine, and mycophenolate mofetil). Patients should discuss their medical history and ongoing medications with their oncologists when considering immunotherapy for bladder cancer.

In patients with unresectable/metastatic urothelial cancer with residual lesions, there is the phase II BLAD-RAD01 study exploring radiotherapy as consolidative treatment after first-line therapy, and the phase II/III Duravelo-2 study, which is investigating zelenectide pevedotin (BT8009) with or without pembrolizumab vs chemotherapy with or without avelumab maintenance therapy as second-line treatment in patients with recurrence more than 12 months after previous mitomycin C/epirubicin, intravesical chemotherapy, or immune checkpoint inhibitor therapy. There are also many experimental therapeutics currently in the clinical development pipeline to improve on immunotherapy outcomes. Further research needs to be completed after progression with EV-pembrolizumab to address mechanisms of resistance.

What challenges have you encountered when trying to fit NCCN guidelines to individualized treatment approaches for patients with bladder cancer?

Fed Ghali, MD:
As with all guidelines, the recommendations within NCCN guidelines are meant to serve as a framework for care and not to an algorithmic method for treating all patients. Those of us lucky enough to care for patients clinically know that the real world can rarely be fit into neat universal categories.

Tian Zhang, MD, MHS:
An issue practitioners may encounter is that NCCN recommendations may not be applicable/appropriate worldwide. For example, if EV-pembrolizumab is not available, as in some of the European countries where EV is not yet available, HCPs may still be offering cisplatin-gemcitabine with nivolumab as a triplet therapy or cisplatin-based or carboplatin-based chemotherapy followed by maintenance avelumab.

Your Thoughts?
How do you plan to incorporate the recent updates to NCCN guidelines in the care of patients with bladder cancer?

Watch the on-demand webcast from the live event and download the slides for NMIBC or muscle-invasive bladder cancer/mBC to further your learning on this topic. Join the discussion by leaving a comment!

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