Insights Into Urothelial Carcinoma Therapies From the 2021 Genitourinary Cancers Symposium

A number of presentations at this year’s meeting focused on urothelial carcinoma. Which abstracts were the most clinically interesting with regard to promising new research or new insights into the standard of care?

The 2 studies describing the outcomes of EV-301¹ (ClinicalTrials.gov Identifier: NCT03474107) and EV-201 Cohort 2² (ClinicalTrials.gov Identifier: NCT03219333) were particularly important at this year’s symposium because enfortumab vedotin is increasingly being studied and incorporated into the care of patients who, historically, have had limited therapeutic options.
 
Additionally, updated analysis from the POUT trial³ (ClinicalTrials.gov Identifier: NCT01993979) demonstrated that improved disease-free survival with perioperative chemotherapy was maintained with longer follow-up in patients with upper-tract urothelial carcinoma.
 
Last, several presentations, discussed below, aimed to optimize multimodal management of patients with localized bladder urothelial carcinoma.

Results of a study⁴ of patients with metastatic urothelial carcinoma found that, when treated with local radiotherapy plus chemotherapy, these patients experienced improved overall survival compared with those receiving chemotherapy alone. The researchers, in their conclusion, indicated that a prospective trial is warranted. What should future research on this topic look like? Should these results hold true, how might they facilitate the treatment of patients with metastatic urothelial carcinoma in the future?

We have historically thought of metastatic cancer as a condition that can be treated only with systemic therapy, given that there are generally multiple areas of involvement throughout the body. Therefore, it is highly likely that microscopic cancer cells are present elsewhere.
 
However, randomized studies in multiple cancers,⁵ including of the prostate⁶ and lung,^7,8 suggest that local therapy might improve survival in some patients with limited metastatic cancer. In bladder cancer, there are no randomized trials completed that inform the role of local radiotherapy.
 
In an analysis of data from the National Cancer Database, the authors selected patients with metastatic urothelial cancer who received chemotherapy either alone or with local radiotherapy and found increased survival in the group that received combination therapy.⁴
 
Although these results are interesting, they are prone to selection bias, and it is possible that there are variables other than the treatment that resulted in the difference in survival. Randomized trials are needed to confirm that there is a benefit before we pursue treatment of the primary tumor in patients with metastatic cancer, outside of low doses to treat symptoms. I would design a study that looks at overall survival as the primary endpoint but also looks at differences in morbidity related to the primary tumor, such as hospitalization and the need for palliative treatment.

A phase 2 study⁹ provided data on a risk-adapted surveillance approach for specific groups of patients with muscle-invasive bladder cancer (ClinicalTrials.gov Identifier: NCT02710734). How can evaluation of specific genetic alterations inform future biomarker-based studies? Furthermore, how might these studies affect outcomes?

This was a prospective, phase 2, nonrandomized trial testing the hypothesis that patients who have specific genetic alterations and a complete response to neoadjuvant chemotherapy can safely avoid cystectomy and undergo active surveillance. These interim results show a low risk of metastatic disease overall, particularly for patients who had candidate genetic alterations.
 
These are encouraging data that are a sign of the future of muscle-invasive bladder cancer therapy, which, I believe, will utilize molecular characteristics and response to neoadjuvant chemotherapy to help select the optimal form of local therapy. However, this study is hypothesis-generating; local therapy using cystectomy or trimodality therapy is still the standard of care, regardless of genetic alterations and response to chemotherapy and therefore should not be omitted outside of a clinical trial.
 
There are ongoing trials evaluating the use of genetic alterations and response to neoadjuvant chemotherapy to select patients for specific approaches using local therapy. These trials will inform us whether these are safe and effective options for patients.
 
There are biomarkers out there, such as DNA damage response markers and the MRE11 gene that repairs double-strand breaks, which might give us an idea of which patients can have a favorable outcome. These are being studied actively and have not yet been incorporated into the standard of care. The trouble is, we don’t have clear data that show that making decisions based on these biomarkers helps patients. It is difficult for us to make the argument that they improve quality of life, effectiveness of treatment, or survival without having studies that demonstrate this. Because this study was not randomized, you can’t really make definitive conclusions. But, these early data are encouraging. 

The DUART clinical trial¹⁰ evaluated the safety and efficacy of combination durvalumab plus radiation therapy followed by adjuvant durvalumab (ClinicalTrials.gov Identifier: NCT02891161). The disease control rate was high (92%) following this combination treatment, and results showed that it appears to be safe and tolerable. Which outcome measures are particularly compelling when evaluating how this research might be applied to patient care in the future?

This study highlights 2 emerging themes in urothelial bladder cancer management. First, based on studies in the metastatic setting, trials are investigating the combination of immune checkpoint inhibition and radiation-based local therapy to the primary tumor in localized bladder cancer. Second, there are few studies that describe the optimal way to treat patients with node-positive, nonmetastatic bladder cancer, but this group is increasingly acknowledged as a group with unique considerations about the best way to integrate local and systemic therapy.
 
The encouraging complete response and toxicity profile of the combination of immunotherapy and radiation in this study¹⁰ are promising for patients with node-negative and node-positive disease who were part of the study. There are multiple trials that are ongoing that are expanding on the findings of this study, including the INTACT trial (ClinicalTrials.gov Identifier: NCT03775265), conducted through the SWOG Cancer Research Network and NRG Oncology,¹¹ which compares trimodality therapy with or without concurrent and adjuvant atezolizumab in patients with node-negative bladder cancer patients, and the INSPIRE trial (ClinicalTrials.gov Identifier: NCT04216290), through the ECOG-ACRIN Research Group and NRG Oncology,¹² which compares trimodality therapy with or without concurrent and adjuvant durvalumab in patients with node-positive disease. These studies will help establish the optimal treatment approach in these patient populations.

A study¹³ presented at the meeting used a multi-institutional database to examine the socioenvironmental conditions associated with urothelial carcinoma clusters. One finding was that people who live in geospatial hotspots for this disease are more likely to be non-White and low income. How does research like this influence decision-making in regard to identifying high-risk populations and improving screening, diagnosis, and treatment?

Scientific advances are critical to advancing the management of urothelial carcinoma. Studies such as this one make us take a step back and remember that many determinants outside of genetic changes in the tumor, diagnostic test findings, and prior medical conditions might have a greater impact on a person’s risk of getting cancer and on outcomes with cancer. It is critical for us to do further studies like this to validate the findings in other geographic areas and determine the impact of these differences on long-term outcomes, for the individual and at a population level.
 
Making sure you really understand a patient’s needs, both medically and socially, to help them to get their diagnostic tests and get through treatment is, I think, critical. All patients have their particular needs that, frequently, are based on their backgrounds, but they sometimes are based on other things that require you to treat each patient as an individual. There are so many genetic things that we find, and imaging advances, that can help us advance the care of patients with urothelial carcinoma, but these are simple things that are frequently outside what medical technology can detect, because they are big-picture problems that patients have.