From February 11 to February 13, 2021, oncologists from around the world came together to review the latest research and innovations in the diagnosis, treatment, and study of genitourinary malignancies presented at the American Society of Clinical Oncology (ASCO®) 2021 Genitourinary Cancers Symposium. More than 100 abstracts on the topic of urothelial carcinoma were presented at this virtual meeting, along with keynote lectures and panel discussions. Abhishek Solanki, MD, radiation oncologist at Loyola University Medical Center and associate professor, Director of Clinical Research, and Quality Medical Director at Loyola University Stritch School of Medicine, in Chicago, spoke with Oncology Nurse Advisor to share his takeaways from this important meeting.
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.
- Radiotherapy plus chemotherapy might improve survival in some patients with limited metastatic cancer. Results are interesting but prone to selection bias and require randomized controlled trials to validate.
- Genetic alternations, biomarkers, and molecular characteristics might someday be used to guide treatment for urothelial carcinoma. However, ongoing trials evaluating these considerations and the response to neoadjuvant chemotherapy must be completed before shifts in treatment can be made.
- Combination radiation therapy plus durvalumab for urothelial carcinoma demonstrated encouraging complete response and toxicity profiles, and ongoing trials — such as INTACT and INSPIRE — are further evaluating the optimal treatment approach in patients with node-positive and node-negative disease.
The Q&A was edited for clarity and length.
The opinions expressed here represent the views of the author and do not reflect the policies of the Veterans Health Administration or the US Department of Veterans Affairs, unless otherwise indicated.
- Powles T, Rosenberg JE, Sonpavde G, et al. Primary results of EV-301: a phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2021;39(6 Suppl). Abstract 393. doi:10.1200/JCO.2021.39.6_suppl.393
- Balar AV, McGregor BA, Rosenberg JE, et al. EV-201 cohort 2: enfortumab vedotin is cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. J Clin Oncol. 2021;39(6 Suppl). Abstract 394. doi:10.1200/JCO.1200/JCO.2021.39.6_suppl.394
- Birtle AJ, Chester JD, Jones RJ, et al. Updated outcomes of POUT: a phase III randomized trial of peri-operative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC). J Clin Oncol. 2021;39(6 Suppl). Abstract 455. doi:10.1200/JCO.2021.39.6_suppl.455
- Fischer-Valuck BW, Patel SA, Gay HA, et al. Association of survival and local radiotherapy to the bladder versus chemotherapy alone for patients with metastatic urothelial carcinoma (mUC). J Clin Oncol. 2021;39(6 Suppl). Abstract 413. doi:10.1200/JCO.2021.39.6_suppl.413
- Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial. J Clin Oncol. 2020;38(25):2830-2838. doi:10.1200/JCO.20.00818
- Parker CC, James ND, Brawley CD, et al; Systematic Therapy for Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) Investigators. Radiotherapy to the primary tumor for newly diagnosed, metastatic prostate cancer (STAMPEDE): A randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366. doi:10.1016/S0140-6736(18)32486-3
- Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomized controlled trial. Lancet. 2015;385(9962):36-42. doi:10.1016/S0140-6736(14)61085-0
- Gomez DR, Tang C, Zhang J, et al. Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: long-term results of a multi-institutional, phase II randomized study. J Clin Oncol. 2019;37(18):1558-1565.
- Geynisman DM, Abbosh P, Ross EA, et al. A phase II trial of risk enabled therapy after initiating neoadjuvant chemotherapy for bladder cancer (RETAIN BLADDER): interim analysis. J Clin Oncol. 2021;39(6 Suppl). Abstract 397. doi:10.1200/JCO.2021.39.6_suppl.397
- Joshi M, Kaag M, Tuanquin L, et al. Phase II clinical study of concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with localized urothelial cancer of bladder: results for primary analyses and survival. BTCRC-GU15-023. J Clin Oncol. 2021;39(6 Suppl). Abstract 398. doi:10.1200/JCO.2021.39.6_suppl.398
- NRG Oncology. SWOG/NRG Joint Study: phase III randomized trial of concurrent chemoradiotherapy with or without atezolizumab in localized muscle invasive bladder cancer. Accessed March 8, 2021. www.nrgoncology.org/Clinical-Trials/Protocol/s1806?filter=s1806
- NRG Oncology. ECOG-ACRIN/NRG Joint Study: a study of chemotherapy and radiation therapy compared to chemotherapy and radiation therapy plus MEDI4736 (durvalumab) immunotherapy for bladder cancer which has spread to lymph nodes, the INSPIRE study. Accessed March 8, 2021. https://www.nrgoncology.org/Clinical-Trials/Protocol/ea8185?filter=ea8185
- Edwards DC, Yankelevich GR, Dreher PC, et al. Socio-environmental conditions associated with geospatial clusters of urothelial carcinoma: a multi-institutional analysis. J Clin Oncol. 2021;39(6 Suppl 6). Abstract 392. doi:10.1200/JCO.2021.39-6_suppl.392
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Reviewed March 2021