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Dr. Leonard Gomella on bladder cancer advances in 2020


Gomella looks back on the year's top headlines in bladder cancer, from FDA approvals to notable clinical trial results.

In this interview, Leonard G. Gomella, MD, discusses advances in bladder cancer treatment in 2020, including the FDA approvals of pembrolizumab (Keytruda) for BCG-unresponsive, high-risk non-muscle invasive bladder cancer and avelumab (Bavencio) as frontline maintenance therapy in urothelial carcinoma; phase 3 data regarding the novel intravesical gene-mediated therapy nadofaragene firadenovec; quality-of-life data for open vs robot-assisted radical cystectomy; and more. Gomella is the Bernard W. Godwin Jr Professor of Prostate Cancer and chairman of the Department of Urology at Thomas Jefferson University and Hospital in Philadelphia, Pennsylvania.

Please discuss the recent research regarding blue light cystoscopy with Cysview that was presented at the 2020 Society of Urologic Oncology annual meeting.

As part of our 2020 meeting update, we should note that in 2018, the FDA expanded the approval of Cysview for its use in the surveillance of non–muscle-invasive bladder cancer; the original approval was for only the initial diagnosis. There were 2 abstracts regarding blue light cystoscopy with Cysview that were presented at the SUO annual meeting. The first, from Chappidi et al, examined the utility of surveillance blue light cystoscopy for detecting bladder cancer recurrence after BCG, suggesting that if blue light cystoscopy could detect tumor recurrence within 6 months of receiving treatment with BCG, patients could then be offered alternative treatments or enrolled into clinical trials.1 The investigators found that using white light cystoscopy alone incorrectly assessed some complete responses in comparison to much more accurate, measured results when blue light cystoscopy was added to surveillance. This study showed that blue light cystoscopy can help increase the detection of BCG unresponsive disease, and may identify more patients eligible for clinical trials. It should be understood that if you use blue light cystoscopy in clinical trials, it could affect the response rates and comparison across trials as well. But this is an important study that should be considered going forward, when blue light cystoscopy is more fully incorporated into clinical trials.

The second SUO paper, from Williams et al, examined the budget impact of incorporating blue light cystoscopy into the surveillance of non–muscle-invasive bladder cancer.2 The investigators studied was called the “budget impact model.” They used the modeling of 50 newly diagnosed bladder cancer patients and evaluated at the impact of in-office blue light surveillance cystoscopy with Cysview. They found that the use of blue light cystoscopy for surveillance did not substantially increase the cost of the cystoscopy and resulted in the identification of
9 additional recurrences over the course of a 2-year period. It appears that using blue light cystoscopy in the outpatient setting for surveillance may be an optimal and potentially cost effective approach.

Please discuss the significance of the FDA approvals of pembrolizumab (Keytruda) for BCG-unresponsive, high-risk non–muscle-invasive bladder cancer and avelumab (Bavencio) as frontline maintenance therapy in urothelial carcinoma.

These new PD-1 and PD-L1 blocking antibody treatments for bladder cancer fit right in with urology’s approach to immuno oncology and bladder cancer, dating back to the first use of intravesical BCG.

The avelumab approval was for advanced bladder cancer as maintenance therapy for patients who had a good response to platinum-containing chemotherapy.

One of the very interesting recent advances came with the use of pembrolizumab (Keytruda) in the KEYNOTE-057 trial (NCT02625961) that led to that treatment’s approval early in 2020 for non–muscle-invasive bladder cancer. This is a unique approach because for the first time, we have a systemic therapy used for BCG-unresponsive, non–muscle-invasive disease. The KEYNOTE-057 trial demonstrated durable responses with systemically administered pembrolizumab, and in fact, 75% of the patients had a complete response of more than 6 months, and more than half of patients had a complete response of greater than 9 months. Pembrolizumab is now a valuable salvage agent available for BCG refractory non–muscle-invasive bladder cancer.

What are your thoughts on the recently presented final data from the OLYMPUS phase 3 study of mitomycin-containing reverse thermal gel (Jelmyto) for the treatment of upper tract urothelial carcinoma?

This is a landmark study in the management of upper tract urothelial carcinoma. With this treatment, we’re now able to maintain the renal unit in many patients who have low-grade upper tract urothelial carcinoma. The presentation at the SUO annual meeting3 was a validation of the previously published OLYMPUS phase 3 trial4. The SUO presentation confirmed that the findings from OLYMPUS were in fact durable. The use of Jelmyto in patients with low-grade upper tract urothelial carcinoma had a significantly meaningful response in the intention-to-treat population. In patients who were deemed to have unresectable disease, approximately 60% achieved a complete response, with durability of the responses at 12 months.

It should be noted that Jelmyto is a reverse thermal gel; it is in liquid form when injected but assumes a gel form when it is heated in body temperature. Urologists who are going to use this should be aware that there is the potential for ureteral narrowing and stricture formation, but these issues might be mitigated by skipping some of the treatments. There is also some suggestion that steroid therapy is helpful in limiting this issue.

Please discuss results from the phase 3 trial of the novel intravesical gene-mediated therapy nadofaragene firadenovec recently published in the Lancet Oncology5.

This is another exciting advance in BCG-refractory non–muscle-invasive bladder cancer. The Society of Urologic Oncology were leaders in this trial, headed up by Dr. Colin Dinney. Dr. Stephen Boorjian served as first author on this SUO Clinical Trials Consortium study. This was a phase 3 trial of the intravesical agent nadofaragene firadenovec, a gene therapy for bladder cancer. It is a translational research success story that Dr. Dinney was engaged with from early laboratory studies up to a final product. In this phase 3 study, we reported 3-month response rates of approximately 60% in all enrolled patients, and overall, at 12 months, approximately 30% of patients had a durable response, with approximately 25% of patients with carcinoma in situ with or without Ta or T1 tumors and approximately 44% of those with high-grade Ta or T1 tumors only were free of a high-grade recurrence.

Although this was not a head-to-head study of valrubicin (Valstar), which is currently approved in this space, this clearly is an improvement over the reported data in valrubicin for patients with BCG-refractory bladder cancer. Of note, approximately 95% of patients did not progress to muscle-invasive disease during the study, and in a very small group of patients who did, salvage cystectomy was very feasible. This is an intravesical gene therapy based on the anti-tumor effect of interferon alpha for BCG-refractory bladder cancer. When FDA approved, urologists will be primarily involved with its intravesical administration.

Please provide an overview of the antibody-drug conjugates enfortumab vedotin-ejfv (Padcev) and sacituzumab govitecan-hziy (Trodelvy).

This is a new class of oncology agents used in many other solid tumors, including breast cancer. These antibody conjugates take a targeted monoclonal antibody and link it to a lethal chemotherapy payload. The monoclonal antibody connects the molecule to the cancer cell, and the chemotherapy payload is co-localized with the tumor and kills the tumor. Enfortumab vedotin (Padcev) was approved in 2020 for advanced bladder cancer and is also now being tested in earlier stages of disease. This particular antibody drug conjugate targets nectin-4, which is a transmembrane adhesion molecule found to be highly expressed on over 97% of urothelial carcinoma samples. The EV-201 clinical trial that led to the approval of this agent showed a very high response rate with the treatment in patients who had failed prior platinum and check-point therapy.

Also within this family of drugs is sacituzumab govitecan, known as Trodelvy. This agent has been used in metastatic urothelial carcinoma and is directed against the epithelial cell surface marker Trop-2 attached to a chemotherapy payload of an irinotecan derivative. In the Trophy-U-01 study, progression-free survival in patients who had failed prior treatments was approximately 5.4 months. This antibody drug conjugate is being studied in advanced urothelial carcinoma in the TROPiCS-04 phase 3 confirmatory trial (NCT04527991). Currently, these antibody conjugate agents are primarily targeting advanced refractory urothelial carcinoma, but I imagine other trials moving these earlier in the course of disease will be coming shortly.

Quality-of-life data from the RAZOR trial (NCT01157676) of open versus robot-assisted radical cystectomy were published in 2020 in the Journal of Urology6. What are your thoughts on this trial and its significance?

The RAZOR trial was a randomized, 24-month progression-free survival trial comparing robot-assisted radical cystectomy with open radical cystectomy. This trial was initiated because of concerns surrounding the high cost of robotic technology and the risk of cancer dissemination in robotic cystectomy. Although we still don’t have the definitive data in this area, this trial initially demonstrated non inferiority for either treatment approach with no significant difference in 3-month complications.

The issue with this trial that urologists really need to be familiar with is that patients who underwent robot-assisted radical cystectomy received extracorporeal urinary reconstruction. Although the field is moving more toward intracorporeal urinary tract reconstruction, this was not a component of the RAZOR trial. Although the extent to which extracorporeal urinary diversion diluted the advantage of robotic cystectomy remains to be seen, it is clear that there is lower blood loss and transfusion with the robotic cystectomy compared with the open approach. The issue of extracorporeal urinary diversion is something we have to consider when we look at the RAZOR trial, but right now it looks like the robotic approach and open approaches are fairly equivalent. In addition, health quality of life in the months following the two radical cystectomy techniques appear to be similar, but again, the caveat is that the RAZOR trial did use extracorporeal urinary diversion and a lot of the short-term complications can be a result of this. We need more research in this area, but at least from a cancer control standpoint, the finding that the robotic approach is equivalent to open cystectomy is reassuring.


1. Chappidi M, Yang H, Meng M, et al. Utility of surveillance blue light cystoscopy for bladder cancer after BCG: implications for clinical trial recruitment and study analysis. Paper presented at: 2020 Society of Urologic Oncology Annual Meeting. December 3-5, 2020; virtual. Accessed January 4, 2021. http://bit.ly/37CViCe

2. Williams SB, Gavaghan MG, Fernandez A. Budget impact of blue light cystoscopy in the surveillance setting. Paper presented at: 2020 Society of Urologic Oncology Annual Meeting. December 3-5, 2020; virtual. Accessed January 4, 2021. https://bit.ly/3odeHji

3. Lerner S, Matin S, Kleinmann N, et al. Durability of response to chemoablative treatment of low-grade upper tract urothelial carcinoma with a mitomycin-containing reverse thermal hydrogel: Final results of the OLYMPUS trial. Paper presented at: 2020 Society of Urologic Oncology Annual Meeting. December 3-5, 2020; virtual. Accessed January 4, 2021. https://bit.ly/3mDFUd3

4. Kleinmann N, Matin SF, Pierorazio PM, et al. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial. Lancet Oncol. 2020;21(6):776-785. doi:10.1016/S1470-2045(20)30147-9

5. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021; 22(1):107-117. doi:10.1016/S1470-2045(20)30540-4

6. Becerra MF, Venkatramani V, Reis IM, et al. Health related quality of life of patients with bladder cancer in the RAZOR trial: a multi-institutional randomized trial comparing robot versus open radical cystectomy. J Urol. 2020;204(3):450-459. doi:10.1097/JU.0000000000001029

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