Editor's note: Platinum-based neoadjuvant chemotherapy was once the standard of care for muscle-invasive bladder cancer (MIBC), and there is an urgent need to develop alternative treatment options for patients who cannot tolerate platinum-based chemotherapy. Padcev is the first proprietary antibody-drug conjugate (ADC) drug, jointly developed by Seattle Genetics and Astellas, targeting Nectin-4, a cell surface protein that is highly expressed in bladder cancer. The drug is composed of enfortumab, a human IgG1 monoclonal antibody targeting connexin-4 (Nectin-4), conjugated to the cytotoxic agent MMAE (monomethyl auristatin E). Padcev (enfortumab vedotin) has been shown to improve the prognosis of patients with early-stage bladder cancer when combined with Keytruda (pembrolizumab). Bernard H. Bochner, Sloan Kettering Professor of Urology, dissects research advances in this area during the 17th Annual Interdisciplinary Congress on Prostate Cancer.
Expert Profile
Bernard H. Bochner
Memorial Sloan Kettering Cancer Center
Can you talk about the need for multidisciplinary treatment for patients with muscle-invasive bladder cancer (MIBC)?
Bernard H. Bochner: Multidisciplinary treatment for bladder cancer includes surgery and pre- or postoperative medications. In the past and present, platinum-based chemotherapy has been the main treatment to improve the overall efficacy of these patients. Based on a series of studies from 1990 to early 2000, it was shown that if patients with bladder cancer received platinum-based chemotherapy before surgery, the overall survival rate of patients was improved by 1/3.
However, about 40% of patients with MIBC in clinical practice cannot tolerate the adverse reactions associated with platinum-based chemotherapy, such as nephrotoxicity, neural hearing loss, or cardiovascular toxicity, and the overuse of platinum-based chemotherapy may be triggered by the fact that it is not possible to accurately determine the effective population of chemotherapy.
In view of the shortcomings in the above realities, there is an urgent need to explore new therapies for the treatment of MIBC patients to meet the clinical needs. In fact, attempts have been made to see if adjuvant chemotherapy provides the same benefit as before surgery. Existing meta-analyses suggest that adjuvant chemotherapy is likely to confer similar benefits to patients as neoadjuvant chemotherapy. However, these studies were small in size and the data were not reliable enough. Therefore, the premise of adjuvant chemotherapy is still that patients must meet the indications for platinum-based therapy.
What are the current problems and challenges in the treatment of MIBC?
Bernard H. Bochner: As a common malignant tumor of the urinary system, the occurrence and development of bladder cancer is closely related to a variety of genetic abnormalities and molecular mechanisms. Numerous studies have shown that there are biological differences in the biological characteristics of tumor cells in bladder cancer patients or between different patients. This heterogeneity opens up new opportunities for immunotherapy.
We know that patients with bladder cancer tend to have a high tumor mutational burden, and in tumors with high mutational burden, emerging therapies such as immune checkpoint inhibitors have shown significant therapeutic efficacy. Similarly, immunotherapy has been explored in the neoadjuvant setting of MIBC, both in patients who are not candidates for platinum-based therapy and in patients who can receive platinum-based therapy, with the expectation that immunotherapy in combination with conventional chemotherapy will improve the post-treatment staging or pathologic complete response rate (pCR). At present, several studies have achieved good results, showing that this combination therapy can significantly increase the proportion of MIBC patients achieving pathologic complete response in neoadjuvant therapy, thus demonstrating the potential value and application prospects of immune checkpoint inhibitors in neoadjuvant therapy for bladder cancer.
What research in the field of bladder cancer is of interest to you?
Bernard H. Bochner: Researchers have had exciting results in their exploration of ADC drugs. In particular, the combination of enfortumab vedotin and the immune checkpoint inhibitor pembrolizumab has been recognized as a new standard of care for patients with metastatic bladder cancer. This advancement means we have the opportunity to introduce these innovative medicines earlier in the disease management process for patients." In the neoadjuvant setting, ongoing studies are making head-to-head comparisons of standard chemotherapy regimens with the combination of enfortumab vedotin and pembrolizumab in order to establish a new standard of care in this treatment.
On the other hand, despite the fact that the patient has received platinum-based chemotherapy, there is still a high-risk lesion in the bladder, i.e., muscle-invasive disease. These patients usually have a poor prognosis and are at high risk of recurrence. We are working to find drugs that can effectively improve the outcomes of these patients.
Currently, there have been three studies of adjuvant immunotherapy in patients at high risk of bladder cancer. Participants were either progressing on prior neoadjuvant therapy with high-risk residual disease, or patients who were not candidates for neoadjuvant therapy but had pathologic results of high-risk platinum-naïve presentation with pT3/pT4 and node-positive disease, who were at high risk of recurrence. There is now good evidence from two studies that the use of the immune checkpoint inhibitors nivolumab (brand name Opdivo) or pembrolizumab as adjuvant therapy can significantly improve disease-free survival (DFS). Although overall survival (OS) data are not yet fully mature, based on DFS data, this treatment model will translate into OS benefits.
What research do you think is currently underway that has the potential to change the future treatment landscape for MIBC?
Bernard H. Bochner: For patients who are about to undergo surgery, preoperative platinum-based chemotherapy remains the standard of care. Currently, researchers are exploring whether new therapies such as enfortumab/pembrolizumab can add a new survival advantage to chemotherapy. For those patients who do not respond to neoadjuvant chemotherapy, research on adjuvant immunotherapy is being explored gradually, and significant efficacy has been observed in some studies. We hope that in the future, these treatments can help more patients with pCR avoid surgery and preserve their bladder.
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