Bladder cancer research enters a renaissance period

The high prevalence of disease translates to more than 700,000 individuals in the United States with bladder cancer, and the majority of those cases are noninvasive. Furthermore, bladder cancer care has been tagged with the dubious distinction of being the most expensive cancer to treat over a patient’s lifetime. Until recently, few breakthroughs were reported in the past several decades, and consequently there had been not been much improvement in treatment-related outcomes.

Given the magnitude and burden of disease on the health care system, the problem begs for solutions in the form of enhanced detection and more effective treatment for both early- and late-stage disease. However, one of the most important reasons for the lack of advancements in treatment has been disproportionately low funding for research in bladder cancer. This underfunding has resulted in fewer quality studies and novel developments and even fewer new drug approvals. That is, until recently, when patients, clinicians and advocates voices finally began to be heard. The spotlight has fallen squarely on the treatment of patients with BCG-unresponsive NMIBC.

Regulatory guidance by the FDA has led to more standardized definitions of patients who no longer benefit from BCG therapy, as well as clearer definitions of meaningful end points in trial design. The guidance has set the stage for some of the most exciting breakthroughs for high-risk NMIBC in decades.

Intravesical BCG remains the treatment of choice and the most effective treatment for patients with high-grade NMIBC. Unfortunately, 30% to 40% of patients ultimately will fail to respond to BCG therapy. Options for those patients include second-line or salvage therapies and radical cystectomy. Cystectomy may not be an option for older patients or those with multiple comorbidities, and it may be unacceptable to fit patients due to the potential morbidity and negative impact on their quality of life. Aside from cystectomy, intravesical chemotherapy options include gemcitabine, mitomycin C(MMC), paclitaxel, or valrubicin. Combination chemotherapy and enhanced delivery of chemotherapy also are being actively investigated.

Some of the pivotal breakthrough studies include the use of pembrolizumab (Keytruda), a PD-1 immune checkpoint inhibitor, which received FDA approval in 2020 after benefit was demonstrated in patients with BCG-unresponsive CIS. There is also great anticipation over some new agents, including vicinium, a novel fusion protein that has an antibody fragment targeting EpCAM-fused cells to a Pseudomonas toxin that has been trialed in patients with CIS who are BCG-unresponsive. Additionally, the Society of Urologic Oncology Clinical Trials Consortium recently reported impressive results using gene therapy (rAd-IFN-α/Syn3; nadofaragene firadenovec) in BCG-unresponsive CIS. Both of these novel intravesical therapies have resulted in complete response rates of greater than 40% at 12 months in patients with CIS. These and other agents used alone or in combination will revolutionize the treatment of patients who until recently had few bladder-preserving options and were often relegated to radical cystectomy. So, after a long period of stagnation and inertia, the bladder cancer space is alive and full of innovation and activation.