1. Hackethal, Veronica

Article Content

Bladder cancer is a common, growing problem in the U.S. In 2019, the disease ranked fourth among the most common cancers in American men, accounting for 4 percent of cancer deaths in this group. Nationwide, over 80,000 bladder cancer cases were diagnosed that year, taking the lives of almost 18,000 Americans (CA Cancer J Clin 2019; doi: 10.3322/caac.21551).

bladder cancer aware... - Click to enlarge in new windowbladder cancer awareness. bladder cancer awareness

While advances in bladder cancer may not have leapt forward as quickly as breast or prostate cancer, the last decade has seen significant progress.


"It's been a very fruitful decade for bladder cancer. There's been significant advances, from upper tract urothelial to non-muscle invasive bladder cancer to metastatic bladder cancer," Karim Chamie, MD, MSHS, told Oncology Times. Chamie conducts clinical trials in bladder cancer, and serves as Associate Professor of Urology at UCLA Jonsson Comprehensive Cancer Center.


Improved Understanding of Genetics

Over the last several years, researchers have gained improved understanding of the genetics of bladder cancer. That could translate into better screening, treatment, and identification of predictive biomarkers.


For example, one recent study of 586 patients treated for bladder cancer at Memorial Sloan Kettering Cancer Center found that 14 percent (n=80) had pathogenic/likely pathogenic genetic variants. Eighty-three percent of this group (n=66) had mutations in DNA damage repair genes. The most common high or moderate penetrance variants were mutations in BRCA2 (n=9, 1.5%), MSH2 (n=8. 1.4%), BRCA1 (n=8, 1.4%), and CHEK2 (n=6, 1.0%) (J Clin Oncol 2020; doi:10.1200/JCO.19.01395).


"We're starting to see similarities among various cancers that have high genetic mutational burden, like lung cancer, bladder cancer, and melanoma. Those mutations in the DNA will show up as alterations in the proteins, and those proteins can be potentially targeted by the immune system to better treat these cancers," Chamie said.


Treatments for Advanced Bladder Cancer

The advent of immunotherapy has expanded treatment options for patients with advanced and muscle-invasive bladder cancer.


"With the advances of checkpoints inhibitors such as anti-PDL1s and anti-PD1s, we can take the brakes off the immune system to help attack these cells that express foreign and abnormal proteins," Chamie said. "When that happens, we have a much more robust response among tumors with high mutational burden, like bladder cancer."


Since 2016, five checkpoint inhibitors have received FDA approval for the treatment of bladder cancer. These include the PD-1 inhibitors pembrolizumab, nivolumab, durvalumab, avelumab, and the PD-L1 inhibitor atezolizumab. All of these are FDA-approved in the second-line setting. Pembrolizumab is also FDA-approved as first-line in cisplatin-ineligible patients (JAMA 2020; doi: 10.1001/jama.2020.17598).


Additionally, researchers have found that some patients with bladder cancer have mutations in the fibroblast growth factor receptor (FGFR), which has opened treatment options for using targeted therapy in these types of tumors. In April 2019, the pan-FGFR inhibitor erdafitinib became the first targeted therapy to gain FDA approval for the treatment of metastatic bladder cancer. The drug was approved in the second-line setting for locally advanced or metastatic bladder cancer with genetic variants in FGF3 or FGFR2.


Results from a Phase II, open-label study showed an objective response of 40 percent among 99 patients treated with erdafitinib for locally advanced and metastatic bladder with FGFR variants that was nonresponsive to prior therapy (N Engl J Med 2019; doi: 10.1056/NEJMoa1817323). Median overall survival was 13.8 months, which was comparable or slightly better than pembrolizumab (10.3 months)(N Engl J Med 2017;376:1015-1026), atezolizumab (11.1 months)(Lancet 2018;391:748-757), enfortumab vedotin (12.5 months)(J Clin Oncol 2018;36:Suppl:4504-4504), or sacituzumab govitecan (15.5 months) (Ann Oncol 2017;28:Suppl 5:858P-858P), although study populations differed.


Finally, advances in antibody-drug conjugates-which provide therapy targeted to highly expressed tumor proteins to deliver cytotoxic payloads-have provided additional treatment options for patients refractory to both chemotherapy and immunotherapy.


In February 2020, enfortumab vedotin received breakthrough therapy designation as first-line therapy combined with pembrolizumab in the treatment of metastatic or locally advanced urothelial cancer in patients unable to receive cisplatin. Sacituzumab govitecan, another antibody-drug conjugate, has shown promise for treating dual refractory disease, and was granted fast track status by the FDA in April 2020.


"These classes of drugs have really changed the landscape for advanced disease," said Chamie.


Non-Muscle Invasive Bladder Cancer

Researchers are also expanding the arsenal of newer drugs for treating bladder cancer in the metastatic setting to earlier stage disease.


"There's a new push for using at least some of these drugs in the non-invasive setting, such as checkpoint inhibitors for patients who have bladder cancer that is no longer responsive to BCG," said Chamie.


Intravesical bacillus calmette-guerin (BCG) has been used for over 4 decades as standard of care in the treatment of non-invasive bladder cancer. However, about 40 percent of patients fail BCG and need repeat therapy with BCG or other agents (Can Urol Assoc J 2009; doi:10.5489/cuaj.1196). Other patients with high-risk disease may have very little option but cystectomy.


Recent research has shown up-regulation of the PD-1 pathway among patients with BCG-resistant non-muscle invasive bladder cancer, suggesting that pembrolizumab may be beneficial in this setting (J Clin Oncol 2019; doi:10.1200/JCO.2019.37.7_suppl.350)


Following suit, the FDA approved pembrolizumab for the treatment of high-risk non-muscle invasive bladder cancer unresponsive to BCG in January 2020. The approval was based on results from the Phase II, KEYNOTE-057 trial, which found a complete response rate of 41 percent with a median duration of response of 16.2 months among patients with non-muscle invasive BCG-resistant bladder cancer.


Other agents that have shown promise for treating BCG-unresponsive bladder cancer include gene therapy with nadofaragene firadenovec (a replication-deficient recombinant adenovirus that delivers human IFN[alpha]2b genes into the bladder lining), vincinium (EPCAM-targeted Pseudomonas exotoxin A), and N-803 (an IL-15 superagonist)(Rev Urol 2019; 21(4):145-153)


Bladder Cancer in the Age of COVID-19

When the COVID-19 pandemic first hit, cancer screenings were put on hold. During that time, over one-third of Americans may have missed recommended cancer screenings based on their age and risk factors.


One of the most important risk factors for bladder cancer is older age, which may explain recent increases in bladder cancer as baby boomers head into their 60s, 70s, and 80s.


"If you look at the curves of the most common cancers, you'll see that, in men at least, colon cancer and bladder cancer have crossed. Bladder cancer is becoming the third most common cancer in men, behind prostate and lung cancer," Chamie said.


Risk for bladder cancer is also increased among men, smokers, and people exposed to occupational hazards like solvents, hair dyes, and diesel fumes.


It is critically important to get patients back for cancer screening and catch up for missed patient visits, especially among those who are symptomatic or have risk factors, Chamie emphasized.


"My concern is that some of these patients who did not seek cancer screenings during early COVID may now be harboring tumors that are actively growing," he said. "We may end up seeing a spike in some of these cancers over the next couple of years. I just hope that we don't see a spike of more aggressive and invasive cancers."


Veronica Hackethal is a contributing writer.