Bladder cancer treatments are based on the type of bladder cancer and the stage of the disease. The most common type of bladder cancer is transitional cell carcinoma, also called urothelial carcinoma, which begins in cells in the innermost tissue layer of the bladder. There are other types of bladder cancers such as squamous cell carcinoma, small cell carcinoma, and adenocarcinoma, among others.

The mainstays of bladder cancer treatment are surgery, radiation therapy, chemotherapy, and immunotherapy, depending on the stage. Scientists continue to study novel treatments and drugs, along with new combinations of existing treatments. 

Chemotherapy Combo Effective for Common Bladder Cancer

Gemcitabine and docetaxel combo proves a good alternative to BCG for high-risk non-muscle-invasive bladder cancer.

Non-muscle-invasive bladder cancer is cancer that has grown through the lining of the bladder but hasn’t yet invaded the muscle layer of the bladder. Treatment for this cancer is usually to remove the tumor by scraping it from the bladder wall.

Some patients may receive additional treatment after surgery with an immune-based therapy called bacillus Calmette-Guérin (BCG), or with chemotherapy drugs such as mitomycin C (Jelmyto) or gemcitabine put directly into the bladder to reduce the risk that the cancer will recur. 

Immunotherapy

Immunotherapy is treatment that helps the body’s immune system fight cancer more effectively. Certain immunotherapy drugs, called immune checkpoint inhibitors, are approved to treat some patients with locally advanced or metastatic bladder cancer. 

Patients whose bladder cancers respond to immune checkpoint inhibitors tend to maintain those responses for long periods. Ongoing clinical trials will help researchers learn whether these extended responses help patients live longer. 

However, only a small number of patients respond to immune checkpoint inhibitors. Scientists are trying to develop biomarkers that could help doctors identify which patients with bladder cancer are likely to respond to these drugs. For example, a checkpoint protein called PD-L1 has been studied as a biomarker for response to treatment with immune checkpoint inhibitors.

Scientists have now begun to test immune checkpoint inhibitors in earlier stages of bladder cancer and in combination with other treatments, such as chemotherapy:

• The NCI-sponsored AMBASSADOR trial is comparing the immune checkpoint inhibitor pembrolizumab (Keytruda) with observation. This is being done in patients with bladder cancer that invades the muscle layer of the bladder wall (localized muscle-invasive disease) or that has spread to nearby lymph nodes (locally advanced disease) and has been surgically removed. The trial will see if pembrolizumab improves overall survival or disease-free survival.
• In 2021, the Food and Drug Administration (FDA) approved the immune checkpoint inhibitor nivolumab (Opdivo) as an additional (adjuvant) treatment of patients with urothelial carcinoma who are at high risk of recurrence after undergoing surgery for the disease. This was the first FDA approval for the adjuvant treatment of patients with this type of cancer. In 2023, updated trial results showed that people who received nivolumab had a median disease-free survival of 22 months, compared with about 11 months for those who received a placebo. 
• In 2020, the FDA approved the immune checkpoint inhibitor avelumab (Bavencio) for people with advanced bladder cancer that has shrunk or stopped growing after receiving platinum-based chemotherapy. The approval is for the use of avelumab as maintenance therapy for advanced disease that has not spread (locally advanced) or disease that has spread beyond the bladder (metastatic).

Targeted Therapy 

Targeted therapy treats cancer by targeting proteins that control how cancer cells grow, divide, and spread. In 2019, erdafitinib (Balversa) became the first targeted therapy to be approved by FDA to treat patients with locally advanced or metastatic urothelial carcinoma. This drug can be used to treat some patients whose cancers have certain alterations in the FGFR2 gene or FGFR3 gene. Only about 20% of bladder cancers harbor an FGFR gene alteration.

An ongoing phase 3 study is comparing erdafitinib with standard chemotherapy and with pembrolizumab in patients with advanced bladder cancer whose tumors have an FGFR gene alteration. This study could help researchers learn whether patients with FGFR-altered bladder cancer benefit more from erdafitinib or an immune checkpoint inhibitor versus chemotherapy. 

Combination Therapy

Researchers are testing many combinations of therapies for bladder cancer, either by combining several immunotherapy drugs or by combining an immunotherapy drug with another type of treatment.

• An early-phase clinical trial for patients with muscle-invasive bladder cancer is studying the combination of durvalumab (Imfinzi) with tremelimumab before surgery. Giving these drugs together before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.
• A phase 3 trial is testing chemotherapy and radiation therapy with or without the immune checkpoint inhibitor atezolizumab in patients with localized muscle-invasive bladder cancer. Combining chemotherapy with radiation therapy may kill more tumor cells than chemotherapy alone. Adding atezolizumab (Tecentriq) to radiation therapy and chemotherapy may further improve outcomes in patients with localized muscle-invasive bladder cancer.
• A study is testing the safety and efficacy of the combination of the immune checkpoint inhibitor durvalumab and the drug oportuzumab monatox (Vicinium) for treating bladder cancer that has not spread to the muscle in the bladder. Non-muscle-invasive bladder cancer is early-stage cancer, but it usually comes back after treatment. The two drugs may act together to help the immune system find and destroy cancer cells.
• One study is testing the experimental drug enfortumab vedotin alone and with different combinations of treatments, including pembrolizumab, for treating bladder cancer. Some parts of the study will focus on patients with locally-advanced and metastatic urothelial cancer, whereas other parts will focus on patients with muscle-invasive bladder cancer. 

Antibody Drug Conjugates

A monoclonal antibody is a type of protein made in the lab that can bind to certain targets in the body, such as those on cancer cells. An antibody drug conjugate is a substance made up of a monoclonal antibody that is chemically linked to a drug. It has the ability to kill cancer cells without harming other cells. 

The antibody drug conjugate enfortumab vedotin-ejfv (Padcev) has been approved to treat advanced/metastatic bladder cancer. It showed positive results in patients who had previously been treated with chemotherapy and an immune checkpoint inhibitor. Researchers continue to study this drug to see whether it can be used to treat bladder cancer earlier in the disease process and to evaluate it in combination with immunotherapy and/or chemotherapy.

The combination of enfortumab vedotin-ejfv and pembrolizumab is also being evaluated as a treatment for patients with previously untreated advanced bladder cancer. 

Gene Therapy

In 2022, the FDA approved a type of gene therapy called nadofaragene firadenovec-vncg (Adstiladrin) for some adults with a certain type of high-risk, non-muscle-invasive bladder cancer. By helping the immune system recognize and kill cancer cells, this treatment can benefit patients whose tumors don’t respond to the commonly used BCG therapy. 

Clinical Trials for Bladder Cancer

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Trials are available for bladder cancer treatment.

UPDATE: On December 15, 2023, the Food and Drug Administration (FDA) approved enfortumab vedotin (Padcev) in combination with pembrolizumab (Keytruda) for people with bladder cancer that has spread to other parts of the body or cannot be removed surgically.

The approval was based on the results of the EV-302 trial, which showed that the enfortumab-pembrolizumab combination doubled how long people with advanced bladder cancer survived compared with people treated with standard chemotherapy. Details on the trial results are discussed in the story below.

For the first time in decades, people with advanced bladder cancer have more effective treatment options, according to results of two large clinical trials. One treatment—the combination of enfortumab vedotin (Padcev) and the immunotherapy drug pembrolizumab (Keytruda)—proved to be particularly powerful.

November 30, 2023, by Shana Spindler

The findings mark a pivotal moment following years of little progress, according to several leading bladder cancer experts. Both studies included people whose bladder cancer had spread to other parts of the body or could not be removed by surgery, and both studies involved immunotherapy drugs.

In the first trial, known as CheckMate-901, patients received standard chemotherapy for advanced bladder cancer, either alone or in combination with the immunotherapy drug nivolumab (Opdivo), as initial treatment for advanced bladder cancer.

The second trial, called EV-302, compared the enfortumab–pembrolizumab combination with a standard chemotherapy regimen. Enfortumab is a type of treatment known as an antibody–drug conjugate.

In both trials, people treated with the new combination treatment lived longer than those who received chemotherapy—a never-before-seen improvement over the standard initial treatments for advanced bladder cancer.

Researchers reported the results of both trials on October 22 at the European Society for Medical Oncology (ESMO) annual meeting in Madrid.

It was the improvement in survival in people treated with the enfortumab and pembrolizumab combo—a doubling compared with chemotherapy—that received the greatest praise, even drawing a standing ovation during the presentation of the results at the ESMO meeting.

Discovering two treatments that improve survival for people with advanced bladder cancer “is monumental in our field,” said Andrea Apolo, M.D., of NCI’s Genitourinary Malignancies Branch.

After many failed attempts to improve upon chemotherapy, Dr. Apolo said, with the results of both trials “the future looks bright for our patients.”

Long-awaited improvements in bladder cancer treatment

Despite the advent of many new immunotherapies and targeted drugs for cancer in the last decade, chemotherapy regimens that include platinum drugs (e.g., cisplatin) have been the standard initial treatment for people diagnosed with advanced bladder cancer for decades. However, most patients experience a worsening of their cancer during or soon after treatment.

Recently, evidence has begun to suggest that immunotherapy may have a role in treating this disease. In 2020, for example, researchers reported that giving avelumab (Bavencio) right after chemotherapy improved overall survival and has become the new standard treatment for bladder cancer.

And a few years before that, the Food and Drug Administration (FDA) granted accelerated approval to nivolumab for treating advanced bladder cancer that had worsened following treatment with chemotherapy.

But, despite multiple efforts to improve the initial treatments for advanced disease, no treatments tested in previous clinical trials have increased how long patients lived compared with chemotherapy alone, said Michiel S. van der Heijden, M.D., Ph.D., of the Netherlands Cancer Institute, who led CheckMate-901 and participated as an investigator in the EV-302 trial.

In those previous trials, researchers compared an array of immunotherapy combinations with several different drugs with chemotherapy alone, but none proved to be more effective.

Now, with the EV-302 and CheckMate-901 trials, researchers used some of the lessons learned from those earlier studies in the hope of finding the right drug combination to help their patients live longer.

Antibody combination doubles survival without chemotherapy

“It’s a big day for us in bladder cancer,” said EV-302 lead investigator Thomas Powles, M.D., of the Barts Cancer Institute Queen Mary University of London, as he began his ESMO presentation of the trial’s results.

Enfortumab, a targeted therapy that uses an antibody to carry a deadly payload into bladder cancer cells, received FDA accelerated approval in 2019 to treat bladder cancer that has worsened despite treatment with other therapies. In 2023, another accelerated approval of the drug was granted for treatment of patients with advanced bladder cancer who are unable to receive cisplatin-containing chemotherapy.

Both approvals were based on early-phase clinical trials showing that cancers stopped growing or disappeared entirely in some people who received enfortumab.

In the EV-302 trial, funded by Astellas Pharma and Seagen, nearly 900 people with advanced bladder cancer were randomly assigned to receive enfortumab plus pembrolizumab or chemotherapy as an initial treatment. People in the chemotherapy group received a maximum of six infusions of chemotherapy. About a third of those patients also received avelumab, but it was not required as part of the trial.

Overall, tumors shrank or stopped growing in about 67% of participants treated with enfortumab plus pembrolizumab, compared with 44% of those who received platinum-based chemotherapy.

In addition, the cancer disappeared entirely, known as a complete response, in almost 30% of participants in the enfortumab-plus-pembrolizumab group compared with about 12% in the chemotherapy group.

Having a complete response in nearly one-third of patients “is not something we’ve seen before,” Dr. Powles noted.

Most patients in each group experienced treatment-related side effects. The most common side effects in the enfortumab-plus-pembrolizumab group included skin reactions and pain or numbness in the hands and feet. Fatigue, nausea, and a decrease in red and white blood cells were more common in those who received chemotherapy.

After following participants for a median of about a year and a half, Dr. Powles and his colleagues found that patients in the enfortumab-plus-pembrolizumab group lived nearly twice as long as those in the chemotherapy group: a median of 31 months versus 16 months.

Enough patients continued to respond to the new combination on the EV-302 trial that the median length of response could not be determined. At the longest assessment reported, more than 30 months out, about 40% of patients who received enfortumab plus pembrolizumab continued to respond to treatment. However, the patients will need to be followed longer, Dr. Apolo noted.

Before the EV-302 trial, no therapy had ever increased patient survival compared with chemotherapy as the initial treatment, Dr. Powles said.

“This is the first time we’ve achieved that goal,” he continued—at which point the ESMO audience erupted in applause.  

With nivolumab, improved survival, long remissions

In the CheckMate-901 study—funded by Bristol-Myers Squibb, the manufacturer of nivolumab—about 600 patients were randomly assigned to receive nivolumab plus chemotherapy (cisplatin and gemcitabine) or chemotherapy alone, as their initial treatment.

The addition of nivolumab extended the median amount of time participants lived to about 22 months, compared with 19 months in people treated with chemotherapy alone. Results from this trial were also published in the New England Journal of Medicine.

The median length of complete remission was about 3 years, triple the length of remission in those who received chemotherapy alone. And about one-fifth of those who received nivolumab remained in remission at the last assessment reported, nearly 5 years after beginning treatment.

A new standard of care raises important questions

Dr. Apolo called enfortumab plus pembrolizumab the new standard of care as the initial treatment of patients with advanced bladder cancer.

The combination led to the highest percentage of patients whose cancers shrank or stopped growing, she noted, and gave patients the best chance at living longer.

Enfortumab plus pembrolizumab “takes first place” as the best up-front treatment for the disease, she said.

“But,” Dr. Apolo added, “with new standards of care come questions and challenges.”

For example, she wondered what the order of treatments should be if a patient’s cancer stops responding to the enfortumab–pembrolizumab combination and if there is a role for additional immunotherapy once people have completed treatment with enfortumab and pembrolizumab. Additional studies are needed to address these critical questions, Dr. Apolo said.

She also emphasized the importance of understanding why enfortumab and pembrolizumab work together so well in people with advanced bladder cancer, noting that a deeper knowledge about the biology could bring new advances and reveal ways to prevent resistance to treatment. 

And “we must discuss the cost,” Dr. Apolo said. Enfortumab and pembrolizumab are expensive, so it will be important to ensure that people who need the treatment can access it, she continued.

Nevertheless, she said, the results of these trials—particularly EV-302—have set a new standard. Enfortumab plus pembrolizumab “has raised the bar.”

It was once thought that after guiding the development of male sex organs in a fetus, the Y chromosome didn’t do much else. But over the past few years, results from multiple studies have challenged that belief. The most recent evidence comes from a new study that suggests that the Y chromosome may actually protect men from aggressive bladder cancer.

Most biological females have two X chromosomes in every cell, whereas most biological males have one X and one Y chromosome. But as males grow older, some of their cells may naturally lose the Y chromosome. More than half of males in their early 90s have lost the Y chromosome in some of their blood cells.

The new study, carried out in both mice and humans, found that loss of the Y chromosome in bladder cancer cells helped tumors evade the immune system and grow unchecked. On the upside, loss of the Y chromosome also appeared to make bladder cancer more susceptible to immunotherapy drugs called immune checkpoint inhibitors, the researchers reported June 21 in Nature.

“It’s stunning that losing the Y chromosome would have such a biological implication” for the immune system, said the study’s lead investigator, Dan Theodorescu, M.D., Ph.D., director of Cedars-Sinai's Samuel Oschin Comprehensive Cancer Institute. “It wouldn’t have been expected at all, based on prior science,” Dr. Theodorescu added.

Many studies have shown that losing the Y chromosome puts men at higher risk of getting cancer and of dying from cancer, but it hasn’t been understood why that is, said Konstantin Salnikow, of NCI’s Division of Cancer Biology, who was not involved in the study.

Findings from the new study, which was partially funded by NCI, start to answer that question, Dr. Salnikow said. And they may begin to unravel the long-standing mystery of why men have higher rates of many cancers than women, he added.

Tumors with loss of Y evade the immune system

The Y chromosome is one of the smallest of the bunch, and it carries only a few genes. Most of those genes are involved in sex development or sperm production, giving rise to the idea that the Y chromosome is a one-trick pony.

But “it actually does a lot more than we thought,” Dr. Theodorescu said. Loss of Y has been linked with higher rates of Alzheimer’s disease and heart disease, and has been found in several types of cancer. For instance, up to 40% of older men with bladder cancer lack the Y chromosome in their tumors. 

Because men are three to five times more likely to develop bladder cancer than women, the researchers wondered whether there may be a connection between Y chromosome loss and bladder cancer. To explore that possibility, the researchers looked at data from a large group of men with bladder cancer. 

Men with little to no expression of Y chromosome genes in their tumors (Y-negative tumors) didn’t live as long as men with high expression of Y chromosome genes in their tumors (Y-positive tumors), they found. 

To learn why, the researchers turned to mouse bladder cancer cells with (Y-positive) and without (Y-negative) a Y chromosome. Both groups of cells grew at the same rate in lab dishes and when implanted into male mice without immune systems, they found. 

But when the researchers implanted the cells into male mice with normal immune systems, the Y-negative cells grew twice as fast. That was the first hint that Y-negative cells were better at evading the immune system, Dr. Theodorescu explained. 

Another clue emerged when the team saw that Y-negative tumors in both mice and men had higher levels of PD-L1, a protein that shuts down T cells—immune cells that are primarily responsible for seeking out and destroying cancer cells. Indeed, T cells in Y-negative tumors appeared to be less active than those in Y-positive tumors. 

Not only that, but T cells in Y-negative tumors showed signs of exhaustion, a phenomenon that occurs when T cells run out of steam trying to rid the body of cancer or a chronic infection. 

These findings illustrate that “cells with loss of Y chromosome somehow influence the immune response and … the immune system is really affected,” Dr. Salnikow said.

Immunotherapy for Y-negative bladder cancer?

Immune checkpoint inhibitors are a type of immunotherapy that help get exhausted T cells back into attack mode. If loss of the Y chromosome leads to T cell exhaustion, the team wondered, would an immune checkpoint inhibitor help rally the T cells against Y-negative tumors?

Treating mice with an immune checkpoint inhibitor slowed the growth of Y-negative tumors far more than Y-positive tumors. And in the Y-negative tumors, T cells showed fewer signs of exhaustion.

Data from a 2016 clinical trial of the immune checkpoint inhibitor atezolizumab (Tecentriq) for bladder cancer also revealed that men with Y-negative tumors lived longer than men with Y-positive tumors. 

“We are at the beginning of understanding this process, but loss of the Y chromosome could … be a biomarker for telling us that these will be more sensitive to checkpoint inhibitors,” Dr. Salnikow noted. 

Dr. Theodorescu and his colleagues are now developing a test that looks for loss of the Y chromosome in tumors.

Controlling gene expression across the genome

The research team did additional experiments to find out more about the role of the Y chromosome in bladder cancer. They zeroed in on two genes on the Y chromosome whose absence seemed to be responsible for faster growth of Y-negative tumors. 

The genes, called UTY and KDM5D, affect how DNA is packaged into chromosomes. That packaging, in turn, affects the activity of genes on those chromosomes.

“ appears that chromosome Y contains important factors that are involved in the regulation of gene expression,” Dr. Salnikow said. That regulation could extend beyond the Y chromosome to the entire genome, he added.

“The big question for us is, how do you connect those genes back to the immune system?” Dr. Theodorescu said. “There are a lot of pieces in between UTY and KDM5D—and potentially other genes on the Y chromosome—and inducing exhaustion. We’re going to try to find those pieces now.”

A separate study, also published June 21 in Nature and partially funded by NCI, found that KDM5D may have the opposite role in colorectal cancer. In mice, the loss of KDM5D made colorectal tumors less able to evade T cells and less likely to spread.

Sex differences in cancer

Compared with women, men have higher rates of nearly 30 different types of cancer, including bladder, colon, and brain cancer, Dr. Salnikow said. 

Researchers have historically attributed this discrepancy to different sex hormones and different lifestyles, he explained, noting that males are more likely to drink, smoke, and be exposed to cancer-causing chemicals at work.

But newer studies have shown that lifestyle and hormonal factors alone can’t account for the stark differences between men and women in incidence and death rates of many cancers. Now there is growing evidence that biological differences between males and females in everything from epigenetics to metabolism and immunity could potentially contribute to differences in cancer outcomes.

That evidence, along with findings from the new study, make it clear that “we really need to be mindful of sex-specific issues when we do experimental biology, and sex and gender when we do human biology ,” Dr. Theodorescu emphasized. 

“Obviously, males and females aren’t the same. And we need to be mindful of both the biological and gender differences when we do experiments,” he added.

NCI’s Division of Cancer Biology is planning to host a workshop on the biological basis of sex differences in cancer, Dr. Salnikow noted. He hopes that bringing experts together will help identify existing gaps in research and facilitate collaborations to address the remaining mysteries.  

“I think there’s going to be quite a bit of activity in this whole field now," Dr. Theodorescu said. "This is very exciting as I think it will lead to impactful clinical advances for our patients.”

Long before the COVID pandemic–fueled supply chain crisis, there was a shortage of a cancer therapy called BCG that’s used to treat the most common form of bladder cancer. BCG has long been the go-to initial treatment for a form of the disease called high-risk non-muscle-invasive bladder cancer (NMIBC).

The continuing BCG shortage has forced doctors to rely on other treatments for their patients with high-risk NMIBC. Among the alternatives they have turned to is a combination of two chemotherapy drugs, gemcitabine and docetaxel. And researchers from the University of Iowa have now published results from the largest study to date of people with high-risk NMIBC treated with this combination.

Overall, they reported, 82% of people who received periodic treatment with both drugs after surgery to remove their bladder tumor were still alive 2 years later without the cancer returning. The findings were published July 27 in the Journal of Urology.

None of the more than 100 patients in the study died from bladder cancer during the study period, and side effects from the drugs, which are delivered directly into the bladder, were largely minor.

The results with the chemotherapy combination were “similar to, or even somewhat better, than what is typically seen in patients treated with BCG,” said the study’s lead investigator, Vignesh Packiam, M.D., of the University of Iowa Health Care Department of Urology. “We’re very excited to have this treatment option for patients who would otherwise be left without an effective alternative.” 

There was broad agreement among urologic oncologists that the findings show the chemo combination is an excellent option when BCG is not available. 

The study’s findings “will be extremely helpful for the urologist to discuss with patients when BCG is not available, as all patients want to know how their outcomes could be affected by the BCG shortage,” wrote Joshua Meeks, M.D., Ph.D., a urologic oncologist at Northwestern University’s Feinberg School of Medicine, and colleagues in an accompanying editorial.

Sandeep Gurram, M.D., of the Urologic Oncology Branch in NCI’s Center for Cancer Research, called the findings “very promising.” In particular, Dr. Gurram noted that the combination appeared to work well even in people with the most concerning types of high-risk NMIBC.

He cautioned, however, that this study had important limitations and is not the final word on the treatment of high-risk NMIBC, regardless of BCG’s availability. For example, it wasn’t a clinical trial that directly compared BCG with gemcitabine and docetaxel.

Several ongoing and soon-to-be-launched clinical trials should help address some of the most important outstanding questions, he noted.

From BCG to chemo combos

Non-muscle-invasive bladder cancer is so called because the tumor resides strictly in the bladder’s interior lining, called the mucosa. Among other tasks, this mucosal lining operates as a barrier between the smooth muscle that encases the bladder and the urine within it.

About 70%–75% of bladder cancer diagnoses are NMIBC and about 25% of these are at high risk of progressing to muscle-invasive bladder cancer.

A tumor is called high-risk when its size or other features suggest that it’s biologically aggressive. One form of high-risk NMIBC, for example, is called carcinoma in situ, in which the tumor spreads along the mucosa in a pancake-like shape. These tumors are not only aggressive, Dr. Packiam explained, but particularly resistant to treatment with BCG. And when they do come back, it’s often in a more invasive form.

The treatment course for high-risk NMIBC begins with removing the bladder tumors via a surgical procedure called TURBT.  Surgery is followed by additional treatments, known as adjuvant therapy, to kill off any remaining cancer cells and reduce the risk of the cancer coming back. 

For most people with NMIBC, if no additional treatment is given after surgery, the disease often recurs at some point. So the primary goal of adjuvant therapy is to prevent recurrences for as long as possible and also to prevent recurrences from invading into the bladder, Dr. Packiam said. Tumors that invade to the muscle wall of the bladder require more aggressive surgery, including potentially removing the bladder entirely.

For decades, adjuvant therapy with BCG—a severely weakened form of a bacterium that was originally developed as a tuberculosis vaccine—was “the gold standard for preventing progression and recurrence” in high-risk NMIBC, he explained.

But starting in the early 2010s, supplies of BCG started to run short after one of the two companies that produced it stopped doing so. Only Merck now manufactures BCG for use in the United States. And according to the company, manufacturing issues as well as increased global demand continue to limit its availability. 

Last year, the company announced that it was building a new manufacturing facility for BCG, allowing the company to triple its output of the therapy. However, BCG supply isn’t expected to recover for at least several more years.

Single chemotherapy drugs have been among the most common alternatives used during the BCG shortage, Dr. Packiam said. But they have been shown to have decreased effectiveness against high-risk NMIBC. 

Combinations of chemotherapy drugs have proven to be effective in people with high-risk NMIBC whose cancer comes back after BCG treatment, Dr. Gurram said. So it made sense, he continued, to study chemotherapy combinations as an initial, or first-line, treatment.

Promising recurrence-free survival

Michael O’Donnell, M.D., another member of the University of Iowa research team, pioneered the use of the gemcitabine–docetaxel combination to treat high-risk NMIBC not long after the BCG shortage began. 

So for this study, the team looked back in time at data from patients who received adjuvant treatment with the chemo combination at their hospital. The data review covered patients treated from May 2013, about 1 year after the BCG shortage started, through April 2021.

Patients in the study initially received both drugs—each one delivered separately via a catheter directly into the bladder—once a week for 6 weeks (induction therapy). If there were no serious problems with side effects or the cancer did not come back, patients then got both drugs once a month for up to 2 years (maintenance therapy). The analysis included 107 people and the median follow-up was 15 months.

In addition to more than 80% of patients remaining alive without their cancer returning at 2 years, only one patient in the study had to go on to surgery to have their bladder removed. The most common side effect was having to urinate frequently and often feeling the urge to urinate.

Dr. Packiam acknowledged that the study has several limitations. Among them was that the study looked back in time, all of the patients were treated at the same hospital, and nearly all patients in the study were White.

All of these things may limit how applicable the findings are to the broader US population. “Absolutely, larger studies in more diverse populations are needed,” he said. However, he continued, the BCG shortage created a situation where doctors and their patients had no choice but to use something else.

“Iowa has been seriously affected by the shortage. We have very little supply here,” Dr. Packiam said. “So we really have come to rely on this .”

More definitive answers on the horizon

One of the most important takeaways from the study, Dr. Gurram said, is that the gemcitabinedocetaxel combination appeared to work well in all high-risk patients, including those with carcinoma in situ.

The study had a large population of people with high-risk tumors “that are often resistant to BCG and they are still getting very good numbers,” he said.

Nevertheless, evaluating how the combination performs in people from different racial and ethnic backgrounds will be important.

“We’ve seen time and again that something can perform well in , but once it gets to the community, we can see differing results,” Dr. Gurram said. 

The need to travel to the hospital monthly to get the maintenance treatment is a challenge of this particular regimen, Dr. Packiam noted. That’s particularly true in rural areas and for people without easy access to transportation.

“It does produce some logistical burdens for patients,” he said.

Along those lines, Dr. Meeks and his colleagues wondered about the extent to which maintenance therapy is even needed. As with BCG treatment, over time, many patients stop taking it. So “it will be important to determine if 6, 12 or 24 months of is necessary,” they wrote.

In the meantime, Dr. Gurram said, researchers are looking more carefully at existing and potential new treatments for high-risk NMIBC. 

For example, a large NCI-supported trial that will randomly assign patients to either BCG or the docetaxel–gemcitabine combination is in the works but hasn’t yet launched. And a series of clinical trials are underway testing BCG in combination with immunotherapy drugs for patients with high-risk NMIBC.

Dr. Gurram said he’s hopeful that newer therapies can further improve treatment of NMIBC across the board. 

“But, honestly, revisiting old chemotherapies that give promising results is great to see.”

UPDATE: On July 1, 2020, the Food and Drug Administration (FDA) approved avelumab (Bavencio) for people with advanced bladder cancer that has shrunk or stopped growing after chemotherapy using a platinum-based drug. The approval is for the use of avelumab as maintenance therapy for advanced disease that has not spread (locally advanced) or disease that has spread beyond the bladder (metastatic). The clinical trial leading to the approval, called the JAVELIN Bladder 100 study, is described in the Cancer Currents post below.

For most people with advanced bladder cancer, starting immunotherapy shortly after initial treatment with chemotherapy is better than taking an extended break from cancer treatment, according to results from a new study.

In the study, people who received the immunotherapy drug avelumab (Bavencio) before any sign of cancer recurrence lived substantially longer than people who received supportive care alone until their cancer returned. 

The findings were reported May 31 at the 2020 American Society of Clinical Oncology Virtual Scientific Program.

Patients who received avelumab as maintenance therapy  had “the longest overall survival ever documented” in a clinical trial for patients with metastatic bladder cancer, said Elizabeth Plimack, M.D., head of bladder cancer research at Fox Chase Cancer Center, who was not involved with the study, speaking at the ASCO meeting.

“It’s great to see positive results” in a clinical trial for bladder cancer, said Andrea Apolo, M.D., head of the Bladder Cancer Section at NCI’s Center for Cancer Research. However, she cautioned, some uncertainties remain about the best order of treatments for people with advanced bladder cancer.

Rapid Recurrence

People with bladder cancer that has spread to other parts of the body (metastasized) have a poor prognosis, with only about 5% living for 5 years after diagnosis. Although most bladder cancers stop growing, shrink, or even disappear in response to chemotherapy that uses a platinum-based drug (such as cisplatin), the cancer almost always returns rapidly, sometimes within just a few weeks or months, and grows aggressively. 

Since 2016, the Food and Drug Administration has approved five different immunotherapy drugs for the treatment of metastatic bladder cancer. These therapies all belong to a class of drugs called immune checkpoint inhibitors. Checkpoint inhibitors bind to proteins that can keep cancer cells from being killed by the body’s immune cells. This can free immune cells to attack cancer cells throughout the body.

Several of these drugs were approved as initial therapies (first-line therapy) for some people with advanced bladder cancer who, for various health reasons, cannot receive platinum-based chemotherapy. Other approvals were for bladder cancer that recurs after platinum-based chemotherapy (second-line therapy).

But the aggressive nature of bladder cancer when it recurs means that many people never have the opportunity to receive immunotherapy—or any other second-line therapy, explained Thomas Powles, M.D., of the CRUK Barts Cancer Centre in London, who led the new study and presented the results at the ASCO meeting.

“After first-line chemotherapy, only a minority of patients get second-line treatment. And outcomes with second-line treatment are poor, because the disease is aggressive and grows rapidly,” said Dr. Powles.

Patients are left in what can feel like a no-win situation, explained Arjun Balar, M.D., director of Genitourinary Medical Oncology at NYU Langone Health’s Perlmutter Cancer Center, who was not involved with the study. Platinum-based chemotherapy can be grueling, he continued, and “these patients have had four to six cycles of treatment, and they’re pretty beat up. They want a break .”

So, researchers wanted to see whether moving more quickly to using a checkpoint inhibitor could not only forestall the disease’s return but also be tolerable to patients.

Treatment Definitions

• First-line therapy: The first treatment given for a disease.
• Maintenance therapy: Treatment that is given to help keep cancer from coming back after it has disappeared following the initial therapy.
• Second-line therapy: Treatment that is given when initial treatment (first-line therapy) doesn’t work or stops working.
• Supportive care: Care given to improve the quality of life of patients who have a serious or life-threatening disease.

Substantial Improvement in Survival

Dr. Powles and his colleagues enrolled 700 people with locally advanced or metastatic bladder cancer in the international JAVELIN Bladder 100 study, which was funded by Pfizer, the drug's manufacturer.

All trial participants had already received chemotherapy—with either cisplatin and gemcitabine (Gemzar) or carboplatin and gemcitabine, if their health did not allow them to receive cisplatin—and their disease had not worsened during chemotherapy. 

Participants were then randomly assigned to receive either maintenance treatment with avelumab plus supportive care or supportive care alone. People in the maintenance group received infusions of avelumab every 2 weeks until their cancer started growing again or they left the study for other reasons. Supportive care for both groups included pain management, nutritional support, and treatment of infections. 

People in the supportive care group whose cancer got worse did not receive avelumab as part of the trial. However, they could receive it or any other immunotherapy drug after leaving the study.

Maintenance treatment with avelumab after chemotherapy turned out to have substantial benefits. The median overall survival for people who received maintenance avelumab was more than 21 months, compared with about 14 months for people who received only supportive care until their cancer got worse.

This improvement in survival was seen whether or not participants’ tumors had high levels of a protein called PD-L1, which is the target of avelumab. PD-L1 levels have been widely studied as a predictor of response to treatment with checkpoint inhibitors.

About 47% of people in the avelumab group and 25% of people in the supportive care group experienced serious side effects thought to be related to treatment. The most common serious side effects in the avelumab group included urinary tract infections, anemia, and fatigue.

Twelve percent of people who received avelumab had side effects that caused them to stop treatment. Two deaths during the study—one from sepsis and one from stroke—were determined to be due to the drug. 

Subtleties and Future Questions

Several factors have to be carefully considered in interpreting the trial results, explained Dr. Apolo.

A major one is that the study did not directly compare survival between people who got avelumab immediately versus when their cancer progressed. Only about half of the participants who initially received supportive care alone went on to receive immunotherapy after their cancer got worse. There could be many reasons for this, including lack of access to these drugs in different countries, Dr. Apolo said. 

But it also might be that, for some people, the cancer was progressing too rapidly, she added. “When these tumors start growing, they start growing very quickly. So if you wait to start at the time of progression, maybe it’s too late,” added Dr. Apolo. 

“Not all patients will be caught by the second-line safety net,” agreed Dr. Plimack.

So, for now, said Dr. Balar, the takeaway message from the JAVELIN study is “after chemotherapy, don’t wait to give immunotherapy.” 

But more and more, studies are looking at whether some patients should receive immunotherapy as first-line treatment, he continued. “Immunotherapy is one of the most important advances we’ve made in the last 30 years,” Dr. Balar said. 

The JAVELIN results can’t provide any insight into which patients benefit from first-line treatment with a platinum-based chemotherapy, he added. “This trial wasn’t designed to ask: Is chemotherapy necessarily the best choice for every patient?” he explained.

And some patients who receive immunotherapy for bladder cancer have remissions that last for years, he continued. “So, we need to figure out: What’s the best way to introduce that treatment to patients at some point in their cancer care?” 

Ongoing studies will help answer those questions, while others are studying whether immunotherapy should be given to people with bladder cancer that has not yet metastasized, said Dr. Apolo.

"I'm thrilled that so much time and effort is being dedicated to this tumor,” she said. “There were so many years when nobody was interested in doing in bladder cancer, because nothing worked. Now that we have immunotherapy that works, we're building on that so we can improve survival for patients.”

On December 18, 2019, the Food and Drug Administration (FDA) granted accelerated approval to enfortumab vedotin-ejfv (Padcev) for people with advanced bladder cancer that has progressed despite treatment with two previous therapies.

Enfortumab vedotin was the second targeted drug to be approved for the treatment of advanced bladder cancer in 2019. Earlier in the year, FDA granted accelerated approval to erdafitinib (Balversa). However, erdafitnib can only be used to treat cancers that have an alteration in one of several genes called FGFR. Only about 20% of bladder cancers harbor an FGFR alteration.

“We have been desperately looking for a new treatment option for patients” with advanced, progressive disease, said Joaquim Bellmunt, M.D., Ph.D., who directs the Bladder Cancer Program at Beth Israel Deaconess Medical Center in Boston.

The approval of enfortumab vedotin was based on findings from a cohort of participants in a small clinical trial called EV-201 that enrolled people with metastatic bladder cancer. All 125 participants in the cohort had been treated with chemotherapy that used platinum-containing drugs (such as cisplatin and oxaliplatin) as their initial, or first-line, treatment. When their cancer progressed, an immune checkpoint inhibitor had been used as their second-line treatment. 

All patients in the trial received enfortumab vedotin. Overall, 55 participants (44%) had their cancers shrink or stop growing during treatment. Fifteen of these had their tumors disappear entirely, known as a complete response. Responses to treatment lasted for a median of 7.6 months. The trial was funded by the drug’s manufacturers, Seattle Genetics and Astellas Pharma.

Currently, the standard third-line treatment for people with metastatic bladder cancer is chemotherapy that uses taxane agents, such as paclitaxel and docetaxel. 

“And less than 10% of our patients actually have responses to these regimens,” said Tian Zhang, M.D., of Duke University, who is involved with another ongoing study of enfortumab vedotin. “We've seen some great responses , and I'm really hopeful for a lot of my patients who might benefit from this drug.”

A Common Target

Enfortumab vedotin is a type of targeted therapy called an antibody‒drug conjugate. Antibody‒drug conjugates consist of a monoclonal antibody chemically linked to a drug. 

The monoclonal antibody part of enfortumab vedotin binds to a protein called nectin-4, which is found on the surface of most bladder cancer cells. The antibody is chemically linked to monomethyl auristatin E, or MMAE, a type of chemotherapy drug called a microtubule inhibitor. Once the conjugate is taken up by cells, the drug stops them from dividing and leads to their death.

Because nectin-4 is present on the majority of bladder cancers, it's not necessary to have a diagnostic test to determine which patients are eligible for treatment, explained Dr. Bellmunt. 

The participants enrolled in EV-201 received infusions of the drug about 3 times a month until disease progression or unacceptable side effects occurred, or if they chose to leave the study for any reason. 

The most common side effects included fatigue, hair loss, decreased appetite, changes in the ability to taste, and peripheral neuropathy. Febrile neutropenia—fever and a reduced number of white blood cells—was the most common serious side effect related to treatment.

Treatment-related rash also occurred in about half of participants but was usually mild.

Overall, side effects led 32% of patients to receive a lower dose of enfortumab vedotin and 12% to discontinue treatment. Peripheral neuropathy was the most common cause of dose reduction or treatment discontinuation.

At the time the trial’s preliminary results were published, almost half of the 55 patients who had had a response to the drug still hadn’t experienced progression of their cancer. Responses lasted from about 3 months to more than 11 months. 

Though the trial is still ongoing, the researchers estimated that the median progression-free survival was 5.8 months, and the median overall survival was 11.7 months.

More to Study

Under an accelerated approval, a drug’s manufacturer must further study and verify a treatment’s clinical benefit. An ongoing phase 3 clinical trial is comparing enfortumab vedotin with taxane-based chemotherapy as third-line treatment.

There are currently unanswered questions about which third-line drug should be given first to people with FGFR-positive bladder cancer, who would also be eligible to receive erdafitinib.

“We don't know if the order matters. There's no clinical trial or data ,” explained Dr. Bellmunt.

And because treatment response rates in the EV-201 trial were so high—comparable to what’s normally seen with first-line therapy—researchers are beginning to test enfortumab vedotin earlier in treatment, Dr. Zhang said. 

For example, an ongoing trial is testing enfortumab vedotin alone and in combination with immunotherapy, chemotherapy, or both as an initial treatment for people with advanced bladder cancer.

Preliminary results from one arm of that trial were presented in September 2019 at the European Society for Medical Oncology’s annual meeting. That data showed response rates of around 70% with the combination of enfortumab vedotin and the immune checkpoint inhibitor pembrolizumab (Keytruda) in patients who were too sick to receive platinum-based chemotherapy. Such a response rate is “phenomenal” for people with metastatic bladder cancer, explained Dr. Zhang.

“The concept is really to try to bring active treatments earlier in the disease process,” Dr. Zhang said.  “We want to more about enfortumab vedotin, potentially even for localized disease.”