In the landscape of cancer treatment, stories of dedication and breakthroughs often intertwine, offering hope amid the challenges faced by patients. In this 

, we examine the impressive potential of antibody-drug conjugates (ADCs) in the treatment of bladder cancer, a class of drugs showing greater activity that we have seen with prior chemotherapy agents.

Antibody-drug conjugates, described by Dr. Yousef Zakharia of the University of Iowa as “targeted chemotherapy,” are designed to deliver a payload of chemotherapy directly to cancer cells, thereby intended to spare healthy cells from the impact of toxic treatments.

with the discovery of bladder cancer three years ago, leading to a series of treatments including surgery, chemotherapy and immunotherapy. Despite these efforts, she experienced multiple recurrences, but has had no evidence of disease for more than a year since starting treatment with Padcev (enfortumab vedotin-ejfv), an ADC that is reshaping the landscape of bladder cancer treatment.

Padcev’s transformative impact was high- lighted by the remarkable results of the EV-302 clinical trial, which revealed significantly improved outcomes compared to traditional chemotherapy, a near doubling of the median time to tumor progression.

Padcev and Keytruda (pembrolizumab) combination therapy 

by the Food and Drug Administration in December 2023 for patients with locally advanced or metastatic bladder cancer represents a pivotal event, one described as a “eureka moment” by Dr. Bamidele Adesunloye, medical oncologist at City of Hope Atlanta.

Yet, as Zakharia aptly notes, the quest for a cure remains ongoing. While ADCs represent a significant stride forward, they are not without their challenges. Unmet needs persist, reminding us of the imperative to continue the pursuit of innovation and progress in cancer care.

“Certainly, we are heading [in] that direction,” he said, “but we are far away from curing everybody.” Further innovations in the more precise delivery of increasingly more potent drugs directly to tumor cells while protecting normal cells and tissue are expected over time.

For more news on cancer updates, research and education, don’t forget to 

Articles

Reshaping the Landscape of Bladder Cancer Treatment

For patients with bladder cancer, exciting innovations in treatment have arrived, as we detail in this special issue of CURE. 

The Food and Drug Administration (FDA) has approved Anktiva (nogapendekin alfa inbakicept-pmln) with the bacillus CalmetteGuérin (BCG) vaccine for the treatment of adult patients with BCG-unresponsive non-muscleinvasive bladder cancer with carcinoma in situ with or without papillary tumors. The agency has also granted approval to Opdivo (nivolumab) in combination with the chemotherapy drugs cisplatin and gemcitabine for the first-line treatment of adults with unresectable or metastatic urothelial carcinoma. This issue provides more information on both of these approvals. 

Additionally, antibody-drug conjugates such as Padcev (enfortumab vedotin-ejfv) and Trodelvy (sacituzumab govitecan) are making a big impression on both patients and providers by showing significant survival benefits over chemotherapy, the standard of care for decades, in a landmark trial. One expert, Dr. Bamidele Adesunloye of City of Hope Atlanta, said the treatment option has “revolutionized the way we … look at bladder cancer.” 

Elsewhere, we examine the relationship between vitamin D and bone health among patients with prostate cancer, with research showing that while patients receiving androgen deprivation therapy may experience bone mineral density loss from the treatment, those who were vitamin D deficient and took supplements experienced reduced hip and femoral neck bone loss. 

We also provide multiple perspectives on radiation therapy, with a look at radiotherapy as a noninvasive treatment option for patients with kidney cancer and, as part of our “Speaking Out” interview series, one physician explained how MRI-guided stereotactic body radiation therapy is a significant advance in the treatment of prostate cancer. 

“In terms of radiation oncology, our field seems like it’s changing every year with advancements in technology,” said Dr. Matthew Solhjem, a radiation oncologist with Providence Cancer Institute and The Oregon Clinic. “Even in the past decade, radiation delivery has improved for patients, and this is nationwide, worldwide.” 

Beyond treatment advances, we also explore the emotional aspect of a cancer journey, with an article on the potential impact of humor in testicular cancer. 

This issue of CURE highlights the relentless pursuit of better therapies and the power of resilience. As always, we hope you find our stories inspirational and informative. Thank you for reading.

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Within the genitourinary cancer space, there have been many treatment advances over the past year. 

Innovation and Resilience in the Genitourinary Cancer Space

Dr. Matthew Solhjem, a radiation oncologist with Providence Cancer Institute and The Oregon Clinic, both in Portland, knows how rapidly things can change.

“In terms of radiation oncology, our field seems like it’s changing every year with advancements in technology,” he said. “Even in the past decade, radiation delivery has improved for patients, and this is nationwide, worldwide.”

as part of the “Speaking Out” video series, Solhjem discussed advancements in treating patients with prostate cancer, with methods of delivering greater doses of radiation in fewer treatments via tactics such as stereotactic body radiation therapy (SBRT) and high dose rate (HDR) brachytherapy.

He also discussed study findings published in 

 that showed that among patients with prostate cancer, MRI-guided radiation therapy resulted in a 24.4% incidence of grade 2 (severe) or higher genitourinary toxic effects versus a 43.4% incidence among patients treated with computerized tomography (CT)-guided treatment. Likewise, acute grade 2 (moderate) or higher gastrointestinal toxic effects occurred in none of the patients treated with MRI-guided radiation therapy and 10.5% of the patients who received treatment with CT-guided therapy.

“Compared with CT guidance, MRI-guided SBRT significantly reduced both moderate acute physician-scored toxic effects and decrements in patient-reported quality of life,” researchers wrote in the study findings, noting that “longer-term follow-up will confirm whether these notable benefits persist.”

: What are some recent advancements in the field of radiation oncology that patients with prostate cancer should be aware of?

: We want to obviously cure prostate cancer, and prostate cancer is very curable with radiation. ... There are organs surrounding the prostate gland that need to be carefully spared from radiation. One is the rectal wall, which is just behind the prostate gland, and then the bladder wall, which is just above the prostate gland. So one fairly recent advancement is using a rectal spacer, which actually is a gel-like material that’s placed between the prostate gland and the rectum before radiation even starts, and it acts to push the rectum away and thereby spare the rectal wall from radiation dose. So that’s a huge advancement. And recently, we’re starting to do that very frequently.

Another advancement that is at least very important with SBRT is the use of MRI-guided treatment. In terms of imaging the prostate gland, there’s MRI, there’s CT, there’s PET [positron emission tomography] scan and ultrasound. And by far the best in terms of image quality and anatomical detail is MRI.

Fortunately, Providence Cancer Institute purchased an MRI-guided treatment machine for our department so we can deliver this amazing treatment.

Basically, patients come in every day [and] an MRI scan is taken. And we plan or replan the treatment every day to the unique anatomy on that day. The rectal wall is very visible, the bladder wall, the urethra. I think with the extreme accuracy of the MRI scan, we can deliver treatments much more accurately and spare the organs around the prostate gland better.

: What advantages does MRI-guided radiation therapy offer versus more traditional forms of radiation therapy in prostate cancer?

: I think it is just that: the very detailed anatomy. When we plan or replan the treatment every time ... how full the bladder is or how empty the bladder is can make a difference. Same with rectal contents. It’s a very customized treatment delivery for each treatment, so it takes a fair amount of time; patients are in the unit for an hour to an hour and a half or so. But I think in the long run, the reduction in the radiation dose to the rectum and the bladder will lead to fewer complications and risks. And, coupling the MRI-guided treatment with the rectal spacer should even limit that further for patients.

We’re also starting to use the spacer for the high dose rate [brachytherapy]. So HDR brachytherapy is basically using needles as conduits for a radioactive source. So it’s started under general anesthesia. We’re going to be placing the rectal spacer to move the rectum away from the prostate, then place the needles into the prostate. And then once they’re in place, the radioactive source can go into each needle and deliver the radiation dose.

: What patients are ideal candidates for this line of treatment?

: We separate or classify patients into low, intermediate and high risk. And during the time of consultation, we make a determination whether [there are] lymph node risks; the prostate cancer can first spread to lymph nodes in the pelvis. And if we make that determination that there might be a chance of having lymph nodes involved, we typically use [intensity-modulated radiation treatment] for treating the lymph nodes in the prostate gland, and that’s a longer course of treatment. And we typically do 28 treatments or five and a half weeks for those patients. But if there is minimal lymph node risk and we’re just treating the prostate gland and the seminal vesicles, they are then candidates for the MRI-guided SBRT or the HDR brachytherapy.

: What does recent research have to say about MRI-guided radiation therapy?

: There are two ways of doing the SBRT. The MRI-guided treatment is what we do here. And it’s really compared with CT-based delivery of SBRT. ... One study did compare the two. [For] MRI-guided delivery versus CT-guided delivery, at least in the short term, the bladder and rectal side effects were actually quite a bit less with the MRI-guided [treatment], and I think that just has to do with the better visualization of the prostate gland and its interface or proximity to the rectum and the bladder and the ability to spare those organs. We really don’t know the long-term potential benefits, but I’m guessing there will be benefits to MRI-guided SBRT in the long term as well.

Transcript edited for clarity and conciseness.

As part of the “Speaking Out” series, a radiation oncologist discusses the benefits of MRI-guided stereotactic body radiation therapy.

MRI-Guided Radiation a 'Very Important' Advancement in Prostate Cancer Treatment

Stacey Reeves' cancer journey only began a few years ago, but it has been filled with twists and turns.

A 54-year-old South Carolina resident and a social worker for the U.S. Department of Veterans Affairs, Reeves was diagnosed with bladder cancer three years ago. After experiencing disease recurrence following treatment via surgery, chemotherapy and immunotherapy, she has had no evidence of disease (NED) for more than a year since beginning treatment with Padcev (enfortumab vedotin-ejfv), an antibody-drug conjugate that has been making waves in the oncology world.

“Since probably March 2023, every other week, I do my Padcev infusion,” she says. “I had my first PET [positron emission tomography] scan in April 2023 with Padcev, and I had a total response, nothing lit up in the PET scan. [I] did my next PET scan, [and there] was no evidence of disease. And then I just had my third one to mark my 12-month anniversary of [having] NED.”

“[Padcev] really made an evolution, if you will, in the urothelial or bladder cancer world,” Dr. Yousef Zakharia, co-leader of the Genitourinary Oncology Program at the University of Iowa in Iowa City, says.

Attendees at the European Society for Medical Oncology Congress 2023 in Madrid gave a standing ovation to the results of the EV-302 clinical trial comparing the safety and efficacy of Padcev and Keytruda (pembrolizumab) among patients with previously untreated locally advanced or meta- static urothelial carcinoma versus chemotherapy, which had been the standard of care for approximately 30 years, Zakharia says.

showed the median overall survival (the time a patient lives regardless of disease status) via treatment with Padcev and Keytruda, an immunotherapy (which helps the body’s immune system fight cancer cells), to be 31.5 months, nearly double that of the 16.1-month overall survival conferred by chemotherapy.

The median progression- free survival (the time a patient lives without their disease worsening) was 12.5 months among patients treated with Padcev and Keytruda versus 6.3 months among those treated with chemotherapy, and the overall response rate (patients whose disease responded partially or completely to treatment) was 67.7% with Padcev and Keytruda and 44.4% with chemotherapy, with complete response (NED) rates of 29.1% and 12.5%,  respectively.

“This drug is so effective compared with chemotherapy that we used to have before,” Dr. Bamidele Adesunloye, medical oncologist at City of Hope Atlanta in Newnan, Georgia, says. “Our gold standard used to be cisplatin [platinum-based chemotherapy]. And when you look at the antibody-drug conjugates, specifically when you combine it with immunotherapy, which is Keytruda, [in] first-line [treatment of] bladder cancer, you get almost 70% response rates.”

(FDA) approved the combination of Padcev and Keytruda 

for patients with locally advanced or metastatic bladder cancer in December 2023, less than a year after the agency granted the drug combination accelerated approval for the treatment of patients who were ineligible for treatment with cisplatin-based chemotherapy.

“It was a eureka moment for me,” Adesunloye says of the addition of this treatment to providers’ tool kits. “Because you look at the fact that most of these patients, when they present to us, are very, very sick. They have multiple metastatic sites of their disease, and bladder cancer is an aggressive cancer that can progress rapidly. Most of the time, your first- line therapy may be your last line of therapy. So you had better make sure you have a very good drug as your first line, because if you don’t have a good drug to control the disease, you may never have another option again. ... This really revolutionized the way we ... look at bladder cancer.”

 for the treatment of patients with locally advanced or metastatic urothelial cancer who received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant (presurgical)/adjuvant (postsurgical) locally advanced or metastatic setting based on the results of a phase 2 trial.

The drug then received a full approval in 2021 for patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy or were ineligible for cisplatin-containing chemotherapy and had received at least one prior line of therapy.

In traditional chemotherapy, “you put an IV [line] in the vein of the patient, you give the drug, and the platinum goes all over the body and kills cancer cells,” Dr. Terence Friedlander explains. Friedlander is a professor of medicine and Robert and Virginia O’Reilly Family Endowed Chair as well as chief of the Zuckerberg San Francisco General Hospital Division of Hematology/Oncology at the Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco.

“While yes, it works in some patients — for example, patients who are about to have their bladder removed — giving platinum saves lives. It prevents recurrences that would otherwise happen, and in the metastatic setting, it can slow down the disease even if it doesn’t cure people. The big problem with platinum, beyond that it wasn’t a cure for every- body, was that it’s toxic, and the platinum deposits in multiple tissues in the body,” Friedlander says. “So what that means is people can get hearing loss from the platinum. They can get ringing in the ears: tinnitus. They can get taste changes; they can taste the metal molecules. It can damage the kidneys. It can damage the nerves, so the peripheral nerves can get numbness or tingling too.

“So it causes a lot of other shorter-term side effects like severe nausea. People feel ill when they take it. It runs them down; they have a lot of fatigue. They can have electrolyte problems; the salts in their blood can get out of whack. So it’s a really unsatisfying treatment, even though it works and has value.”

Antibody-drug conjugates such as Padcev or Trodelvy (sacituzumab govitecan), which received accelerated approval from the FDA in 2021 for the treatment of locally advanced and metastatic urothelial cancer, are described by Zakharia as forms of “targeted chemotherapy.”

“It is an antibody that is directed toward certain receptors on the cancer cells,” he says. “In bladder cancer more specifically, we have NECTIN4 and TROP2. Both of them have antibody-drug conjugates manufactured toward those and are specific toward those receptors. And basically, this antibody is attached to a payload, which is a very effective chemotherapy.

“And the way it works [is that] it takes that chemotherapy, carries it directly to the cancer cells, and it gets internalized within the cancer cells. And basically that payload or chemotherapy gets integrated within the microtubules and starts disrupting the cell growth, and that results in cell killing. In other words, it is basically carrying the cytotoxic material directly and specifically to the cancer cells with the hope to save the normal cells from the toxic side effects associated with that if they do not have that specific receptor expressed.”

The targeted nature of antibody- drug conjugates is “refreshing” to Patricia Gilleland, 77, who lives in Georgia and received a diagnosis of bladder cancer in April 2022, joining a number of other issues she is faced with.

“I’ve got a tumor in my brain, which is an acoustic neuroma that is benign. I have a little spot on my lung, which right now is stable. I have a prolapsed vagina, which gives me hell, but you know, I’m thankful every day I get up,” she says. “I’m grateful.”

Gilleland, who walks with the assistance of a cane and has experienced hearing loss, underwent surgery in 2022 to remove her bladder and uterus as well as part of her vagina and began treatment with Padcev about a month after her surgery.

“I don’t want to do any more damage to the rest of my body and cells,” she says. “I try not to read a lot of articles about the side effects and what’s going to happen later on. You know, I just live in the moment. I like that. I want [the treatment] to help the good cells and destroy the bad cells.”

A patient of Adesunloye’s at City of Hope Atlanta, she says the only side effect she’s experienced is fatigue.

“When I go to the cancer center, I forget I’m sick,” she says. “I feel better. I feel well. And I feel like a lot of it has to do with my medication.”

Reeves received a diagnosis of stage 3 high-grade urothelial cancer in June 2021 after questions about blood in her urine led to the discovery of a mass in her left ureter tube. Surgery removed the tumor, but there were soon signs of trouble.

“I went in for my three-month cystoscopy for follow-up, and I would say probably a month before that, I knew something was wrong,” Reeves says. “I had called my surgeon, asked for some other scan or something, and it just didn’t feel right. [I] felt like I had when I had been diagnosed with cancer.”

A new tumor was found in her bladder, and Reeves underwent four months of treatment with the commonly used chemotherapy pair of cisplatin and gemcitabine.

“I had a lot of side effects from that [and] struggled a lot through that chemotherapy,” she says. “All your typical [side effects], like what you see in the movies and TV: losing hair, getting sick, vomiting, weight loss, fatigue, all those sorts of things.”

Surgery followed in June 2022. What physicians had thought was a thickening of her bladder wall turned out to be a tumor that had spread to her pelvic wall, vaginal wall and uterus, with a growth also found in her appendix, necessitating a total hysterectomy as well as removal of much of the vaginal and pelvic walls, bladder and appendix.

Reeves began treatment with the immunotherapy Opdivo (nivolumab) in August 2022. Following an infusion in November, she began experiencing severe diarrhea due to a case of colitis. She stopped her treatment with Opdivo, and a PET scan to assess her colitis showed that her cancer had metastasized again, this time to her lymph nodes.

She started treatment with Padcev, and after initially experiencing severe side effects — “I don’t think I got out of bed for five days. I could not stop throwing up,” she says — she is now on a modified dosing schedule and has become a self-described “huge fan” of the treatment.

Research continues into antibody-drug conjugates for the treatment of bladder cancer, with Zakharia saying that the Padcev-Keytruda combination is currently being studied in the neoadjuvant setting, and Friedlander saying phase 3 trial data are expected that could convert Trodelvy’s accelerated approval to a full approval. Meanwhile, HER2 receptor-targeting antibody-drug conjugates Enhertu (trastuzumab deruxtecan) and disitamab vedotin are also being studied in bladder cancer.

Despite recent advancements, unmet needs persist.

“Certainly, there are a significant number of patients who [were] not responding,” Zakharia says. “[For] about 30%, 40% of patients, we’re not shrinking their tumors, at least based on the reported clinical trial [findings, and so] ... there is an unmet need of curing every patient. Certainly we are heading [in] that direction, but we are far away from curing everybody.”

Side effects of antibody-drug conjugates, Adesunloye said, can include motor and sensory neuropathy, hyper- glycemia, dry eye, blurry vision and rash.

Reeves lost her hair during her time on Padcev and has experienced severe dry eye and inflammation of the corneas, in addition to cataracts, which she attributed to treatment with steroids, as well as fatigue, rash and crepey skin.

“But it’s better than having metastatic cancer and all the side effects that I’ve had from the other stuff,” she says. “It’s manageable, it’s tolerable. But [if you experience side effects], let your care team know what’s going on.”


For more news on cancer updates, research and education, don’t forget to 

Antibody-drug conjugates represent a paradigm shift for patients with cancer and providers.

Genitourinary Cancers Special Issue | CURE

Reshaping the Landscape of Bladder Cancer Treatment

Innovation and Resilience in the Genitourinary Cancer Space

MRI-Guided Radiation a 'Very Important' Advancement in Prostate Cancer Treatment

Evolution and Revolution in Bladder Cancer Treatment

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