Padcev-Keytruda combo redefines standard of care in urothelial carcinoma

For 30 years, metastatic urothelial carcinoma was a therapeutic dead end. Platinum-based chemotherapy remained the first-line therapy standard, yet countless trials failed to move the needle, with survival gains measured in weeks rather than years.

Drug companies grew weary of investing in a rare cancer with toxicities that left frail patients unable to tolerate treatment.

Now, a new combination has rewritten the narrative.

Padcev (enfortumab vedotin), an antibody-drug conjugate developed by Astellas, when paired with MSD’s immunotherapy Keytruda (pembrolizumab), has more than doubled overall survival compared with chemotherapy alone.

Presented at ESMO 2023 and validated in real-world clinics since, the EV-302 trial showed median survival extending from 16.1 months to 31.5 months, with complete response rates jumping to nearly one-third of patients -- a result unthinkable just a few years ago.

Korea Biomedical Review met with Dr. Daniel Petrylak, Professor of Medicine and Urology at Yale School of Medicine, and Professor Shin Sang-jun of Yonsei Cancer Center, to discuss how this breakthrough is reshaping global standards and what it means for patients in Korea where reimbursement remains unresolved.

Decades of stagnation, then a breakthrough

The barren track record in urothelial carcinoma is well known. Traditional second-line regimens like docetaxel or paclitaxel rarely pushed survival beyond seven months, and even novel combinations such as docetaxel plus ramucirumab failed to improve overall survival. With repeated disappointments, industry enthusiasm withered.

For decades, progress in metastatic urothelial carcinoma proved elusive worldwide.

In the U.S., repeated failures in clinical trials underscored the challenge.

“Docetaxel and paclitaxel used in the second-line setting consistently delivered median overall survival of only about seven months,” Petrylak said. “Even when novel regimens such as docetaxel plus ramucirumab improved progression-free survival, they failed to extend overall survival.”

These disappointments discouraged pharmaceutical companies from further investment, he added.

Shin added that the hurdles were even more acute in Korea.

“The number of patients is smaller, so pharma had little incentive to invest,” Shin said. “On top of that, renal dysfunction and frailty in this population meant patients simply could not tolerate traditional cytotoxic therapy.”

Korea was stuck in an endless cycle of toxicity and futility, he added.

It was against this backdrop of stagnation that Petrylak first encountered Padcev.

In 2012, a colleague shared early phase 1 data suggesting striking efficacy in bladder cancer.

“What caught my eye was not incremental benefit but dramatic responses, even in liver metastases,” he recalled. “Some of those patients from the very first cohort are still alive today.”

That kind of durable outcome, he emphasized, had never been seen before in this disease.

Biology behind the synergy

What makes Padcev different is not only its potency but its immunologic profile. The drug induces immunogenic cell death via dendritic cells and macrophages, essentially priming the immune system.

When combined with checkpoint blockade, this creates a unique synergy not seen with most ADCs.

That biology translated into numbers that stunned even seasoned investigators. Hazard ratios below 0.5, median survival nearly doubled, and complete responses in 30 percent of patients.

Shin admits he was floored when he first reviewed the EV-302 abstract.

“In urothelial carcinoma, extending survival by two months was considered success,” he said. “Now we are doubling it and this is a paradigm shift.”

From data to clinic: real-world validation

In the U.S., where Padcev plus Keytruda has been approved frontline for two years, clinicians are already seeing outcomes mirror trial data.

Petrylak points to visceral metastases, historically the toughest subgroup.

“Even aggressive subtypes like plasmacytoid bladder cancer are responding,” he said. “Some of my phase 1 patients remain alive with good quality of life. We’ve never seen this before.”

In Korea, despite the lack of reimbursement, the impact is evident. About 20 percent of Shin’s patients elect to pay out of pocket for the regimen.

“Initially I hesitated to recommend it because of cost,” he said. “But after seeing such robust responses, I now actively encourage patients, and their confidence grows when they realize remission is possible.”

Cure enters the conversation

Perhaps the most striking change is not in the data but in the language.

For the first time, physicians are talking about “cure” in metastatic urothelial carcinoma.

Traditionally, this meant five-year survival, a benchmark now being reached.

In the U.S., Petrylak points out that long-term survivors from the earliest Padcev trials are already redefining expectations.

“In urothelial cancer, cure has always meant five years. Now we are beginning to see that even in metastatic disease,” he said.

He noted that in the EV-103 trial, pathologic complete responses reached 30 to 35 percent in cisplatin-ineligible patients, a rate comparable to platinum chemotherapy.

With ongoing studies moving Padcev combinations into the perioperative setting, he expects cure rates to climb even higher.

In Korea, Shin has already seen patients once deemed inoperable become surgical candidates, only to have pathology reports show no viable tumor.

In some cases, localized radiotherapy has consolidated residual disease, raising genuine prospects of long-term remission.

“This changes everything for patients,” Shin said. “It is one thing to continue therapy with residual disease, and another to talk about stopping treatment because no cancer is detectable.”

That psychological difference matters profoundly, he added.

Managing toxicities: a marathon approach

The regimen is not without toxicity. More than half of patients in EV-302 experienced grade 3 or higher adverse events.

Yet physicians insist most are manageable if detected early.

Skin rash, often emerging within two months, can be controlled through vigilant monitoring. Neuropathy, which tends to arise later, may require dose adjustment or temporary discontinuation.

Petrylak emphasizes communication.

“The key is anticipating these side effects and educating patients in advance,” he said. “Most toxicities can be managed by dose holds or reductions, then resuming therapy once they resolve.”

This is not a sprint, it’s a marathon, he added.

In Korea, where body mass index is lower than in the U.S., Shin observes slightly lower rates of some toxicities.

But interstitial lung disease (ILD) remains a concern. After EV-301, seven Korean centers pooled cases and found CT evidence of ILD in roughly 18 percent of patients.

Most were mild and asymptomatic, but the finding underscored the need for vigilance.

“This was not meant to alarm but to raise awareness,” Shin noted. “ILD requires rapid recognition and intervention.”

Interestingly, no consistent racial or ethnic differences in side effect rates have been demonstrated across global trials.

Petrylak noted that while Korean investigators reported a higher incidence of interstitial lung disease (ILD) following the EV-301 study, this reflected careful case collection and CT-based detection rather than a statistically proven ethnic predisposition.

“We must be cautious not to over-interpret small subsets of data,” he said, stressing that vigilance and early recognition matter more than genetic background.

Still, researchers are exploring whether biological variables such as the gut microbiome may influence immune responses and toxicity profiles.

Differences in diet, lifestyle, and environment across regions could theoretically shape the microbial composition of the intestine, which in turn modulates systemic immunity.

Such hypotheses remain speculative but are drawing increasing scientific interest, as they could help explain why certain populations appear to experience slightly different patterns of immune-related adverse events.

For now, experts agree that proactive monitoring is the most reliable safeguard.

Regardless of geography or ethnicity, early detection of rashes, neuropathy, or pulmonary symptoms and swift intervention remain the decisive factors in keeping patients on therapy.

Access, economics, and the Korean dilemma

While clinical value is clear, access in Korea remains constrained by cost.

Padcev plus Keytruda is not reimbursed, leaving patients to shoulder the full expense.

According to Astellas Korea, patients currently face treatment costs ranging from about 7 million to 10 million won ($5,040-7,200) every three weeks, depending on dose and schedule.

Because treatment is administered continuously on a three-week cycle, this means 17 to 18 cycles a year, translating into an annual burden of roughly 120 million to 180 million won -- well over 2 hundred million won in some cases when additional supportive care and hospital fees are included.

Shin warns this is a short-sighted view.

“We are treating people in their forties and fifties — working-age individuals,” he said. “Old regimens could not return them to society, but with Padcev, cure is possible.”

That is not just a medical cost, it is an economic investment, he added.

Petrylak echoes the sentiment, pointing out a shift in epidemiology.

“We are seeing younger patients without classic risk factors like smoking or chemical exposure,” he said. “These are productive citizens and restoring them to health means restoring them to the workforce.”