Key Ideas

Enfortumab vedotin plus pembrolizumab has replaced platinum-based chemotherapy as the standard first-line treatment for metastatic urothelial cancer and has now moved into the perioperative setting for muscle-invasive bladder cancer, with pathologic complete response rates approaching 60%. Molecular testing at progression, along with emerging circulating tumor DNA (ctDNA) data, is increasingly guiding both what comes after this combination and whether bladder-sparing approaches are feasible.

A New Standard in Metastatic Urothelial Cancer

For decades, platinum-based chemotherapy (cisplatin- or carboplatin-based regimens combined with gemcitabine) was the mainstay of treatment for metastatic urothelial cancer, with little improvement from added agents. That changed with the EV-302 trial, which compared enfortumab vedotin (an antibody-drug conjugate targeting Nectin-4) plus pembrolizumab against platinum-based chemotherapy in the first-line metastatic setting. Enfortumab vedotin plus pembrolizumab roughly doubled both progression-free and overall survival compared with chemotherapy, with an apparent tail on the progression-free survival curve suggesting durable benefit for a subset of patients. This result was presented in 2023 to considerable excitement at the meeting, and enfortumab vedotin plus pembrolizumab has since become the clear standard of care in this setting.

Moving Into the Perioperative Setting

Over the past year, enfortumab vedotin plus pembrolizumab has moved earlier, into perioperative treatment for muscle-invasive bladder cancer, through two related trials.

EV-303 enrolled cisplatin-ineligible patients, who received enfortumab vedotin plus pembrolizumab for three cycles before surgery, followed by six cycles of enfortumab vedotin and pembrolizumab, followed by additional pembrolizumab afterward for about a year total. EV-304 tested a slightly different schedule of the same combination in cisplatin-eligible patients, with neoadjuvant gemcitabine-cisplatin as the comparator arm. In both trials, pathologic complete response rates with enfortumab vedotin plus pembrolizumab approached 60%, compared with roughly 35% to 40% with standard neoadjuvant chemotherapy historically, or single digits in the placebo/immediate-surgery comparator arm of EV-303. Restricting the analysis to only patients who actually underwent cystectomy pushes the pathologic complete response rate for enfortumab vedotin plus pembrolizumab closer to 60% to 65%. Both trials also showed clear separation in event-free survival and overall survival curves favoring the combination, an unusually strong signal in bladder cancer or oncology more broadly. These results led to FDA approval within about a month of presentation for the cisplatin-ineligible population, and a second approval, in 2026, for the cisplatin-eligible population.

Is Enfortumab Vedotin Effective Across All Bladder Cancer Histologies?

Variant histologies (bladder cancers with components beyond pure urothelial carcinoma) are not uncommon, and real-world data from the UNITE database show that enfortumab vedotin monotherapy produces broadly similar outcomes regardless of whether the primary tumor originates in the bladder or upper tract, and regardless of pure urothelial versus mixed variant histology, although objective response rates run somewhat lower when variant histology predominates, and neuroendocrine or small cell components in particular show little activity. More recent UNITE data in the era of combination enfortumab vedotin plus pembrolizumab suggest that adding the immunotherapy component improves response rates further across histologic variants, supporting enfortumab vedotin plus pembrolizumab as the default choice even when some variant histology is present. Nectin-4 staining, while not required, is available at some institutions for cases where uncertainty about treatment selection exists, though very high expression does not appear necessary to see benefit.

Managing Enfortumab Vedotin Toxicity for the Long Haul

Because enfortumab vedotin plus pembrolizumab is generally continued for an extended period (unlike the four to six cycles typical of platinum-based chemotherapy), managing toxicity proactively, rather than reactively, matters more than it did in the chemotherapy era. Key toxicities include peripheral neuropathy, which tends to build cumulatively and is best managed with early, proactive dose or schedule adjustment rather than waiting until it becomes severe; skin rash, which can range from mild to debilitating or blistering and is managed with topical or oral steroids and antihistamines, ideally with dermatology involvement; and a labeled warning for hyperglycemia. The general principle is to treat this as a marathon rather than a sprint, preserving a patient's toxicity tolerance and quality of life for the long term using dosing and schedule changes, rather than maximizing the duration of the initial dose.

What Comes After Enfortumab Vedotin Plus Pembrolizumab?

Once a patient’s cancer progresses on enfortumab vedotin plus pembrolizumab, treatment selection benefits from having molecular testing results in hand before progression occurs, including HER2 immunohistochemistry and somatic DNA testing (particularly for FGFR3 alterations).

For HER2-positive disease, trastuzumab deruxtecan, an antibody-drug conjugate, is FDA approved based on the DESTINY-PanTumor02 basket trial, with response rates around 56% in HER2 IHC 3+ disease and about 35% in IHC 2+ disease, and broadly similar progression-free survival between the two groups, even though the approval is specific to IHC 3+. Cardiotoxicity (requiring monitoring with regular echocardiograms) and interstitial lung disease or pneumonitis (occurring in a low single-digit to roughly 10% range depending on severity threshold, with rare fatalities reported) both require ongoing attention with this agent.

For FGFR3 alterations (or FGFR2 mutations or fusions), erdafitinib is the treatment of choice, based on the phase 3 THOR trial, which showed improved progression-free and overall survival compared with later-line chemotherapy, with response rates in the 40% to 50% range. Erdafitinib dosing starts at 8 mg with titration to 9 mg depending on phosphate levels (targeting a level below 7), and requires close partnership with an ophthalmologist given a meaningful risk of ocular toxicity that, in rare cases, can threaten vision within a couple of months of starting treatment. Stomatitis and hair or nail changes are also common and can be bothersome. In practice, the rate of biomarker-eligible patients is probably in the range of 15%, though this may be underestimated if testing is not pursued consistently.

What's Changing: ctDNA-Guided Bladder Sparing and New Combinations on the Horizon

One of the more provocative recent updates concerns whether cystectomy remains necessary for all patients treated with neoadjuvant therapy. The RETAIN2 study allowed patients with an excellent response to neoadjuvant therapy and favorable biomarkers to forgo cystectomy and radiation entirely in favor of surveillance. A ctDNA-based update to this study found that patients who were ctDNA-negative and underwent surveillance alone fared similarly to those who were ctDNA-negative and underwent cystectomy, while ctDNA-positive patients did not appear to benefit much from cystectomy either. This raises real questions about the current role of cystectomy for ctDNA-negative patients, though the field is not yet at the point of recommending against surgery based on this data alone. Several additional trials, including EV-309 (testing chemoradiation with enfortumab vedotin plus pembrolizumab against standard chemoradiation in a bladder-sparing approach) and a Hoosier Cancer Research Network trial extending the induction-and-surveillance strategy using enfortumab vedotin plus pembrolizumab, are further exploring this direction, though results are still years away.

In the metastatic setting, several biomarker-driven combinations are in active development: a global phase 3 trial (DV-001) is testing the HER2-directed antibody-drug conjugate disitamab vedotin plus pembrolizumab in the first-line setting for HER2-expressing urothelial cancer, following promising results from a China-based study; and a separate trial is testing erdafitinib combined with enfortumab vedotin plus pembrolizumab in the first-line setting for patients with FGFR3 alterations. For the growing question of what to use after progression on enfortumab vedotin plus pembrolizumab, a trial is comparing platinum-based chemotherapy against an antibody-drug conjugate directed at EGFR and HER3 carrying a topoisomerase-1 inhibitor payload, in the post-immunotherapy setting.

For Patients

Treatment for advanced bladder cancer (urothelial cancer) has changed dramatically over the past few years. A combination of two drugs, enfortumab vedotin and pembrolizumab, has replaced older chemotherapy as the standard first treatment for cancer that has spread beyond the bladder, roughly doubling how long patients live without their cancer progressing and how long they survive overall compared with older chemotherapy regimens.

This same combination has now also moved earlier in the course of cancer treatment and is now used for the treatment of bladder cancer that has invaded the muscle wall of the bladder but has not yet spread elsewhere, where it is given before and after surgery to remove the bladder. In clinical trials, this approach eliminated all detectable cancer in the surgical specimen in roughly 6 out of 10 patients, compared with roughly 3.5 to 4 out of 10 with older chemotherapy.

Because this treatment is often continued for an extended period, managing its side effects, particularly nerve damage (neuropathy) and skin rash, proactively and early is important for maintaining quality of life over the course of treatment.

For patients whose cancer progresses despite this treatment, doctors now rely on specific genetic and protein testing of the tumor (looking for HER2 protein expression and FGFR3 alterations in the DNA, in particular) to select the next most effective treatment, since different targeted drugs work best for different molecular subtypes of bladder cancer.

There is also emerging research exploring whether some patients who respond very well to treatment before surgery might be able to avoid bladder removal surgery altogether, using a blood test that looks for tiny fragments of tumor DNA (called circulating tumor DNA, or ctDNA) to help identify who might safely be monitored instead. This approach is still being studied and is not yet a standard option.

Anyone with bladder cancer, whether newly diagnosed, facing surgery, or dealing with a cancer that has progressed on prior treatment, should ask their care team about genetic and protein testing of their tumor, and whether newer combination therapies or a clinical trial might apply to their specific situation.

Key Takeaways

  • Enfortumab vedotin plus pembrolizumab (from the EV-302 trial) has replaced platinum-based chemotherapy as the standard first-line treatment for metastatic urothelial cancer, roughly doubling progression-free and overall survival.

  • The same combination, tested in the EV-303 and EV-304 trials, has moved into perioperative treatment for muscle-invasive bladder cancer, achieving pathologic complete response rates near 60%, approaching double historical rates with neoadjuvant chemotherapy, and it is now FDA approved in both cisplatin-eligible and cisplatin-ineligible populations.

  • Enfortumab vedotin retains meaningful activity across variant bladder cancer histologies, with the exception of neuroendocrine or small cell components.

  • Because treatment continues long-term, proactive management of neuropathy and skin rash, rather than reactive management after they become severe, is key to maintaining quality of life.

  • HER2 and FGFR3 testing should be completed early on to guide next-line therapy: trastuzumab deruxtecan for HER2-positive disease, erdafitinib for FGFR3-altered disease.

  • Emerging ctDNA data from the RETAIN2 study raise the question of whether cystectomy remains necessary for ctDNA-negative patients who respond well to neoadjuvant therapy, though this is not yet a standard practice change.

References

  1. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer (EV-302). N Engl J Med. 2024;390:875-888.

  2. van der Heijden MS, Sonpavde G, et al. Perioperative enfortumab vedotin plus pembrolizumab in muscle-invasive bladder cancer, cisplatin-ineligible (EV-303) and cisplatin-eligible (EV-304) populations. N Engl J Med. 2026 (July).

  3. Meeks JJ, et al. Trastuzumab deruxtecan in HER2-expressing urothelial cancer: DESTINY-PanTumor02.

  4. Loriot Y, Matsubara N, Park SH, et al. Erdafitinib or chemotherapy in advanced or metastatic urothelial carcinoma (THOR). N Engl J Med. 2023;389:1961-1971.

  5. Galsky MD, Powles T, et al. Phase 3 study of disitamab vedotin with pembrolizumab versus chemotherapy in previously untreated HER2-expressing locally advanced or metastatic urothelial carcinoma (DV-001/SGNDV-001).