For decades, treatment sequencing in advanced urothelial carcinoma followed a relatively predictable path. Platinum-based chemotherapy represented the cornerstone of first-line treatment, followed by immune checkpoint inhibitors, targeted therapies for selected molecular subgroups, and antibody-drug conjugates in later treatment lines. This paradigm changed fundamentally with the publication of the phase III EV-302/KEYNOTE-A39 trial, which established enfortumab vedotin (EV) plus pembrolizumab as the preferred first-line regimen after demonstrating superior overall survival, progression-free survival, and objective response rates compared with platinum-based chemotherapy. However, this advance also created one of the most important new challenges in genitourinary oncology: determining the optimal treatment strategy after progression on both an antibody-drug conjugate and PD-1 blockade.
Unlike previous treatment algorithms, the current sequencing landscape is supported by surprisingly little prospective evidence. Most pivotal studies evaluating platinum chemotherapy, erdafitinib, and emerging HER2-directed therapies were completed before EV plus pembrolizumab became the standard first-line treatment. As a result, clinicians increasingly rely on indirect evidence, molecular profiling, previous treatment exposure, toxicity, and patient characteristics when selecting subsequent therapy. Rather than following a fixed algorithm, treatment sequencing has become increasingly individualized.
This evolving treatment landscape will be among the important topics discussed at the OncoDaily Community Oncology Global Congress 2026, where international experts and frontline oncology professionals will examine current sequencing strategies, emerging targeted therapies, novel antibody-drug conjugates, and practical approaches to optimizing treatment after first-line EV plus pembrolizumab. The virtual congress will take place from August 28–30, 2026.
Enfortumab Vedotin (Padcev): Uses in Cancer, Side Effects, Dosage, Expectations, and More
The Changing Landscape of Advanced Urothelial Carcinoma
The introduction of EV plus pembrolizumab represents more than the approval of another effective regimen—it reflects a fundamental shift in the treatment of advanced urothelial carcinoma. Enfortumab vedotin combines a monoclonal antibody targeting Nectin-4 with the microtubule inhibitor monomethyl auristatin E (MMAE), while pembrolizumab restores antitumour immunity through PD-1 blockade. Together, these complementary mechanisms provide greater antitumour activity than either approach alone and have redefined expectations for first-line systemic therapy.
This evolution has also changed the questions clinicians must answer. Historically, sequencing focused on when to introduce immunotherapy or antibody-drug conjugates after platinum chemotherapy. Today, patients frequently receive both treatment modalities at the beginning of their metastatic disease course, leaving far less evidence to guide therapy after progression. The challenge is no longer whether EV plus pembrolizumab should be used first, but which therapy should follow once resistance develops.
Several factors now influence treatment selection, including prior platinum exposure, molecular alterations such as FGFR2/3, emerging biomarkers including HER2, cumulative toxicity, performance status, and access to approved therapies or clinical trials. Together, these variables have transformed sequencing from a predefined pathway into a personalized treatment strategy that must balance tumour biology with individual patient characteristics.
Targeting FGFR: The First Precision Medicine Opportunity
Among patients who progress after EV plus pembrolizumab, FGFR2 and FGFR3 alterations represent the best-established molecular target for subsequent therapy. Approximately 15–20% of advanced urothelial carcinomas harbor susceptible FGFR alterations, making comprehensive molecular profiling an essential component of treatment planning. Unlike chemotherapy, which is selected primarily according to patient fitness, erdafitinib offers a biomarker-driven approach based on the molecular biology of the tumor.
The phase III THOR trial established erdafitinib as the first targeted therapy to improve overall survival compared with investigator’s choice chemotherapy in previously treated patients with FGFR3-altered metastatic urothelial carcinoma. Although the study was completed before EV plus pembrolizumab became the preferred first-line regimen, it remains the strongest evidence supporting targeted therapy after progression in this molecular subgroup. Until prospective post-EV sequencing studies become available, erdafitinib remains the preferred option for eligible patients with susceptible FGFR alterations.
The growing role of precision oncology also highlights the importance of early molecular testing. Delaying comprehensive genomic profiling until disease progression may postpone treatment decisions or limit access to biomarker-directed therapies. Identifying FGFR alterations early allows clinicians to anticipate future treatment options and integrate targeted therapy into a broader sequencing strategy rather than using molecular testing only after standard treatments have been exhausted.
HER2: An Emerging Therapeutic Target
HER2 is rapidly emerging as another important biomarker in advanced urothelial carcinoma. While HER2 testing has long guided treatment in breast and gastric cancers, its role in urothelial carcinoma has only recently gained attention with the development of HER2-directed antibody-drug conjugates. These therapies have introduced a new opportunity for biomarker-driven treatment beyond FGFR alterations and may further expand the number of patients eligible for precision oncology approaches.
Among the most promising agents are trastuzumab deruxtecan and disitamab vedotin, both of which have demonstrated encouraging clinical activity in HER2-expressing urothelial carcinoma. Although prospective sequencing studies after first-line EV plus pembrolizumab remain unavailable, these therapies may become increasingly important as clinical experience grows and regulatory approvals expand. Their introduction also raises new questions regarding the optimal sequencing of multiple antibody-drug conjugates targeting different tumour antigens and carrying different cytotoxic payloads.
The evolution of HER2-directed therapy suggests that HER2 testing may soon become part of routine molecular assessment alongside FGFR testing. As additional evidence emerges, treatment selection is likely to depend increasingly on comprehensive biomarker profiling rather than previous treatment exposure alone. This shift reflects a broader movement toward precision medicine, where sequencing is guided not only by the order of available therapies but also by the biological characteristics of each individual tumour.
When Access Determines Treatment
Scientific evidence alone does not determine treatment sequencing. In many healthcare systems, access to therapy depends on regulatory approval, reimbursement policies, molecular testing, and the availability of clinical trials. Consequently, the optimal treatment described in international guidelines is not always the treatment that can be delivered in routine practice. For many patients, sequencing is influenced as much by healthcare resources as by tumour biology.
Several factors contribute to these differences. New therapies often become available at different times across countries, reimbursement may limit access despite regulatory approval, and restricted molecular testing can prevent identification of patients eligible for FGFR- or HER2-directed treatment. In addition, many patients receive care outside academic centres, where opportunities to participate in clinical trials remain limited. These disparities highlight an important reality of modern urothelial cancer care: successful sequencing requires not only effective therapies but also equitable access to biomarker testing and innovative treatments.
Balancing Efficacy With Toxicity
As patients receive multiple sequential therapies, cumulative toxicity becomes an increasingly important consideration. Selecting the next treatment is not based solely on antitumour activity but also on the adverse effects of previous therapies, many of which may persist long after treatment has ended.
Peripheral neuropathy remains one of the most clinically relevant toxicities following enfortumab vedotin and may influence the use of subsequent neurotoxic therapies, including platinum chemotherapy. Cisplatin and carboplatin continue to carry well-recognised risks of nephrotoxicity, myelosuppression, ototoxicity, and additional neurotoxicity, requiring careful patient selection according to renal function, performance status, and comorbidities. Erdafitinib has a distinct safety profile characterised by hyperphosphataemia, stomatitis, nail disorders, and central serous retinopathy, making regular ophthalmologic assessment an essential component of treatment.
HER2-directed antibody-drug conjugates introduce additional considerations. Trastuzumab deruxtecan carries a clinically important risk of interstitial lung disease or pneumonitis, whereas disitamab vedotin more commonly causes peripheral neuropathy and hematologic toxicity. Because these adverse events arise through different biological mechanisms, sequencing decisions increasingly require balancing efficacy with cumulative toxicity, quality of life, and patient preferences rather than considering each treatment independently.
Which Questions Remain Unanswered?
Despite the rapid evolution of treatment for advanced urothelial carcinoma, several important sequencing questions remain unresolved because prospective studies specifically evaluating therapy after first-line EV plus pembrolizumab are still lacking. As the treatment landscape continues to change, answering these questions will be essential for developing evidence-based sequencing strategies rather than relying on indirect comparisons between historical trials.
Which therapy should be used immediately after EV plus pembrolizumab? Platinum chemotherapy, erdafitinib, HER2-directed therapies, and investigational agents all represent potential treatment options in selected patients. However, none has been directly compared in patients progressing after first-line EV plus pembrolizumab, making the optimal sequence uncertain.
Can sequential antibody-drug conjugates overcome resistance? As multiple ADCs targeting different tumour antigens become available, an important question is whether changing the target or cytotoxic payload can restore treatment sensitivity. Prospective evidence addressing sequential ADC therapy remains limited, and the extent of cross-resistance between these agents is still unknown.
How should biomarkers guide sequencing? FGFR2/3 alterations currently identify candidates for erdafitinib, while HER2 expression is emerging as another clinically relevant biomarker. Whether additional molecular or immune biomarkers can further personalise sequencing remains an active area of investigation.
Should molecular profiling be repeated during disease progression? Repeat tissue biopsy or circulating tumour DNA analysis may identify newly acquired actionable alterations or mechanisms of resistance that were absent at diagnosis. Whether routine reassessment should become part of standard sequencing strategies requires prospective validation.
As precision oncology continues to advance, treatment sequencing is expected to evolve from a predominantly treatment-based approach toward one guided by tumour biology, molecular profiling, and predictive biomarkers. The challenge is no longer simply identifying additional therapies, but determining which patients are most likely to benefit from each treatment and at what point in the disease course they should receive it.