Contemporary management of metastatic urothelial carcinoma

Abstract

Urothelial carcinoma, the most common malignancy of the urinary tract, presents a significant challenge, particularly in its metastatic stage, where prognosis remains poor despite advancements in treatment. Historically, platinum-based chemotherapy has been the standard first-line therapy, achieving moderate response rates but limited long-term survival. Recent breakthroughs have introduced immune checkpoint inhibitors, antibody-drug conjugates (ADCs), and targeted therapies as more effective alternatives. Enfortumab vedotin plus pembrolizumab has demonstrated superior efficacy as a first-line treatment, improving overall survival (OS) and objective response rates compared to chemotherapy. Maintenance therapy with avelumab has further prolonged survival in patients responding to initial platinum-based chemotherapy. Additionally, sacituzumab govitecan, an ADC targeting Trop-2, and erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor, have provided promising options for patients with refractory disease or FGFR alterations. The evolving treatment paradigm now prioritizes biomarker-driven, personalized approaches over traditional chemotherapy-based regimens. However, challenges remain in optimizing treatment sequencing and managing toxicity. Future research should focus on refining patient selection criteria and exploring novel combination therapies to enhance efficacy and durability of response.

Graphical Abstract

INTRODUCTION

Urothelial carcinoma (UC), primarily originating in the bladder, is the most common malignancy of the urinary tract [1]. It accounts for approximately 573,000 new cases and 213,000 deaths annually, making it a significant global health burden [2]. The disease predominantly affects older adults, with a median age of diagnosis around 73 years, and is more common in men than women [3]. Risk factors include smoking, occupational exposure to carcinogens, and chronic urinary tract infections [2,4].

While localized UC can often be effectively managed with surgery and intravesical therapies, metastatic UC (mUC) presents a significant therapeutic challenge [4,5]. Historically, platinum-based chemotherapy has been the cornerstone of treatment, achieving response rates of approximately 50%–60%, with a median overall survival (OS) of 14–16 months in cisplatin-eligible patients [6]. Therefore, there has been a growing demand for new therapeutic agents, and continuous research has been conducted on novel drugs and their combinations. Several clinical trials have been conducted to overcome the aforementioned limitations of standard platinum-based chemotherapy [7,8,9].

The National Comprehensive Cancer Network (NCCN) guidelines currently recommend enfortumab vedotin (EV) plus pembrolizumab as the preferred first-line treatment for metastatic UC, regardless of cisplatin eligibility. However, due to various reasons, particularly economic factors and insurance coverage limitations in certain countries, standard platinum-based chemotherapy is still widely used.

In this review, we aim to provide a comprehensive and clinically applicable summary of contemporary mUC management, focusing on treatment sequencing, patient selection criteria, and future research directions. This study examines the current treatment strategies for mUC, evaluating their effectiveness and associated adverse effects.

STANDARD CHEMOTHERAPY APPROACHES

1. Platinum-based chemotherapy

Platinum-based chemotherapy has been the cornerstone of mUC treatment for decades. Among cisplatin-based regimens, methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) was initially established as the standard. However, its substantial toxicity led to the development of alternative combinations, such as gemcitabine and cisplatin (GC), which demonstrated comparable efficacy with improved tolerability [6,10]. Clinical trials have shown that GC achieve an objective response rate (ORR) of approximately 50%–60%, with a median progression-free survival (PFS) of 7.7 months and a median OS of 14–16 months in cisplatin-eligible patients [11]. Dose-dense MVAC has demonstrated a higher response rate of 55%–65% but with increased toxicity, limiting its widespread use [12] (Table 1).

Table 1. Summary of comparisons of treatments in metastatic urothelial carcinoma.

Treatment	Population	ORR	Key advantages	Key limitations
Platinum-based chemotherapy (cisplatin-based)	Cisplatin-eligible mUC	46% (MVAC), 49% (GC)	High initial efficacy	Toxicity limits use
Carboplatin-based chemotherapy	Cisplatin-ineligible mUC	36%	Broader eligibility	Lower efficacy than cisplatin
Pembrolizumab (KEYNOTE-045)	Post-chemotherapy mUC	21.10%	Durable response	Lower ORR than chemotherapy
Nivolumab (CheckMate 275)	Post-chemotherapy mUC	19.6% (28.4% in PD-L1 high)	Biomarker-based benefit	Limited to platinum-refractory cases
Erdafitinib (FGFR inhibitor, BLC2001)	FGFR2/3-altered mUC	40%	Precision medicine option	Restricted to mutation-positive cases
Enfortumab vedotin (EV-301)	Post-platinum and ICI	40.60%	Effective in heavily pretreated mUC	Peripheral neuropathy
Sacituzumab govitecan (TROPHY-U-01)	Heavily pretreated mUC	27%	Effective across subgroups	Moderate toxicity

ORR, objective response rate; mUC, metastatic urothelial carcinoma; MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin; GC, gemcitabine and cisplatin; PD-L1, programmed cell death ligand 1; FGFR, fibroblast growth factor receptor; ICI, immune checkpoint inhibitor.

• Adverse effects: Platinum-based chemotherapy is associated with significant toxicity. Common side effects include nephrotoxicity, ototoxicity, myelosuppression, and gastrointestinal symptoms such as nausea and vomiting [13]. Nephrotoxicity, particularly with cisplatin, requires careful monitoring of renal function. Neuropathy is another dose-limiting toxicity observed with cumulative exposure. Due to these toxicities, a substantial proportion of patients are unable to complete their full chemotherapy regimen, with discontinuation rates ranging from 20% to 40% depending on the regimen and patient comorbidities [14].

2. Chemotherapy in cisplatin-ineligible patients

For patients deemed ineligible for cisplatin due to renal impairment, hearing loss, or poor performance status, carboplatin-based regimens are often employed. Gemcitabine and carboplatin have shown modest activity, with response rates of approximately 36% and median OS of 9.3 months [15]. These outcomes, while inferior to cisplatin-based regimens, provide a viable option for this subset of patients.

• Adverse effects: Carboplatin-based regimens tend to have a better tolerability profile but still pose risks of hematologic toxicities such as thrombocytopenia (occurring in approximately 40%–50% of patients) and anemia (30%–40%) [16]. Other side effects include fatigue, alopecia, and mild gastrointestinal symptoms. Despite its improved tolerability compared to cisplatin, carboplatin-based chemotherapy is still associated with a treatment discontinuation rate of 20%–30%, primarily due to hematologic toxicity and cumulative fatigue [17].

3. Sequential and maintenance strategies

Maintenance therapy has emerged as a strategy to prolong disease control after chemotherapy. Avelumab, an anti–PD-L1 antibody, has set a new benchmark in this space. In the JAVELIN Bladder 100 trial, avelumab maintenance therapy demonstrated a significant OS benefit, with a median OS of 21.4 months compared to 14.3 months in the best supportive care group, representing a 31% reduction in the risk of death (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.56–0.86, p<0.001) [9]. The benefit was even more pronounced in PD-L1–positive tumors, with a median OS of 25.0 months. Due to these significant findings, avelumab maintenance therapy has been incorporated into current treatment guidelines for mUC.

ANTIBODY-DRUG CONJUGATES

1. Enfortumab vedotin plus pembrolizumab

EV is an antibody-drug conjugate (ADC) that targets nectin-4, a cell adhesion molecule highly expressed in UC. The combination of EV with pembrolizumab has shown superior efficacy compared to standard chemotherapy as a first-line treatment for mUC, as demonstrated in the EV-302 trial published in 2024 [7].

In this trial, EV+pembrolizumab achieved an ORR of 68%, significantly higher than the 44% observed with chemotherapy. Furthermore, the complete response (CR) rate was also markedly increased, with 29% of patients achieving complete tumor regression compared to 12% in the chemotherapy group. The median PFS was 12.5 months, doubling that of chemotherapy at 6.3 months (HR 0.45, 95% CI 0.38–0.54, p<0.001). More importantly, the median OS was 31.5 months, which was nearly twice as long as the 16.1 months observed with chemotherapy (HR 0.47, 95% CI 0.38–0.58, p<0.001), reinforcing the survival advantage provided by this regimen.

Despite its remarkable efficacy, EV+pembrolizumab is associated with notable toxicities. Peripheral neuropathy was the most frequently reported adverse event, occurring in 55% of patients, with 12% experiencing Grade 3 or higher severity. Skin toxicities, including rash and pruritus, were observed in 47% of patients, with 10% experiencing severe cases. Hyperglycemia occurred in 12% of patients, with Grade 3+ severity in 4%. Additionally, immune-related adverse events (irAEs) occurred in 25% of patients, leading to complications such as pneumonitis, colitis, and hepatitis. However, the overall treatment discontinuation rate due to toxicity was relatively low at 18%, suggesting that the regimen maintains a manageable safety profile compared to chemotherapy. Given these significant findings, EV+pembrolizumab has been incorporated into current treatment guidelines as the preferred first-line treatment for mUC, further solidifying the role of ADCs in the evolving therapeutic landscape of UC.

2. Sacituzumab govitecan

Sacituzumab govitecan is another ADC that has demonstrated efficacy in mUC [18]. This ADC targets Trop-2, a transmembrane glycoprotein overexpressed in mUC, and delivers a potent topoisomerase I inhibitor directly to tumor cells. In a recent study published in 2025, sacituzumab govitecan achieved an ORR of 27%, with a median PFS of 5.4 months and a median OS of 10.9 months in previously treated mUC patients [18]. Due to these promising results, sacituzumab govitecan is emerging as a viable treatment option for patients who have progressed on prior platinum-based chemotherapy and immune checkpoint inhibitors (ICIs).

Despite its effectiveness, sacituzumab govitecan is associated with notable toxicities, including neutropenia (reported in 34% of patients, with Grade 3+ in 18%) and diarrhea (seen in 20% of patients, with severe cases in 8%). These side effects necessitate careful monitoring, particularly in heavily pretreated patients. However, the overall treatment discontinuation rate due to toxicity was 15%, suggesting that most patients can tolerate therapy with appropriate supportive care [18].

CHECKPOINT INHIBITORS IN mUC

Nivolumab, a programmed death-1 (PD-1) inhibitor, has emerged as a critical therapeutic option in the first-line treatment of mUC. The combination of nivolumab with GC has been established as a Category 1 recommendation in the NCCN guidelines, based on its efficacy demonstrated in clinical trials. The phase III trial conducted by van der Heijden et al. [19] evaluated this combination followed by nivolumab maintenance therapy, showing superior survival outcomes compared to chemotherapy alone.

In this trial, patients receiving nivolumab plus gemcitabine-cisplatin achieved a median OS of 21.7 months, compared to 18.9 months in the chemotherapy-only arm, representing a significant reduction in the risk of death (HR 0.78, 95% CI 0.65–0.94, p=0.002). The ORR was 57%, with CR observed in 22% of patients, compared to 43% and 14%, respectively, in the chemotherapy arm. Furthermore, nivolumab maintenance therapy prolonged PFS to 7.9 months, compared to 6.1 months with chemotherapy alone.

Despite its efficacy, nivolumab plus gemcitabine-cisplatin is associated with irAEs, which require careful monitoring. The most common Grade 3 or higher adverse events included pneumonitis (3.5%), colitis (2.1%), and hepatitis (1.8%). However, the treatment discontinuation rate due to toxicity was 19%, which was comparable to the chemotherapy-alone arm, suggesting that the combination is generally well tolerated.

Given these findings, nivolumab plus gemcitabine-cisplatin followed by nivolumab maintenance therapy is now included in clinical guidelines as a first-line treatment option for cisplatin-eligible mUC patients.

IMMUNOTHERAPY IN PATIENTS INELIGIBLE FOR COMBINATION THERAPY

For patients with GFR <30 mL/min who are ineligible for combination chemotherapy, ICIs such as pembrolizumab and atezolizumab have been considered as first-line treatment options. Both agents have received regulatory approval based on their clinical efficacy in platinum-ineligible patients with mUC [20].

Clinical trials evaluating pembrolizumab and atezolizumab in this setting have demonstrated ORR ranging from 20% to 30%, with durable responses observed in a subset of patients. The KEYNOTE-052 trial reported a median OS of 11.3 months with pembrolizumab monotherapy, whereas the IMvigor210 trial showed a similar benefit with atezolizumab, particularly in patients with high PD-L1 expression [21,22].

However, subsequent phase III studies (IMvigor130 and KEYNOTE-361) indicated that patients with low PD-L1 expression had inferior survival outcomes compared to those receiving platinum-based chemotherapy. As a result, the U.S. Food and Drug Administration revised its approval criteria, limiting the use of pembrolizumab and atezolizumab as firstline therapies to patients who are either platinum-ineligible or have high PD-L1 expression in their tumors [23].

Given these considerations, the selection of pembroli-zumab or atezolizumab as first-line therapy for patients with GFR <30 mL/min should be guided by PD-L1 expression levels and patient-specific factors to optimize treatment outcomes.

FGFR-TARGETED THERAPY: ERDAFITINIB

Erdafitinib is an oral fibroblast growth factor receptor (FGFR) inhibitor approved for the treatment of locally advanced or mUC harboring FGFR2 or FGFR3 genetic alterations. FGFR3 mutations are present in approximately 15%–20% of UC cases, particularly in luminal-papillary subtypes, making FGFR a viable therapeutic target [24].

The BLC2001 trial evaluated the efficacy of erdafitinib in patients with FGFR-altered mUC who had progressed after prior platinum-based chemotherapy. The study demonstrated an ORR of 40%, with a CR rate of 3% and a partial response rate of 37% [25]. The median PFS was 5.5 months, and the median OS was 9.0 months. Notably, patients who had previously received immunotherapy also showed clinical benefit, suggesting a potential role for erdafitinib in a broader treatment landscape.

Despite its efficacy, erdafitinib is associated with significant toxicities that require careful management. Hyperphosphatemia is the most commonly reported adverse event, occurring in 74% of patients, with 32% requiring dose modification or temporary discontinuation [25,26]. Other notable toxicities include stomatitis (45%), skin-related toxicities (30%), diarrhea (27%), and fatigue (23%). Ocular toxicity, including central serous retinopathy, was observed in approximately 10% of patients, necessitating regular ophthalmologic monitoring. Due to these adverse effects, dose adjustments are frequently required, and clinicians should closely monitor phosphate levels and manage side effects proactively.

Ongoing research is investigating the combination of erdafitinib with ICIs or ADCs to enhance therapeutic outcomes while mitigating toxicity. These combination strategies may further refine the role of FGFR-targeted therapy in the evolving treatment landscape of mUC.

DISCUSSION

The management of mUC has evolved significantly over the past decade, with the introduction of ICIs, ADCs, and FGFR-targeted therapies complementing the traditional platinum-based chemotherapy regimens [27]. This study has reviewed the efficacy and limitations of these therapeutic approaches, considering the current treatment landscape and potential future directions.

The treatment flowchart (Fig. 1) highlights the importance of renal function and biomarker status in determining first-line therapy for mUC. Patients with glomerular filtration rate (GFR) ≥30 mL/min are generally eligible for EV plus pembrolizumab, a regimen that has demonstrated a high ORR of 68% in clinical trials [7,28]. However, if patients are ineligible for EV, traditional platinum-based chemotherapy remains an option, particularly in combination with avelumab maintenance therapy or nivolumab plus gemcitabine-cisplatin for durable responses [29,30,31]. For patients with GFR <30 mL/min, first-line treatment is largely dependent on PD-L1 status, with pembrolizumab or atezolizumab being potential options for PD-L1–positive tumors, though in some cases, best supportive care is the only viable choice [32].

Fig. 1. Treatment flowchart of metastatic urothelial carcinoma. GFR, glomerular filtration rate; EV, enfortumab vedotin; PD-L1, programmed cell death ligand 1; CPI, immune checkpoint inhibitor; PD, programmed death; GC, gemcitabine and cisplatin.

Despite their effectiveness, platinum-based regimens are associated with significant toxicity. Cisplatin-based chemotherapy (MVAC or GC regimens) has demonstrated an ORR of 46%–49%, making it one of the most effective treatments for cisplatin-eligible patients [33]. However, nephrotoxicity, ototoxicity, and myelosuppression frequently limit its applicability, necessitating alternative regimens such as carboplatin-based chemotherapy (ORR 36%) for cisplatin-ineligible patients [34]. Unfortunately, carboplatin regimens generally yield inferior survival outcomes compared to cisplatin-based therapy.

ICIs have transformed the treatment paradigm by offering durable responses in a subset of patients, albeit with lower initial response rates compared to chemotherapy. Pembrolizumab (KEYNOTE-045) and nivolumab (CheckMate 275) have demonstrated ORRs of 21.1% and 19.6%, respectively, with improved survival outcomes, especially in patients with high PD-L1 expression [35,36]. However, their role is primarily in the post-chemotherapy setting, as their efficacy in first-line treatment remains limited unless patients are platinum-ineligible.

ADCs have emerged as crucial options in post-platinum and post-ICI settings. EV (EV-301) and sacituzumab govitecan (TROPHY-U-01) have both demonstrated ORRs of approximately 40.6% and 27%, respectively, making them effective salvage therapies in heavily pretreated patients [32,37]. The main limitation of ADCs is their toxicity, particularly peripheral neuropathy in EV and hematologic toxicity in sacituzumab govitecan.

FGFR-targeted therapy, specifically erdafitinib, has introduced precision medicine into the mUC treatment paradigm. Erdafitinib is particularly relevant for patients with FGFR2/3 mutations, offering an ORR of 40%, comparable to ADCs and ICIs [38]. However, it is restricted to a small subset of patients (approximately 15%–20% of mUC cases) and is associated with unique toxicities such as hyperphosphatemia, stomatitis, and ocular toxicity, which require vigilant monitoring [24,32].

The sequencing of therapies remains a critical challenge in mUC management. The patients who fail platinum-based chemotherapy may benefit from either ICIs or ADCs, depending on PD-L1 status and prior treatment history. Laterline therapy options include switching between ADCs and erdafitinib, with the choice largely influenced by molecular profiling and prior response to treatment.

Future research is focusing on combination therapies to overcome the limitations of monotherapies. Ongoing trials are evaluating the combination of ADCs with ICIs to enhance anti-tumor efficacy while maintaining manageable toxicity. Additionally, the integration of FGFR inhibitors with immune therapies is under investigation to determine whether FGFR-altered tumors exhibit improved responses to immunotherapy [39].

CONCLUSIONS

In conclusion, the treatment landscape of mUC has shifted significantly from a chemotherapy-dominated approach to a more personalized, biomarker-driven strategy integrating ICIs, ADCs, and FGFR-targeted therapies. Treatment selection should be guided by renal function, biomarker status, and prior therapy. While significant progress has been made, optimizing treatment sequencing, reducing toxicity, and expanding the use of precision medicine remain key challenges for the future.