Treatment of metastatic bladder cancer according to clinical considerations: a narrative review

Sung Goo Yoon; Seok Ho Kang

doi:10.5124/jkma.25.0047

J Korean Med Assoc > Volume 68(4); 2025 > Article

Yoon and Kang: Treatment of metastatic bladder cancer according to clinical considerations: a narrative review

Focused Issue of This Month

Current Status of Medical Therapy for Bladder Cancer

J Korean Med Assoc 2025; 68(4): 208-214.

Published online: April 10, 2025

DOI: https://doi.org/10.5124/jkma.25.0047

Treatment of metastatic bladder cancer according to clinical considerations: a narrative review

Sung Goo Yoon, MD

, Seok Ho Kang, MD, PhD

Department of Urology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea

Corresponding author: Seok Ho Kang E-mail: mdksh@korea.ac.kr

Received March 17, 2025 Accepted April 7, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose: Metastatic bladder cancer has historically been treated with platinum-based chemotherapy as the standard first-line therapy. Since the introduction of cisplatin-based regimens, advancements in treatment strategies have been limited. However, the recent emergence of immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) has significantly transformed the treatment landscape. Notably, the combination of enfortumab vedotin (EV) and pembrolizumab has demonstrated considerable clinical benefits, challenging traditional chemotherapy. This review aims to provide an overview of recent advancements in the treatment of metastatic bladder cancer.
Current Concepts: Recent phase III clinical trials, notably EV-302/KEYNOTE-A39 and CheckMate 901, have reshaped the first-line management. EV combined with pembrolizumab has shown superior progression-free survival and overall survival compared to platinum-based chemotherapy, establishing it as a new standard of care. Patients ineligible for this regimen due to underlying comorbidities or toxicity may still benefit from alternative options. Such alternatives include platinum-based chemotherapy with ICI maintenance therapy, including avelumab or nivolumab. The selection of treatments should be individualized, taking into account specific patient factors, particularly platinum eligibility, renal function, and performance status.
Discussion and Conclusion: The incorporation of ICIs and ADCs into the therapeutic landscape for metastatic bladder cancer has significantly improved patient outcomes. EV plus pembrolizumab has demonstrated substantial survival benefits, establishing it as a preferred first-line regimen for eligible patients. However, not all patients are candidates for this combination, emphasizing the necessity of individualized treatment strategies. Future research should focus on managing treatment-related adverse events and developing personalized therapies to maximizing efficacy while minimizing toxicity.

Keywords: Urinary bladder neoplasms; Neoplasm metastasis; Immune checkpoint inhibitors; Immunoconjugates

Introduction

The treatment paradigm for metastatic bladder cancer has historically been dominated by cisplatin-based chemotherapy, established as the standard first-line therapy over two decades ago, following clinical trials demonstrating survival benefit [1–3]. However, in recent years, this longstanding approach has been challenged by the emergence of immunotherapies, particularly immune checkpoint inhibitors [4]. Subsequently, results from two pivotal randomized clinical trials (EV-302/KEYNOTE-A39 and CheckMate 901), published in October 2023, have fundamentally altered this treatment paradigm [5,6]. Two therapies—enfortumab vedotin (EV) and pembrolizumab—have emerged prominently in this evolving landscape. This review aims to introduce recent advances in the treatment of metastatic bladder cancer with an emphasis on clinical applicability. This is not a human-subject study; thus, neither institutional review board approval nor informed consent was required.

Initial Treatment Approach for Metastatic Bladder Cancer Based on Patient Status

The first-line treatment for metastatic bladder cancer is generally categorized into two major groups: patients eligible for combination therapy and those who are not. This categorization is guided by findings from the two aforementioned pivotal clinical trials. For patients who qualify for combination therapy, further stratification depends on their eligibility for platinum-based chemotherapy.

Patients eligible for combination therapy typically meet the following criteria: (1) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–2; (2) glomerular filtration rate (GFR) ≥30 mL/min; and (3) adequate organ function suitable for receiving EV plus pembrolizumab. When all these conditions are fulfilled, EV plus pembrolizumab is the recommended regimen. If one or more conditions are not met, platinum/gemcitabine-based chemotherapy combined with maintenance avelumab, or cisplatin/gemcitabine combined with nivolumab is utilized instead. When immune checkpoint inhibitors are contraindicated, platinum/gemcitabine alone may be administered. For patients who are ineligible for combination therapy but have programmed death-ligand 1 (PD-L1)–positive tumors, atezolizumab or pembrolizumab treatment may be considered (Table 1).

EV Plus Pembrolizumab Combination Therapy

The combination regimen of EV and pembrolizumab has become the new standard therapy for patients eligible for combination treatments. EV is an antibody-drug conjugate (ADC) composed of an anti–nectin-4 antibody linked to the cytotoxic agent monomethyl auristatin E (MMAE). Nectin-4, a cell surface protein frequently overexpressed in urothelial carcinoma and other tumors, facilitates targeted delivery of MMAE into tumor cells via endocytosis, resulting in cell death [7].

Pembrolizumab, an immune checkpoint inhibitor, binds to programmed cell death protein 1 (PD-1), blocking the interaction between PD-1 and PD-L1. This action prevents tumor cells from evading immune detection by restoring immune surveillance mediated by T cells, thus enabling an effective immune response against tumor cells.

A 2023 trial comparing EV plus pembrolizumab with platinum/gemcitabine as first-line therapy in patients with inoperable or metastatic bladder cancer found a significant benefit in both progression-free survival (PFS) and overall survival (OS). Median PFS was 12.5 versus 6.3 months (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.38–0.54), and median OS was 31.5 versus 16.1 months (HR, 0.47; 95% CI, 0.38–0.58). The objective response rate (ORR) was also significantly higher in the EV/pembrolizumab arm (67.7%, including 29.1% complete response) than in the platinum/gemcitabine arm (44.4%, including 12.5% complete response) (P<0.00001) [5].

Regarding treatment-related adverse events, grade ≥3 events occurred in 55.9% of patients receiving EV plus pembrolizumab and in 69.5% of patients in the platinum/gemcitabine group. Common side effects in the EV plus pembrolizumab arm included papulopustular rash (7.7%), hyperglycemia (5.0%), and neutropenia (4.8%). The most frequently reported grade ≥3 toxicities were cutaneous rash, peripheral neuropathy, and hyperglycemia [8]. These findings have established EV plus pembrolizumab as a preferred first-line treatment option for metastatic bladder cancer.

Defining Suitability for Platinum-Based Chemotherapy

Criteria to determine suitability for cisplatin-based or carboplatin-based chemotherapy, or to identify patients unsuitable for any platinum-based chemotherapy, have been established based on expert consensus [9]. Patients are considered ineligible for cisplatin if they meet at least one of the following criteria: (1) PS>1, (2), GFR≤60 mL/min, (3) grade ≥2 hearing loss, (4) grade ≥2 peripheral neuropathy, (5) New York Heart Association class III heart failure (Table 2) [10].

Approximately 50% of patients with metastatic bladder cancer fulfill at least one criterion for cisplatin ineligibility [11]. Among these factors, renal function is considered the most critical. When the GFR is uncertain, measurement using radioactive isotopes such as ⁹⁹mTc-DTPA or ⁵¹Cr-EDTA is advisable.

Patients unable to tolerate cisplatin may be offered carboplatin-based regimens. However, patients with (1) PS>2, (2) GFR<30 mL/min, or (3) PS=2 combined with GFR <60 mL/min have poor prognoses regardless of therapy; thus, these patients are generally considered unsuitable for platinum-based chemotherapy [12].

Patients Eligible for Combination Therapy but Unsuitable for EV Plus Pembrolizumab

Despite the proven superiority of EV plus pembrolizumab, this combination is contraindicated for patients with uncontrolled diabetes, grade ≥2 peripheral neuropathy, or severe dermatologic conditions. Additionally, patients who decline EV plus pembrolizumab due to concerns about adverse events are included in this category. For such cases, combining platinum-based chemotherapy with an immune checkpoint inhibitor is typically preferred.

Since the late 1980s, cisplatin-based therapy has been the cornerstone of metastatic bladder cancer treatment, resulting in median survival times of approximately 12 to 14 months in various studies [13]. Two prominent regimens, methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and gemcitabine/cisplatin, achieved median survivals of 14.8 and 13.8 months, respectively [14]. While MVAC has a 46% response rate compared to 49% with gemcitabine/cisplatin, gemcitabine/cisplatin has lower toxicity and thus became the standard regimen [1]. Dose-dense MVAC supported by granulocyte colony-stimulating factor showed reduced toxicity, improved complete response rates, and increased 2-year survival compared to standard MVAC but did not significantly enhance OS [15].

Patients whose disease remains stable or better following platinum-based chemotherapy may benefit from maintenance immunotherapy. In a randomized phase II trial, patients who received pembrolizumab maintenance showed improved PFS (5.4 months vs. 3.0 months; HR, 0.65; P=0.04) [16]. Similarly, the JAVELIN Bladder 100 trial evaluated avelumab maintenance therapy for patients achieving at least stable disease after 4–6 cycles of platinum/gemcitabine. OS improved from 14.3 months with best supportive care to 21.4 months in the avelumab maintenance group (HR, 0.69; 95% CI, 0.56–0.86; P<0.001) [17]. Thus, avelumab maintenance was recently considered the standard of care following platinum-based chemotherapy for patients maintaining stable disease.

The CheckMate 901 trial further assessed nivolumab’s therapeutic efficacy [6], comparing nivolumab combined with gemcitabine/cisplatin for up to 24 months versus gemcitabine/cisplatin monotherapy. Both PFS (7.9 vs. 7.6 months; HR, 0.72; 95% CI, 0.59–0.88) and OS (21.7 vs. 18.9 months; HR, 0.78; 95% CI, 0.63–0.96) significantly improved with combination therapy. The ORR was higher in the combination group (57.6%, including 21.7% complete response) compared to gemcitabine/cisplatin alone (43.1%), with a median response duration of 37.1 months. Grade ≥3 treatment-related toxicities were more frequent in the combination group (62%) compared to monotherapy (52%). Thus, nivolumab plus gemcitabine/cisplatin provides an alternative regimen for patients who cannot receive EV plus pembrolizumab or gemcitabine/cisplatin with avelumab maintenance.

Management of Patients Ineligible for Combination Therapy

Patients with PS >2, GFR <30 mL/min, or severe organ dysfunction are underrepresented in clinical trials. Historically, these patients have had poor clinical outcomes and usually receive supportive rather than systemic treatment. The limited clinical data specific to this population complicate treatment decisions and outcomes assessment.

In the United States, pembrolizumab has Food and Drug Administration (FDA) approval as a first-line treatment for patients ineligible for platinum-based chemotherapy regardless of PD-L1 status, based on a single-arm phase II trial [18]. In Europe, pembrolizumab and atezolizumab are approved as first-line therapies for patients with PD-L1–positive metastatic bladder cancer who are cisplatin-ineligible [19]. In 370 patients unsuitable for cisplatin, pembrolizumab yielded a 29% ORR and a 7% complete response rate.

Subsequent Treatments for Metastatic Bladder Cancer

Although EV plus pembrolizumab has become the standard first-line regimen (EV-302/KEYNOTE-A39), consensus regarding optimal subsequent therapy for progressive disease following this regimen is lacking. Various therapeutic options are under investigation (Table 3).

Chemotherapy

Following EV plus pembrolizumab, platinum/gemcitabine-based chemotherapy may be considered, although clinical data are limited, and potential toxicities must be carefully evaluated. Patients initially treated with platinum-based chemotherapy, who have not progressed for at least 6–12 months afterward, may benefit from platinum re-challenge. A retrospective analysis of 296 patients from the Retrospective International Study of Cancers of the Urothelium cohort demonstrated that subsequent platinum-based combination chemotherapy significantly improved OS compared to non-platinum regimens (7.9 vs. 5.5 months, P=0.035) [20]. Single-agent therapies, including paclitaxel, docetaxel, gemcitabine, nab-paclitaxel, oxaliplatin, ifosfamide, topotecan, pemetrexed, lapatinib, gefitinib, and bortezomib, have yielded response rates ranging from 0% to 28% in phase II studies, highlighting the need for further research in this area [21].

Immunotherapy for Patients without Prior Immune Checkpoint Inhibitor Exposure

Pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab have demonstrated comparable efficacy and safety in patients whose disease progressed during or after initial platinum-based chemotherapy. In a randomized phase III trial involving 542 patients assigned to either pembrolizumab monotherapy or chemotherapy (paclitaxel, docetaxel, or vinflunine), pembrolizumab significantly improved OS (median OS, 10.3 vs. 7.4 months; HR, 0.73; 95% CI, 0.59–0.91; P=0.002), irrespective of PD-L1 expression status [22]. Nivolumab received FDA approval based on results from the single-arm phase II CheckMate 275 trial, which included 270 patients previously treated with platinum-based therapy; in this trial, the ORR was 19.6%, and median OS was 8.74 months [23].

EV Monotherapy for Patients Previously Treated with Immunotherapy and Platinum

EV-201, a single-arm phase II trial, evaluated 125 patients whose disease progressed after prior platinum-based chemotherapy and immune checkpoint inhibitor therapy [24]. The ORR was 44%, with a complete response rate of 12%. These findings led to accelerated FDA and European approvals of EV for patients with metastatic bladder cancer who had previously received PD-1/PD-L1 inhibitors and platinum-based chemotherapy, or who were cisplatin-ineligible and had undergone at least one prior systemic therapy. A subsequent phase III trial comparing EV monotherapy to single-agent chemotherapy demonstrated an OS improvement of approximately four months in the EV arm (12.88 vs. 8.97 months; HR, 0.70; 95% CI, 0.56–0.89) [25].

Fibroblast Growth Factor Receptor Inhibitors

Genomic analyses of urothelial carcinoma have identified fibroblast growth factor receptor (FGFR) alterations as potentially targetable mutations [26]. Erdafitinib, a pan-FGFR tyrosine kinase inhibitor, became the first FDA-approved targeted agent for metastatic bladder cancer harboring FGFR alterations after progression on platinum-based chemotherapy. In the recent THOR cohort study, erdafitinib was compared to docetaxel or vinflunine in patients with FGFR-mutated tumors that progressed after first-line treatment. Erdafitinib significantly improved both OS (median OS, 12.1 vs. 7.8 months; HR, 0.64; 95% CI, 0.47–0.88) and PFS (median PFS, 5.6 vs. 2.7 months; HR, 0.58; 95% CI, 0.44–0.78) [27]. Grade ≥3 toxicities were comparable between arms. The most frequent adverse events associated with erdafitinib included hand-foot syndrome (9.6%), stomatitis (8.1%), onycholysis (5.9%), and hyperphosphatemia (5.2%). Other FGFR inhibitors, such as infigratinib and rogaratinib, are currently under investigation in clinical trials.

Conclusion

Recent clinical studies have profoundly transformed the therapeutic landscape for metastatic bladder cancer that had remained largely unchanged for several decades. Cisplatin-based chemotherapy, previously the definitive standard of care, now competes with newer immune checkpoint inhibitors and ADCs. The combination of EV and pembrolizumab has demonstrated significant benefits in both progression-free and overall survival, becoming the new first-line standard of care. However, not all patients qualify for EV plus pembrolizumab, underscoring the need for individualized therapeutic strategies based on eligibility for platinum-based chemotherapy and suitability for immunotherapy. Continued research aims to further enhance therapeutic efficacy while minimizing toxicity, marking a new era of precision treatment in metastatic bladder cancer.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Table 1.

First-line treatment strategies for metastatic bladder cancer

Patient classification	Recommended treatment
Eligible for combination therapy	Enfortumab vedotin+pembrolizumab
(1) ECOG PS 0–2 and (2) GFR>30 mL/min and (3) adequate organ function	Enfortumab vedotin+pembrolizumab
Eligible for combination therapy	Platinum/gemcitabine+avelumab maintenance or
but ineligible for enfortumab vedotin	cisplatin/gemcitabine+nivolumab
Eligible for combination therapy	Platinum/gemcitabine
but ineligible for checkpoint inhibitor	Platinum/gemcitabine
Ineligible for combination therapy	Atezolizumab or pembrolizumab or best supportive care

ECOG, Eastern Cooperative Oncology Group Performance Status; PS, performance status; GFR, glomerular filtration rate.

Table 2.

Eligibility for platinum-based chemotherapy

Patient classification	Eligibility criteria
Platinum-eligible
Cisplatin-eligible	(1) ECOG PS>1 and
	(2) GFR>50–60 mL/min and
	(3) Audiometric hearing loss grade<2 and
	(4) Peripheral neuropathy grade <2 and
	(5) Cardiac insufficiency NYHA class <III
Carboplatin-eligible	(1) ECOG PS 2 or
	(2) GFR 30–60 mL/min or
	(3) not meeting other cisplatin-eligible criteria
Platinum-ineligible	(1) ECOG PS>2 or
	(2) ECOG PS 2 and GFR<60 mL/min or
	(3) GFR<30 mL/min or
	(4) Comorbidities grade ≥2

ECOG, Eastern Cooperative Oncology Group; PS, performance status; GFR, glomerular filtration rate; NYHA, New York Heart Association.

Table 3.

Further-line treatment strategies for metastatic bladder cancer

Patient classification	Recommended treatment
Pre-treated with enfortumab vedotin and CPI	Platinum-based chemotherapy
	If FGFR-positive: erdafitinib
	Sacituzumab govitecan
	Single-agent chemotherapy (paclitaxel, docetaxel, vinflunine)
	Clinical Trials
Pre-treated with platinum±CPI	Enfortumab vedotin
	If FGFR-positive: erdafitinib
	Checkpoint inhibitor
	Platinum/gemcitabine
	Sacituzumab govitecan
	Single-agent chemotherapy (paclitaxel, docetaxel, or vinflunine)
	Clinical trials
Pre-treated with single agent	Enfortumab vedotin
	If FGFR-positive: erdafitinib
	Checkpoint inhibitor
	Sacituzumab govitecan
	Chemotherapy (platinum-based, paclitaxel, docetaxel, or vinflunine)
	Clinical trials

CPI, checkpoint inhibitor; FGFR, fibroblast growth factor receptor.

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