Treatment of metastatic urothelial carcinoma of the bladder and urinary tract

INTRODUCTION — Bladder cancer is the most common malignancy involving the urinary system. Urothelial carcinoma (UC) is the predominant histologic type in the United States and Europe. In other areas of the world, non-urothelial carcinomas are more frequent. Much less commonly, urothelial cancers can arise in the renal pelvis, ureter, or urethra.

●(See "Malignancies of the renal pelvis and ureter".)

●(See "Urethral cancer".)

●(See "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder", section on 'Epidemiology'.)

The approach to systemic therapy for locally advanced unresectable or metastatic UC of the bladder and urinary tract is evolving. Systemic treatment options include antibody drug-conjugates, chemotherapy, immune checkpoint inhibitors, and targeted therapies, as single agents or in combination. The goals of therapy include controlling tumor burden, treating cancer-related symptoms, and improving overall survival. Although treatment intent for most patients with bladder cancer is palliative, some patients may have a chance at curative intent therapy.

The treatment of metastatic UC of the bladder and urinary tract is presented here. Other topics related to the management of locally advanced muscle-invasive urothelial carcinoma of the bladder cancer are discussed separately.

●(See "Radical cystectomy".)

●(See "Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer".)

●(See "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder".)

PROGNOSTIC FACTORS — Some clinical and molecular factors correlate with prognosis in metastatic urothelial carcinoma. Such prognostic factors can be used to determine which patients may benefit from therapy. (See 'Defining eligibility for systemic therapy' below.)

Clinical factors — Clinical factors associated with decreased survival in metastatic urothelial carcinoma (UC) include:

●Karnofsky Performance Status of less than 80 percent (table 1) [1-4]

●Visceral metastases (ie, lungs, liver, bone) [1-9]

●Low hemoglobin levels [9]

●Shorter duration among lines of therapy [10]

Molecular factors — Specific molecular alterations within the tumor are also being studied to help select treatment and predict survival outcomes.

●FGFR2 or FGFR3 – Tumors that express a fibroblast growth factor receptor (FGFR) 3 or 2 genetic alterations respond to the FGFR inhibitor erdafitinib after progression on a platinum-based chemotherapy regimen. Further details are discussed separately. (See 'Erdafitinib' below.)

●Other molecular alterations – Other molecular factors have also been assessed but are not validated for clinical use [11-13]. (See "Molecular biology of bladder cancer".)

INITIAL THERAPY — The approach to initial therapy for patients with metastatic urothelial cancer (UC) of the bladder and urinary tract is evolving (algorithm 1). Selection of therapy is based upon patient eligibility for systemic therapy (platinum-based chemotherapy, immunotherapy), performance status, and comorbidities. Clinical trial enrollment is encouraged, where available.

Defining eligibility for systemic therapy — All patients who are candidates for systemic therapy (chemotherapy, immunotherapy, and/or targeted therapy) should undergo evaluation of their suitability to tolerate therapy. Important factors to evaluate include age, performance status, concurrent comorbidities, and organ function (including cognitive function assessment). The selection of therapy should incorporate the patient's performance status and ability to tolerate therapy. An assessment that incorporates physiologic and biologic considerations can stratify patients into medically "fit" and "frail" populations, which are used to determine treatment options. This stratification of medically "fit" and "frail" is frequently used to classify patients in clinical trials but may eventually be redefined as therapy evolves and becomes well tolerated across different populations.

●Cisplatin eligibility – Patients being evaluated for cisplatin-based chemotherapy should also undergo assessment of kidney function, the presence of hearing loss and/or peripheral neuropathy (all of which could be adversely affected by cisplatin), and heart failure status (which determines the patient's ability to tolerate the fluid administered concurrently with cisplatin). For patients with impaired kidney function, reversible causes (eg, urinary tract obstruction secondary to a tumor mass) should be identified and treated prior to initiation of cisplatin-based therapy.

Patients who are medically fit and eligible for cisplatin-based combination chemotherapy meet all of the criteria below (table 2) [14]:

•World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status less than 2 (table 3) or a Karnofsky Performance Status greater than 70 percent (table 1)

•Creatinine clearance greater than or equal to 60 mL/minute

•No significant hearing loss (measured at audiometry of 25 dB at two contiguous frequencies)

•Grade <2 peripheral neuropathy (ie, sensory alteration or paresthesia, including tingling, but not interfering with activities of daily living)

•No clinical evidence of New York Heart Association class III or greater heart failure (table 4)

●Carboplatin eligibility – Patients who are candidates for carboplatin-based chemotherapy may have appropriate performance status but otherwise be ineligible for cisplatin-based combination chemotherapy due to kidney dysfunction, neuropathy, severe hearing loss, neuropathy, and/or heart failure.

●Immunotherapy eligibility – Patients being evaluated for immunotherapy should also undergo assessment for autoimmune conditions, infectious disorders, and previous exposure to immunomodulating agents (ie, steroids) and antibiotics. Further details on eligibility for immunotherapy are discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Defining immunotherapy eligibility'.)

Platinum-eligible

Enfortumab vedotin plus pembrolizumab — For patients with advanced or metastatic UC who are eligible for platinum-based (ie, cisplatin or carboplatin) chemotherapy, we recommend enfortumab vedotin plus pembrolizumab rather than platinum-based chemotherapy, as this combination improved overall survival (OS) with an acceptable toxicity profile in a phase III trial.

Dosing — Enfortumab vedotin is an antibody targeting the cell adhesion molecule nectin-4 linked to a microtubule inhibitor conjugate (monomethyl auristatin E). Enfortumab vedotin is administered intravenously (IV) at 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) on days 1 and 8 of a 21-day cycle. Pembrolizumab is given IV either at 200 mg every three weeks or 400 mg every six weeks and is administered after enfortumab vedotin when given on the same day. Enfortumab vedotin is typically administered in combination with pembrolizumab for a median of seven to nine cycles as tolerated, mainly to avoid the risk of cumulative neurotoxicity. Pembrolizumab is then continued as monotherapy for up to 24 months, or until disease progression or unacceptable toxicity during that period [15-17].

Efficacy — In a phase III trial (EV-302), 886 patients with previously untreated, locally advanced unresectable or metastatic UC who were eligible for platinum-based chemotherapy (ie, cisplatin or carboplatin) were randomly assigned to either enfortumab vedotin plus pembrolizumab or chemotherapy (gemcitabine plus either cisplatin or carboplatin) [17]. Among the patients who received chemotherapy, more than half received subsequent immunotherapy, either as maintenance avelumab (30 percent), upon disease progression (26 percent), or for other reasons (4 percent).

In preliminary results, relative to chemotherapy, enfortumab vedotin demonstrated the following [17]:

●Entire study population – Improved OS (median 31 versus 16 months, hazard ratio [HR] 0.47, 95% CI 0.38-0.58) and progression-free survival (PFS; median 13 versus 6 months, HR 0.45, 95% CI 0.38-0.54), as well as higher objective (68 versus 44 percent) and complete (29 versus 13 percent) response rates.

●Cisplatin-eligible patients – Data for cisplatin-eligible patients are discussed separately. (See 'Enfortumab vedotin plus pembrolizumab (cisplatin-eligible)' below.)

●Cisplatin-ineligible patients – Data for cisplatin-ineligible patients are discussed separately. (See 'Enfortumab vedotin plus pembrolizumab (cisplatin-ineligible)' below.)

●Other subgroups – OS and PFS benefits were also seen across all clinically relevant subgroups including age (older versus younger than 65 years), performance status (ECOG score of 0 versus 1 to 2 (table 3)), upper versus lower tract disease, presence versus absence of liver metastases, and level of programmed cell death ligand 1 (PD-L1) expression.

Toxicity — Some common toxicity considerations for enfortumab vedotin plus pembrolizumab are as follows:

●Peripheral neuropathy – Patients should be monitored for peripheral neuropathy, as enfortumab vedotin is associated with cumulative neurotoxicity. (See "Neurologic complications of cancer treatment with molecularly targeted and biologic agents", section on 'Enfortumab vedotin'.)

●Ocular, pulmonary, and cutaneous toxicities – Enfortumab vedotin has been associated with ocular toxicities, pneumonitis, and in rare cases, severe life-threatening cutaneous skin reactions. Patients on should be closely monitored and treated for these toxicities, which is discussed separately.

•Ocular toxicity (see "Ocular side effects of systemically administered chemotherapy", section on 'Antibody-drug conjugates')

•Pulmonary toxicity (see "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Other antibody-drug conjugates')

•Cutaneous toxicity, including severe cutaneous reactions (see "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'Antibody-drug conjugates')

●Hyperglycemia – Although enfortumab vedotin plus pembrolizumab can cause hyperglycemia, this combination may be safely used in patients with diabetes mellitus that is well controlled on therapy. Baseline HbA1c measurement is recommended. (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults".)

●Immunotherapy toxicity – Diagnosis and management of immune-related adverse events are discussed separately. (See "Toxicities associated with immune checkpoint inhibitors".)

In a phase III trial (EV-302), grade ≥3 toxicity was lower with enfortumab vedotin plus pembrolizumab versus platinum-based chemotherapy (56 versus 70 percent), with no new toxicity profiles noted. Common grade ≥3 toxicities for enfortumab vedotin plus pembrolizumab were maculopapular rash (8 percent), hyperglycemia, and neutropenia (5 percent each), as well as peripheral neuropathy and diarrhea (4 percent). By contrast, common grade ≥3 toxicities for chemotherapy were mainly hematologic, including anemia (31 percent), neutropenia (30 percent), and thrombocytopenia (18 percent).

Cisplatin-eligible — For patients with advanced or metastatic UC who are eligible for cisplatin-based regimens, enfortumab vedotin plus pembrolizumab is a preferred option for initial therapy as this combination improves OS with an acceptable toxicity profile.

For patients who are not eligible for, decline, or lack access to this combination, alternative options for initial therapy include nivolumab plus gemcitabine and cisplatin, or cisplatin-based chemotherapy followed by maintenance avelumab for patients without disease progression. Either approach is reasonable as the optimal sequencing of chemotherapy and immunotherapy for initial therapy (concurrent versus sequential) is not established. (See 'Nivolumab plus gemcitabine plus cisplatin' below and 'Cisplatin-based chemotherapy' below.)

Enfortumab vedotin plus pembrolizumab (cisplatin-eligible) — In a phase III trial (EV-302) of 886 patients with advanced or metastatic UC who were eligible for platinum-based chemotherapy, enfortumab vedotin plus pembrolizumab was compared to gemcitabine plus cisplatin or carboplatin [17]. Approximately one-third of patients in the control arm received maintenance immunotherapy. In preliminary results, among the 478 patients eligible for cisplatin, enfortumab vedotin plus pembrolizumab improved OS (median 32 versus 18 months, HR 0.53, 95% CI 0.39-0.72) and PFS (HR 0.48, 95% CI 0.38-0.62) relative to platinum-based chemotherapy.

Further details on this study, including results for the entire study population and toxicities, are discussed separately. (See 'Enfortumab vedotin plus pembrolizumab' above.)

Nivolumab plus gemcitabine plus cisplatin — Nivolumab plus gemcitabine is one appropriate option for initial therapy in cisplatin-eligible patients with advanced or metastatic UC who are ineligible for, decline, or lack access to enfortumab vedotin plus pembrolizumab. In a phase III trial, the addition of nivolumab to gemcitabine plus cisplatin improved OS but increased toxicity [18].

In an open-label phase III trial (CheckMate-901), 608 cisplatin-eligible patients with previously untreated unresectable or metastatic urothelial carcinoma were randomly assigned to either six cycles of nivolumab plus gemcitabine and cisplatin every three weeks followed by maintenance nivolumab, or six cycles of gemcitabine plus cisplatin every three weeks [18]. Patients assigned to nivolumab plus chemotherapy received up to six cycles of gemcitabine and cisplatin administered concurrently with nivolumab at a dose of 360 mg IV every three weeks followed by nivolumab monotherapy at a dose of 480 mg IV every four weeks up to two years, or until disease progression or unacceptable toxicity during that period.

Patients were permitted prior intravesical therapy (completed more than four weeks before) or prior neoadjuvant therapy, radiation therapy, or adjuvant platinum-based chemotherapy for locally advanced disease, with recurrence one year or more after treatment completion. Patients who discontinued cisplatin could be switched to gemcitabine plus carboplatin for the remainder of the chemotherapy cycles (up to six cycles total).

At median follow-up of 34 months the addition of nivolumab plus gemcitabine plus cisplatin improved OS (median 22 versus 19 months, HR 0.72, 95% CI 0.59-0.88) and PFS (median 7.9 versus 7.6 months, HR 0.72, 95% CI 0.59-0.88). Combination therapy also increased the duration of complete response (median 37 versus 13 months) and improved the objective (58 versus 43 percent) and complete response rates (22 versus 12 percent).

Grade ≥3 toxicity rates were higher with combination therapy versus gemcitabine plus cisplatin (77 versus 68 percent). Health-related quality of life after four months of therapy was similar between the two groups.

It is unclear whether the concurrent administration of immunotherapy with chemotherapy is superior to sequential administration of these agents, and further data are necessary. A subgroup of patients treated with gemcitabine plus cisplatin did receive sequential maintenance immunotherapy, but the efficacy of this approach compared with concurrent administration of nivolumab plus gemcitabine and cisplatin was not reported. Further details on the sequential administration of chemotherapy and maintenance immunotherapy are discussed below. (See 'Cisplatin-based chemotherapy' below and 'Maintenance therapy' below.)

Cisplatin-based chemotherapy — Cisplatin-based chemotherapy is one appropriate option for cisplatin-eligible patients with advanced or metastatic UC who are ineligible, decline, or lack access to enfortumab vedotin plus pembrolizumab. Patients who do not progress on cisplatin-based chemotherapy are treated with maintenance avelumab. (See 'Maintenance therapy' below.)

The choice between available cisplatin-based regimens is individualized based on patient and provider preferences. Options are as follows:

MVAC — Methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) (table 5) is an option for the initial therapy of patients with advanced or metastatic UC who are cisplatin-eligible, as this approach improved OS compared with single-agent cisplatin [5,19]. MVAC is administered as follows:

●MVAC – Methotrexate (30 mg/m² on days 1, 15, and 22), vinblastine (3 mg/m² on days 2, 15, and 22), doxorubicin (30 mg/m² on day 2), and cisplatin (70 mg/m² on day 2), repeated every 28 days for six cycles (table 5).

The efficacy of this regimen was demonstrated in a multicenter trial of 269 patients with advanced urothelial carcinoma who were randomly assigned to treatment with either MVAC or single-agent cisplatin [5]. Compared with cisplatin, MVAC resulted in:

●A significant improvement in the overall response rate (ORR; 39 versus 12 percent)

●A significant increase in median PFS (10 versus 4 months)

●A significant improvement in median OS (13 versus 8 months)

Toxicity is a major concern with MVAC therapy, particularly since many patients with bladder cancer are older adults or have multiple comorbidities. Myelosuppression, neutropenic fever, sepsis, mucositis, and nausea and vomiting are common. As an example, 54 percent of patients in one earlier series were hospitalized due to toxicity [20]. Furthermore, toxicity-related deaths have been reported in most trials evaluating MVAC for advanced urothelial cancer [5,21]. The use of dose-dense MVAC (which incorporates hematopoietic growth factor support) may ameliorate some of these toxicities, especially myelosuppression and mucositis [22,23].

Dose-dense MVAC — Dose-dense MVAC is another option for initial therapy of patients with advanced or metastatic UC of the bladder who are cisplatin-eligible.

Dose-dense MVAC is administered as follows:

●Dose-dense MVAC – Methotrexate (30 mg/m² on day 1), vinblastine (3 mg/m² on day 2), doxorubicin (30 mg/m² on day 2), and cisplatin (70 mg/m² on day 2) with granulocyte-colony stimulating factor (G-CSF) support, repeated every 14 days for six cycles (table 6).

Increasing the dose intensity of MVAC by administering treatment every two weeks with G-CSF support has also been evaluated in an effort to improve long-term survival. In a randomized phase III trial, although dose-dense MVAC failed to improve OS over classic MVAC, it improved PFS and reduced toxicity [24,25]. There is no consensus, and thus, both standard MVAC and dose-dense MVAC (table 6) are used frequently in clinical practice.

In a phase III trial (European Organisation for Research and Treatment of Cancer [EORTC] 30924), 263 patients with advanced or metastatic urothelial cancer were randomly assigned to either dose-dense MVAC (every two-week cycle with growth factor support) or classic MVAC (every four-week cycle) [24,25]. Patients treated with dose-dense MVAC received a median of six cycles and a treatment duration of 12 weeks, whereas those treated with classic MVAC received a median of four treatment cycles and a treatment duration of 21 weeks.

At median follow-up of 38 months, relative to classic MVAC, results for dose-dense MVAC were as follows [24]:

●Improved PFS (median 9.1 versus 8.2 months, two-year PFS 25 versus 12 percent, HR 0.75, 95% CI 0.58-0.98).

●Higher complete response rates (21 versus 9 percent).

●Similar OS (median 15.5 versus 14.1 months, two-year OS 35 versus 25 percent, HR 0.80, 95% CI 0.60-1.06). In subsequent follow-up, five-year OS was higher with dose-dense MVAC than classic MVAC, although the difference was not statistically significant (five-year OS 22 versus 14 percent) [25].

●A more favorable toxicity profile, including lower rates of grade ≥3 leukopenia (20 versus 62 percent) and mucositis (10 versus 17 percent), as well as neutropenic fever of any grade (10 versus 26 percent). These findings were likely attributed to the use of growth factor support.

Gemcitabine plus cisplatin — The combination of gemcitabine plus cisplatin (GC) is another option for initial therapy of patients with advanced or metastatic UC of the bladder who are cisplatin-eligible. GC has similar efficacy and less toxicity compared with MVAC (table 5). This regimen is administered as follows:

●GC – Gemcitabine (1000 mg/m² on days 1, 8, 15) plus cisplatin (70 mg/m² on day 2), repeated every 28 days for a maximum of six cycles (table 7). An alternative regimen consists of gemcitabine (1200 mg/m² on days 1 and 8) and cisplatin (75 mg/m² on day 2), repeated every 21 days for a median of six cycles.

In a phase III trial, 405 patients with metastatic UC were randomly assigned to initial therapy with up to six cycles of either GC or classic MVAC [26,27]. At median follow-up of 19 months, compared with MVAC, GC resulted in:

●Similar ORR (49 versus 46 percent).

●Similar time to disease progression (seven months in each arm, HR 1.05, 95% CI 0.85-1.30).

●Similar OS (14 versus 15 months, HR 1.04 95% CI 0.82-1.32). At five years, there was also a similar five-year survival rate (13 and 15 percent) [1].

●Similar quality of life, though patients experienced less weight loss, a better performance status, and less fatigue.

●Less grade ≥3 toxicity, including neutropenia (71 versus 82 percent), neutropenic sepsis (2 versus 14 percent), and mucositis (1 versus 22 percent) [26,27].

Alternate dosing schedules with the GC regimen have used a three-week instead of four-week schedule [28-30]. Although these different GC schedules have not been compared in randomized phase III trials, the results appear to be similar. Of note, one trial comparing dose-dense GC versus dose-dense MVAC demonstrated no apparent benefit to dose intensification [31].

PGC (paclitaxel plus GC) — The triplet combination of paclitaxel, gemcitabine, and cisplatin (PGC) (table 8) is another option for patients with metastatic UC of the bladder who are cisplatin-eligible. PGC is administered as follows:

●PGC – Paclitaxel (80 mg/m² before gemcitabine and cisplatin on days 1 and 8), gemcitabine (1000 mg/m² on days 1 and 8), and cisplatin (70 mg/m² on day 1), repeated every 21 days for a maximum of six cycles (table 8).

The efficacy of this regimen was demonstrated in the EORTC study 30987, which enrolled 626 patients with advanced UC (81 percent with primary bladder cancer) and randomly assigned them to treatment with GC or PGC for a maximum of six cycles. At median follow-up of 4.6 years, compared with GC, PGC resulted in the following [32]:

●An increase in the ORR (56 versus 44 percent).

●A trend towards an improvement in PFS (median 8.3 versus 7.6 months, HR for progression 0.87, 95% CI 0.74-1.03).

●A trend towards longer OS (median 16 versus 13 months, HR for death 0.85, 95% CI 0.72-1.02). When the analysis was restricted to patients who met all eligibility criteria (92 percent of the randomized population), PGC was associated with a significant increase in OS (median 16 versus 13 months, HR 0.82, 95% CI 0.68-0.98). In addition, PGC was associated with a significant improvement in OS among patients with primary bladder cancer compared with GC (median 16 versus 12 months, HR 0.80, 95% CI 0.66-0.97).

●An increased incidence of serious (grade 3/4) toxicity, including neutropenia (65 versus 51 percent), fatigue (15 versus 11 percent), and infections (18 versus 14 percent), but a lower incidence of serious (grade 3/4) thrombocytopenia (35 versus 52 percent).

Cisplatin-ineligible — For patients who are ineligible for cisplatin-based therapy, we recommend initial treatment with enfortumab vedotin plus pembrolizumab rather than platinum-based chemotherapy, as this combination has high objective response rates and improves OS with an acceptable toxicity profile. (See 'Enfortumab vedotin plus pembrolizumab (cisplatin-ineligible)' below.)

For cisplatin-ineligible patients who are ineligible for, decline, or lack access to this combination, gemcitabine plus carboplatin is an appropriate alternative. (See 'Gemcitabine plus carboplatin' below.)

Enfortumab vedotin plus pembrolizumab (cisplatin-ineligible) — For cisplatin-ineligible patients with advanced or metastatic UC, the efficacy of enfortumab vedotin plus pembrolizumab was initially demonstrated in early phase clinical trials, including a phase Ib/II trial (EV-103/KEYNOTE 869 Cohort A), which demonstrated high ORR response rates (65 percent or more) [33,34].

The clinical benefit of this combination was subsequently confirmed in randomized phase II and III trials [17,34]. Data are as follows:

●In a randomized phase II trial (EV-103/ KEYNOTE-869 Cohort K), 149 patients with previously untreated, locally advanced or metastatic UC who were ineligible for cisplatin-based regimens were randomly assigned to the combination of pembrolizumab plus enfortumab vedotin (76 patients) or enfortumab vedotin alone (73 patients) [34]. At median follow-up of approximately 15 months, relative to enfortumab vedotin alone, the combination resulted in the following:

•A non-statistically significant trend towards an improved objective response rate (65 percent versus 45 percent). Complete response rates were also higher for the combination (11 versus 4 percent).

•A non-statistically significant trend towards longer one-year PFS (55 versus 36 percent) and OS (81 versus 70 percent).

•The median duration of response for the combination was not reached versus 13 months for enfortumab vedotin alone.

•The median time to response was similar for both treatment arms (two months each).

•For the 121 patients from both Cohort A and K treated with the combination, the objective and complete response rates were 68 and 12 percent, respectively [16].

●A subsequent randomized phase III trial (EV-302) comparing enfortumab vedotin plus pembrolizumab to gemcitabine plus cisplatin or carboplatin including a subgroup of 408 patients who were cisplatin-ineligible [17]. In preliminary results, among this subgroup, enfortumab vedotin improved both OS (HR 0.43, 95% CI 0.31-0.59) and PFS (HR 0.43, 95% CI 0.33-0.55) relative to chemotherapy. Further data on the entire population and other subgroups are discussed separately. (See 'Enfortumab vedotin plus pembrolizumab (cisplatin-eligible)' above.)

The US Food and Drug Administration (FDA) granted accelerated approval for the combination of pembrolizumab plus enfortumab vedotin for the treatment of adult patients with locally advanced or metastatic UC who are not eligible for cisplatin-containing chemotherapy [15,16]. Of note, the United States prescribing label does not define criteria for cisplatin-ineligible patients; our definition is discussed separately. (See 'Defining eligibility for systemic therapy' above.)

Gemcitabine plus carboplatin — Gemcitabine plus carboplatin is an appropriate alternative for cisplatin-ineligible patients who are not eligible for, decline, or lack access to enfortumab vedotin plus pembrolizumab. Examples of patients who may be ineligible to receive enfortumab vedotin plus pembrolizumab include those with pre-existing neuropathy (as enfortumab vedotin is associated with cumulative neurotoxicity), active autoimmune disease, and/or pre-existing cutaneous disorders (as severe life-threatening cutaneous reactions have been reported with enfortumab vedotin). (See 'Toxicity' above.)

Patients who do not progress on gemcitabine plus carboplatin are subsequently offered switch maintenance therapy with avelumab. (See 'Maintenance therapy' below.)

In patients with advanced or metastatic UC and impaired kidney function or a poor performance status (ECOG ≥2) who are otherwise candidates for combination chemotherapy, gemcitabine plus carboplatin is well tolerated and as effective as more complex carboplatin-based combination regimens, such as MCAVI (methotrexate, carboplatin, and vinblastine). However, prior to selecting a regimen, it is important to assess the basis for kidney dysfunction. Treating simple and reversible causes, such as urinary obstruction by a primary tumor, may allow the use of cisplatin-based regimens. (See 'Nivolumab plus gemcitabine plus cisplatin' above and 'Cisplatin-based chemotherapy' above.)

In a randomized phase II/III trial (EORTC 30986) of 238 chemotherapy-naïve patients with advanced or metastatic UC, impaired kidney function (glomerular filtration rate <60 but >30 mL/minute) and/or a poor performance status (ECOG ≥2) were randomly assigned to either gemcitabine plus carboplatin or MCAVI [35]. Compared with MCAVI, treatment with carboplatin plus gemcitabine resulted in:

●Similar OS (median nine versus eight months, HR for death 0.94, 95% CI 0.72-1.22).

●Similar PFS (six versus four months, HR for progression 1.04, 95% CI 0.80-1.35).

●A non-statistically significant increase in ORR (41 versus 30 percent, respectively).

●Lower grade 3 to 4 toxicity rates (9 versus 21 percent), including neutropenia (52 versus 63 percent) and febrile neutropenia (5 versus 15 percent). However, gemcitabine plus carboplatin was associated with a higher rate of serious thrombocytopenia (47 versus 18 percent).

Other randomized trials have compared carboplatin-based regimens with cisplatin-based regimens, but interpretation of results were limited by the small number of patients enrolled [36-38]. However, neither efficacy nor toxicity could be evaluated due to the small number of patients enrolled.

Other agents

●Gemcitabine plus taxanes – Regimens that combine gemcitabine with a taxane (either paclitaxel or docetaxel) are active as initial therapy in patients with metastatic UC who are ineligible for cisplatin-based regimens but are still candidates for combination therapy.

•The combination of paclitaxel plus gemcitabine results in objective response rates of 54 to 70 percent and median survival of 13 to 16 months [39-42]. Toxicity with this combination is primarily hematologic, although severe pulmonary toxicity was reported in five patients treated with paclitaxel on a weekly schedule in one series [41].

•Two phase II trials reported outcomes using the combination of docetaxel plus gemcitabine, with ORRs of 33 and 52 percent and median OS of 13 and 15 months [43,44].

●Gemcitabine plus eribulin – The combination of gemcitabine with eribulin has been investigated in one early phase II trial, but its role in the treatment of patients with cisplatin-ineligible advanced urothelial cancer is not established [45].

Platinum-ineligible — For patients who are ineligible for any platinum-based (ie, cisplatin or carboplatin) chemotherapy, we suggest enfortumab vedotin plus pembrolizumab rather than other systemic agents, extrapolating from data in cisplatin-ineligible patients. (See 'Enfortumab vedotin plus pembrolizumab (cisplatin-ineligible)' above.)

Single-agent pembrolizumab (table 9) is an alternative for those who are anticipated to not tolerate this combination therapy or who lack access to enfortumab vedotin (algorithm 1). (See 'Pembrolizumab' below.)

Patients not eligible for initial therapy with any of the above regimens may be candidates for single-agent chemotherapy and/or best supportive care. (See 'Single-agent chemotherapy' below.)

Enfortumab vedotin plus pembrolizumab — We recommend enfortumab vedotin plus pembrolizumab for patients who are ineligible for any platinum-based combination chemotherapy regimen. The use of this combination in this population is extrapolated from data in patients who are ineligible for cisplatin-based therapy, which demonstrated high response rates in non-randomized trials as well as an OS benefit relative to platinum-based chemotherapy in randomized trials. Further details are discussed separately. (See 'Enfortumab vedotin plus pembrolizumab (cisplatin-ineligible)' above.)

Pembrolizumab — In the phase II KEYNOTE-052 study, 370 patients with advanced UC who were not eligible for a cisplatin-based regimen received initial therapy with pembrolizumab at 200 mg every three weeks for up to two years (table 9) [46-48]. The average age of the study population was 74 years, and 29 percent of patients were aged ≥80 years. Liver metastases were present in 21 percent, and 42 percent were performance status 2; 50 percent of patients were included because of kidney impairment.

At a median follow-up of almost five years (56 months), the ORR, the primary endpoint of the study, was 29 percent for the entire cohort, including complete and partial response rates of 9 and 20 percent, respectively [48]. The median duration of response was 33 months. Response rates were consistent across all major subgroups. The ORR was higher in patients with combined positive score (CPS) >10 compared with those with CPS ≤10 (47 versus 21 percent). Overall, the median OS was 11 months and four-year OS was 19 percent.

Based on these data, the US FDA approved single-agent pembrolizumab as initial therapy in patients who are not eligible for any platinum-containing chemotherapy [15].

Single-agent chemotherapy — Many chemotherapy drugs are active as single agents in patients with advanced or metastatic UC, either as initial or later lines of therapy. However, these agents do not improve OS and responses are generally not durable. The choice between agents should be based on clinical factors, such as the patient's performance status, and the patient's values and preferences. Options include platinum agents (cisplatin, carboplatin), gemcitabine, vinca alkaloids (vinblastine, vinflunine), anthracyclines (doxorubicin, epirubicin), methotrexate, taxanes (paclitaxel, docetaxel, and nanoparticle albumin-bound paclitaxel [nabpaclitaxel]), and ifosfamide [49-58].

Other agents — Other regimens either are not used or remain investigational for initial treatment of advanced or metastatic UC.

●Nivolumab plus ipilimumab – We do not offer initial treatment with nivolumab plus ipilimumab. In preliminary results from a phase III trial (CheckMate-901, part 2), nivolumab plus ipilimumab failed to improve OS over gemcitabine plus cisplatin or carboplatin [59].

●Pembrolizumab plus platinum-based chemotherapy – We do not offer initial treatment with pembrolizumab plus platinum-based chemotherapy. In a phase III trial (KEYNOTE-361) of 1010 patients with treatment-naïve unresectable or metastatic urothelial carcinoma, the addition of pembrolizumab to chemotherapy did not improve OS or PFS [60].

●Atezolizumab – We do not offer initial therapy with atezolizumab, either as monotherapy or in combination with cisplatin-based chemotherapy, in patients with metastatic UC.

Atezolizumab was initially granted accelerated approval by the US FDA, based on clinical activity in a single-arm phase II trial [61]. However, in a randomized phase III trial (IMvigor130), the addition of atezolizumab to gemcitabine plus platinum-based chemotherapy as initial therapy improved PFS but not OS [62,63]. Additionally, atezolizumab monotherapy did not improve OS over platinum-based chemotherapy [64]. Based on these data, regulatory approval for atezolizumab was voluntarily withdrawn in the United States for patients with advanced or metastatic UC who are ineligible for either cisplatin-containing chemotherapy and whose tumors express PD-L1, or those who are ineligible for any platinum-containing chemotherapy [65].

●Avelumab – The use of avelumab as initial therapy in metastatic UC remains investigational. In a single-arm phase II trial (ARIES), avelumab demonstrated clinical activity in patients with PD-L1 positive metastatic UC who are cisplatin ineligible [66]. At median follow-up of 10 months, objective and complete response rates were 24 and 9 percent, respectively.

MAINTENANCE THERAPY

Avelumab — For patients with advanced or metastatic urothelial carcinoma (UC) who do not progress (ie, achieve an objective response or stable disease) following platinum-based chemotherapy and are eligible to receive immune checkpoint inhibitors, we suggest maintenance avelumab, rather than best supportive care (BSC) alone, as this approach improved overall survival (OS) and progression-free survival (PFS) in a phase III trial [67,68]. Although this study only evaluated maintenance avelumab in patients who received gemcitabine plus platinum-based chemotherapy, we also offer this approach to those who have not progressed on other platinum-based chemotherapy regimens, extrapolating from the results of this trial.

For those treated with a platinum-based chemotherapy who are ineligible for maintenance immunotherapy, we offer observation with BSC rather than maintenance therapy with other systemic agents (algorithm 1).

Maintenance avelumab is administered at a flat dose of 800 mg every two weeks until disease progression or unacceptable toxicity after 4 to 10 weeks of completing therapy. We initiate maintenance avelumab after patients have completed four to six cycles of chemotherapy and have confirmed response or stable disease on radiographic imaging.

In a randomized phase III trial (JAVELIN Bladder 100), 700 patients with locally advanced unresectable or metastatic urothelial bladder cancer who experienced either an objective response (ie, complete or partial response) or stable disease after four to six cycles of gemcitabine plus platinum-based chemotherapy were randomly assigned to either maintenance avelumab and BSC or BSC alone [67]. The study included a subset of 358 patients (51 percent) with programmed cell death ligand 1 (PD-L1) positive tumors identified using a specific assay [69,70].

At median follow-up of approximately 39 months, in the entire study population, the addition of avelumab to BSC improved OS and PFS (three-year OS 36 versus 30 percent, median 24 versus 15 months, hazard ratio [HR] 0.76, 95% CI 0.63-0.91; three-year PFS 16 versus 5 percent, median 6 versus 2 months, HR 0.54, 95% CI 0.46-0.64) [68]. For those with PD-L1 positive tumors, avelumab also improved OS (HR 0.69, 95% CI 0.53-0.91) and PFS (HR 0.46, 95% CI 0.36-0.59). OS benefit from maintenance avelumab was still maintained despite a high proportion of patients treated with BSC receiving subsequent therapy (72 percent), most commonly programmed cell death protein 1 (PD-1) or PD-L1 inhibitors (53 percent).

Maintenance avelumab also improved survival regardless of the platinum-based chemotherapy regimen received, including gemcitabine plus cisplatin and gemcitabine plus carboplatin [71]. Preliminary data also suggest that avelumab has an OS benefit independent of the number of chemotherapy cycles received (between four and six cycles) [72].

Long-term treatment with maintenance avelumab was well tolerated and maintained quality of life [73]. In all patients, grade ≥3 toxicity rates were higher for maintenance avelumab than BSC (48 versus 25 percent), with no new toxicity signals identified; the most common grade ≥3 toxicities for those treated with avelumab for ≥12 months included urinary tract infection (3 percent each), diarrhea (<1 percent), and arthralgias (<1 percent) [68]. The grade ≥3 immune-related adverse event rate in those treated with avelumab was 7 percent. Two patients died from sepsis and ischemic stroke.

Based on these data, the US Food and Drug Administration (FDA) approved avelumab for maintenance therapy in patients with locally advanced or metastatic UC that has not progressed on initial platinum-based chemotherapy [74].

Other agents — The role of other agents, such as pembrolizumab [75], vinflunine [57,76], and rucaparib for tumors with a DNA repair deficiency phenotype [77], is not established in the maintenance setting, as they have demonstrated PFS but not OS benefit in randomized phase II trials.

SECOND-LINE THERAPY

Prior platinum, no prior immunotherapy — For patients with advanced or metastatic urothelial carcinoma (UC) who progress on a platinum-based regimen and have had not received prior treatment with immunotherapy, we recommend immune checkpoint inhibitors rather than chemotherapy. While we prefer pembrolizumab (table 9), which improved overall survival (OS) in a randomized trial, other options include nivolumab (table 10), and avelumab.

Pembrolizumab — In patients with advanced or metastatic UC who progress on platinum-based chemotherapy, pembrolizumab (table 9) prolongs OS with less toxicity and better quality of life compared with further lines of chemotherapy.

In a phase III trial (KEYNOTE-045), 542 patients with locally advanced or metastatic UC who recurred or progressed on a platinum-containing regimen were randomly assigned to pembrolizumab (200 mg every three weeks for 24 months) or investigator's choice of chemotherapy (paclitaxel, docetaxel, or vinflunine) [48,78-80].

At median follow-up of approximately 28 months, relative to chemotherapy, pembrolizumab improved OS (median OS 10 versus 7 months; one-year OS 44 versus 30 percent; two-year OS 27 versus 14 percent; hazard ratio [HR] 0.70, 95% CI 0.57-0.85) and objective response rates (21 versus 11 percent) [78,80]. Median duration of response was not reached for pembrolizumab versus four months for chemotherapy [80]. Progression-free survival (PFS) was similar between the two treatment arms (median PFS two versus three months, HR 0.96, 95% CI 0.79-1.16).

Grade ≥3 treatment-related adverse events with pembrolizumab were less frequent compared with chemotherapy (17 versus 50 percent) with longer time to health-related quality of life deterioration (3.5 versus 2.3 months, HR 0.72) [79]. Similar outcomes were demonstrated with longer follow-up of this study [48].

Pembrolizumab is approved by the US FDA for patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy [15].

Nivolumab — Nivolumab (table 10) is an option for patients with advanced or metastatic UC who progress on platinum-based chemotherapy, with objective response rates up to 26 percent [81,82].

●Single-agent nivolumab – In phase I and II studies, nivolumab has had significant activity in patients who have progressed after previous platinum-based therapy for metastatic UC [81,83].

In a phase II trial, 270 patients were treated with nivolumab (3 mg per kilogram every two weeks) [81]. The objective response rate was 20 percent, with responses at all levels of programmed cell death ligand 1 (PD-L1) expression. At seven months of follow-up, OS for the entire cohort was 9 months; for those with PD-L1 expression <1 and ≥1 percent, median OS was 6 and 11 months, respectively.

●What is the role of nivolumab plus ipilimumab? – Combination immunotherapy with nivolumab and ipilimumab in locally advanced or metastatic UC remains investigational [82,84-87], and further studies with longer follow-up are needed.

In an open-label phase II study (CheckMate 032), 274 patients with advanced or metastatic UC who progressed on previous platinum-based chemotherapy were randomly assigned to single-agent nivolumab 3 mg/kg until progression or to four cycles of either nivolumab 3 mg/kg plus ipilimumab 1 mg/kg or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, followed in either case by nivolumab 3 mg/kg maintenance therapy [82].

After a minimum follow-up of eight months, the combination of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg demonstrated a response rate of 38 percent (versus 26 percent with nivolumab alone and 27 percent with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). This combination group also demonstrated a nonsignificant trend towards improved PFS and OS (median PFS 4.9 months versus 2.8 and 2.6 months; median OS 15.3 months versus 9.9 and 7.4 months, respectively). Responses occurred in all treatment groups regardless of PD-L1 expression.

Grade ≥3 treatment-related toxicities, as well as serious adverse events, occurred more frequently in the nivolumab plus ipilimumab combination arms. However, many of the treatment-related toxicities resolved with immune-modulating medications.

Nivolumab is approved by the US Food and Drug Administration (FDA) for patients with advanced or metastatic UC who progress during or after previous platinum-based chemotherapy either for metastatic disease or for progressive disease less than 12 months after adjuvant or neoadjuvant chemotherapy.

Avelumab — Avelumab is an option for patients with advanced or metastatic UC who progress on platinum-based chemotherapy.

In a combined analysis of two phase I expansion cohorts, 161 patients with advanced or metastatic UC who progressed on platinum-based therapy were treated with avelumab [88]. At median follow-up of at least six months:

●Objective response rate for the entire cohort was 17 percent, including a complete response rate of 6 percent. The objective response rate was higher for PD-L1 positive versus negative tumors (24 versus 14 percent).

●Common treatment-related adverse events were infusion-related reaction (29 percent; all grade 1 to 2) and fatigue (16 percent). The grade ≥3 toxicity rate was 8 percent; the most common was fatigue (2 percent). One treatment-related death occurred (pneumonitis).

Avelumab is approved by the US FDA for the treatment of advanced UC that progressed during or after platinum-based chemotherapy.

Other agents — We do not offer durvalumab or atezolizumab to patients with advanced or metastatic UC that is refractory to platinum-based chemotherapy. In the United States, accelerated approval for these agents was voluntarily withdrawn for this indication when they both failed to confer an OS benefit over chemotherapy in separate randomized phase III trials (DANUBE for durvalumab [89] and IMvigor211 for atezolizumab [90,91]).

Prior pembrolizumab plus enfortumab vedotin — For patients who progress on pembrolizumab plus enfortumab vedotin, the optimal approach to second-line therapy is not established. Data for second-line therapy are limited for this population, and the approach to therapy is mainly based on clinical rationale. Patients should be encouraged to enroll in clinical trials, including those evaluating the use of other targeted agents as second-line therapy.

For patients who are not eligible for clinical trials, potential options for second-line therapy include the following:

●For cisplatin-eligible patients (table 2), we suggest cisplatin-based chemotherapy, with gemcitabine plus carboplatin as a reasonable alternative. Selection of therapy depends upon patient performance status, comorbidities, and toxicities related to prior therapy. For example, cisplatin-based therapy may be preferred for medically fit patients, whereas gemcitabine plus carboplatin may be preferred for less medically fit patients and/or those with cumulative peripheral neuropathy related to enfortumab vedotin. (See 'Cisplatin-based chemotherapy' above and 'Gemcitabine plus carboplatin' above.)

●For cisplatin-ineligible patients, we offer second-line therapy with gemcitabine plus carboplatin, although data are limited for this approach. (See 'Gemcitabine plus carboplatin' above.)

●Patients whose tumors harbor a fibroblast growth factor receptor (FGFR) alteration may also be evaluated for erdafitinib, regardless of platinum-eligibility. UpToDate experts consider patients who have been treated with enfortumab vedotin (a targeted antibody conjugated to a microtubule inhibitor) as having received prior chemotherapy. (See 'Erdafitinib' below.)

Prior nivolumab plus gemcitabine and cisplatin — For patients who progress on nivolumab plus gemcitabine and cisplatin, we offer second-line therapy using a similar approach to those who progress on both platinum-based chemotherapy and immunotherapy. (See 'Prior platinum and immunotherapy' below.)

Clinical trial enrollment is also encouraged, where available.

LATER-LINE THERAPY — Later-lines of therapy are based on multiple clinical factors including prior therapies received, specific tumor molecular alterations (ie, fibroblast growth factor receptor [FGFR] status), as well as patient comorbidities, preferences, and treatment goals.

Prior platinum and immunotherapy — For patients with advanced or metastatic urothelial carcinoma (UC) who relapse following treatment with a platinum-based regimen and immunotherapy, our approach is as follows:

FGFR mutation negative — For patients with disease lacking an FGFR2 or FGFR3 alteration who were previously treated with both platinum-based chemotherapy and immunotherapy with a programmed cell death 1 protein (PD-1) or PD-1 ligand (PD-L1) inhibitor, we suggest the antibody-drug conjugate enfortumab vedotin (if not previously received), as this agent improved overall survival (OS) in a randomized phase III trial. (See 'Enfortumab vedotin' below.)

Sacituzumab govitecan, another antibody-drug conjugate, is also a reasonable alternative in this setting, with a different toxicity profile from other targeted agents. Further data are also needed to determine a survival benefit for this agent. (See 'Sacituzumab govitecan' below.)

Enfortumab vedotin — Enfortumab vedotin improved both OS and progression-free survival (PFS) over chemotherapy in a randomized phase III trial [92,93].

Based on data from phase I and II trials [94,95], enfortumab vedotin was evaluated in a phase III clinical trial (EV-301) of 608 patients with locally advanced unresectable or metastatic UC (including those with squamous differentiation or mixed cell types) previously treated with platinum-based chemotherapy and PD-1/PD-L1 inhibitor [92,93]; however, those who progressed on maintenance avelumab were not included in this trial. Patients were randomly assigned to either enfortumab vedotin or investigator's choice of chemotherapy (docetaxel, paclitaxel, or vinflunine). At median follow-up of approximately 24 months, compared with chemotherapy, enfortumab vedotin improved OS (median 13 versus 9 months, hazard ratio [HR] 0.70, 95% CI 0.58-0.85), PFS (median 6 versus 4 months, HR 0.63, 95% CI 0.53-0.76), and overall response rates (41 versus 19 percent) [93].

Grade ≥3 toxicity rates for any adverse event were similar between the two treatment arms (52 versus 51 percent). Grade ≥3 toxicities specifically associated with enfortumab vedotin included rash (15 percent), peripheral neuropathy (5 percent), and hyperglycemia (4 percent). Ocular toxicities, pneumonitis (eg, interstitial lung disease) [96,97], and severe cutaneous adverse reactions, including cases of Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have also been reported with this agent. (See 'Toxicity' above.)

Enfortumab vedotin is approved by the US Food and Drug Administration (FDA) for patients with locally advanced or metastatic UC who have progressed on both platinum-based chemotherapy and immunotherapy [16].

Sacituzumab govitecan — Sacituzumab govitecan is an antibody-drug conjugate that targets Trop-2, a transmembrane glycoprotein highly expressed in most UC, and is coupled with SN-38, an active metabolite of irinotecan. Sacituzumab govitecan dose is administered with a dose of 10 mg/kg once weekly on days 1 and 8 every 21 days until disease progression or unacceptable toxicity. Patients should be premedicated to prevent infusion reactions and treatment-induced nausea and vomiting, which is discussed separately. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Use of premedication to prevent infusion reactions'.)

In an open-label phase II trial (TROPHY-U-01), 113 patients with advanced UC previously treated with platinum-based chemotherapy or immunotherapy (either with a PD-1 or PD-L1 inhibitor) received sacituzumab govitecan [98]. In this study, objective and complete response rates were 27 and 5 percent, respectively. Median OS and PFS were 5 and 11 months, respectively [98].

Grade ≥3 toxicities included neutropenia (35 percent), leukopenia (18 percent), anemia (14 percent), diarrhea and febrile neutropenia (10 percent each), lymphopenia (7 percent), urinary tract infection (6 percent), and fatigue and nausea (4 percent each). Neutropenia was among the most common adverse reactions leading to dose interruption, and approximately one-third (30 percent) of patients used growth factor support, such as granulocyte-colony stimulating factor (G-CSF). There was one treatment-related death due to sepsis from febrile neutropenia.

Sacituzumab govitecan has accelerated approval from the US FDA for patients with locally advanced or metastatic UC who have previously received a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor [99]. However, this approval remains contingent on further randomized data confirming survival benefit and acceptable toxicity for this agent.

FGFR mutation positive

Erdafitinib — For patients with advanced or metastatic UC and an FGFR 3 or 2 genetic alteration, we suggest erdafitinib, an FGFR inhibitor, as this approach improved OS in a phase III trial. Although erdafitinib is approved after platinum-based chemotherapy in this population, we use it after disease progression on both platinum-containing chemotherapy (or an antibody-drug conjugate) and immunotherapy.

Enfortumab vedotin, if not previously received, and sacituzumab govitecan are also alternative options in this patient population. These agents have not been specifically tested in patients with FGFR alterations, and further data are necessary to confirm an OS benefit. Randomized trials are also needed to direct the appropriate sequencing of these agents relative to erdafitinib. (See 'Enfortumab vedotin' above and 'Sacituzumab govitecan' above.)

Patients should be selected for therapy with erdafitinib based on the US FDA-approved companion diagnostic test for FGFR2/3 somatic mutations or translocations using reverse transcription polymerase chain reaction (RT-PCR) [100,101]. Tumors may be assessed either at the initial onset of metastatic disease or upon progression after initial lines of systemic therapy. Other genomic platforms may also be used [101].

●The efficacy of erdafitinib was initially demonstrated in early phase clinical trials [102-106]. This included an open-label phase II trial (BLC2001), which demonstrated an objective response rate of 40 percent and median OS of 11 months [102,104].

●Based on these data, erdafitinib was evaluated in an open-label phase III trial (THOR, cohort 1) of 266 patients with advanced unresectable or metastatic UC with an FGFR2 or FGFR3 mutation who progressed on one or two prior lines of therapy, including a PD-(L)1 inhibitor [107]. Patients were randomly assigned to either erdafitinib or investigator's choice of chemotherapy (docetaxel or vinflunine).

At median follow-up of 16 months, erdafitinib improved OS and PFS relative to chemotherapy (median OS 12 versus 8 months, HR 0.64, 95% CI 0.47-0.88; median PFS 6 versus 3 months, HR 0.58, 95% CI 0.44-0.78) [107]. An OS benefit was seen across all clinically relevant subgroups, including those with FGFR mutations or translocations. Erdafitinib also improved objective response rates (46 versus 12 percent) and complete response rates (7 versus 1 percent) compared with chemotherapy.

Grade ≥3 toxicity rates were similar between the two treatment arms (46 percent each). For erdafitinib, grade ≥3 toxicities included palmar-plantar erythrodysesthesia (10 percent), stomatitis (8 percent), onycholysis (6 percent), hyperphosphatemia (5 percent), and diarrhea (3 percent), central serous retinopathy (CSR), and eye disorders other than CSR (2 percent each). (See "Nephrotoxicity of molecularly targeted agents and immunotherapy", section on 'FGFR inhibitors'.)

●Erdafitinib was also compared to pembrolizumab in an open-label phase III trial (THOR, cohort 2) of 351 patients with advanced unresectable or metastatic UC with an FGFR2 or FGFR3 mutation who progressed on one prior therapy and were naïve to a PD-L1 inhibitor [108]. At median follow-up of 33 months, erdafitinib demonstrated similar OS (median 11 months each, HR 1.18, 95% CI 0.92-1.51) relative to pembrolizumab.

Based on the phase II BLC2001 trial, the US FDA granted accelerated approval for erdafitinib for patients with locally advanced or metastatic UC with a susceptible FGFR3 or FGFR2 genetic alteration that has progressed during or following platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant chemotherapy [100].

Cisplatin-ineligible, no prior platinum, prior immunotherapy — For patients who are ineligible for cisplatin-based chemotherapy, have not received prior platinum-based chemotherapy, and progress on immunotherapy, options include enfortumab vedotin, if not previously received, or chemotherapy not previously received.

Enfortumab vedotin — Enfortumab vedotin is active in patients with metastatic UC who are ineligible for cisplatin-based chemotherapy and have progressed on prior immunotherapy. This agent was evaluated in an open-label phase II trial (EV-201) of 91 patients with locally advanced or metastatic disease who were ineligible for cisplatin, had not received prior platinum-based chemotherapy in the locally advanced or metastatic setting, and were previously treated with either a PD-1 or PD-L1 inhibitor [97]. In this study, enfortumab vedotin had an objective response rate of 52 percent, including complete and partial response rates of 20 and 31 percent, respectively. Grade ≥3 toxicities included neutropenia (9 percent), maculopapular rash (8 percent), and fatigue (7 percent). Four patients died of treatment-related toxicities including acute kidney injury, metabolic acidosis, multiple organ dysfunction syndrome, and pneumonitis.

Based on these data, enfortumab vedotin received regulatory approval from the US FDA in patients with locally advanced or metastatic UC who are ineligible for cisplatin-based chemotherapy and have previously received one or more prior lines of therapy [16]. Further randomized trials directly comparing enfortumab vedotin with other agents in this specific patient population are necessary.

The efficacy of enfortumab vedotin in patients who have relapsed after both platinum-based chemotherapy and immunotherapy is discussed above. (See 'Enfortumab vedotin' above.)

Chemotherapy — In patients with treatment-refractory disease who are ineligible for cisplatin-based chemotherapy, single-agent chemotherapy is a reasonable alternative to enfortumab vedotin. Single-agent chemotherapy may also be used for cisplatin-ineligible patients without access to enfortumab vedotin. Patients may be offered alternative chemotherapy not previously received. (See 'Single-agent chemotherapy' above.)

Ineligible for targeted therapy — Patients who are ineligible for or decline targeted therapy may be offered single-agent chemotherapy as an alternative. Patients should be encouraged to enroll in clinical trials, where available.

Single-agent chemotherapy — Some chemotherapy agents have clinical activity in treatment-refractory advanced or metastatic UC, with objective response rates ranging between 10 and 28 percent. Selection of therapy is based on patient and provider preference and prior chemotherapy received.

Vinflunine — Vinflunine is active in treatment-refractory disease [109,110]. In the phase III trial of 370 patients with treatment-refractory advanced or metastatic UC, vinflunine improved survival relative to best supportive care (6.9 versus 4.6 months, hazard ratio [HR] 0.88, 95% CI 0.69-1.12) and an objective response rate of 9 percent.

Vinflunine is approved in Europe for second-line treatment of UC.

Pemetrexed — Pemetrexed is active in treatment-refractory advanced or metastatic UC. In a phase II study of 47 previously treated patients, the objective response rate for 28 percent, including three complete responses (6 percent) [111]; median OS was 10 months. By contrast, pemetrexed had minimal efficacy in a separate phase II study [112].

Taxanes — Taxanes that have clinical activity in treatment-refractory disease include paclitaxel [51,58,113], nanoparticle albumin-bound paclitaxel (nabpaclitaxel) [58,114], and docetaxel [54].

In a randomized phase II trial of 199 patients with platinum-refractory metastatic UC, nabpaclitaxel and paclitaxel demonstrated similar OS (7.5 versus 8.8 months, HR 0.95, 90% CI 0.70-1.30), PFS (3.4 versus 3.0 months, HR 0.92, 90% CI 0.68-1.23), and objective response rate (22 versus 25 percent) [58].

Other agents — Other options include gemcitabine [55], ifosfamide [50,115], and oxaliplatin [40].

INVESTIGATIONAL AGENTS — Various agents remain under investigation in the treatment of patients with treatment-refractory metastatic UC. These include:

●Soluble EphB4-human serum albumin (sEphB4-HSA) – This agent was evaluated in combination with pembrolizumab in a phase II trial of 70 patients with locally advanced or metastatic UC that recurred or progressed on platinum-based chemotherapy [116]. At median follow-up of 23 months, in the entire study population the objective response rate was 37 percent, and median overall survival (OS) was 15 months. Among patients whose tumors expressed EphrinB2, the target of sEphB4-HSA, the objective response rate and complete response rate were 52 and 24 percent respectively, and median OS was 22 months.

●Rogaratinib – Rogaratinib, an oral pan-fibroblast growth factor receptor (FGFR1-4) inhibitor, was investigated in a randomized phase II/III trial (FORT-1) of 175 patients with advanced or metastatic fibroblast growth factor receptor 1 (FGFR1)- or FGFR3-positive (based on RNA overexpression) UC previously treated with platinum-based chemotherapy [117]. At median follow-up of 11 months, in the entire study population, rogaratinib did not improve objective response rate or OS compared with investigator's choice of chemotherapy (docetaxel, paclitaxel, or vinflunine). In a retrospective exploratory analysis, the objective response rate was higher for rogaratinib for the subset of patients with tumors positive for FGFR3 mRNA and with FGFR3 DNA alterations versus the entire study population (52.4 versus 20.7 percent).

SPECIAL CONSIDERATIONS

Oligometastatic disease

●Definition – Based on an expert opinion paper, the definition of oligometastatic disease for urothelial bladder cancer is a maximum of three metastatic sites (other than the pelvic lymph nodes) that are all resectable or amenable to stereotactic body radiotherapy (SBRT) [118].

●Management – There are limited data for the optimal treatment approach. For patients with oligometastatic UC and no disease progression on initial systemic platinum-based chemotherapy, maintenance therapy with avelumab is one appropriate management strategy that confers an overall survival advantage. (See 'Maintenance therapy' above.)

Alternatively, select patients with oligometastatic disease, good performance status, and minimal comorbidities who have a good partial response to initial systemic therapy may be candidates for local therapy (surgical metastasectomy or SBRT) to the remaining sites of disease [118-120]. However, this strategy has not been evaluated in high-quality randomized clinical trials. Multidisciplinary input is necessary for patients being evaluated for this approach. Patient selection may also be influenced by age and anticipated life expectancy. Restaging imaging studies to confirm oligometastatic disease must be obtained after the completion of systemic therapy and prior to evaluating for local therapy. Patients who are disease-free after local therapy to oligometastatic disease also require close surveillance for disease recurrence.

Non-urothelial bladder cancer — Urothelial carcinomas constitute most bladder cancers in the United States, while squamous cell carcinomas and adenocarcinomas comprise a small fraction of bladder cancers. The management of non-urothelial bladder cancer, including chemotherapy for the treatment of advanced disease, is discussed separately. (See "Non-urothelial bladder cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Bladder cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Bladder cancer diagnosis and staging (Beyond the Basics)" and "Patient education: Bladder cancer treatment; muscle invasive cancer (Beyond the Basics)" and "Patient education: Bladder cancer treatment; non-muscle invasive (superficial) cancer (Beyond the Basics)")

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bladder cancer".)

SUMMARY AND RECOMMENDATIONS

●General principles – The approach to systemic therapy for locally advanced unresectable or metastatic urothelial carcinoma (UC) of the bladder and urinary tract is evolving. Systemic treatment options include antibody-drug conjugates, chemotherapy, immune checkpoint inhibitors, and targeted therapies, as single agents or in combination. (See 'Introduction' above.)

The goals of therapy include controlling tumor burden, treating cancer-related symptoms, and improving overall survival. Although treatment intent for most patients with bladder cancer is palliative, some patients may have a chance at curative intent therapy.

●Initial therapy – For patients with advanced unresectable or metastatic UC, we recommend initial therapy with enfortumab vedotin plus pembrolizumab rather than platinum-based chemotherapy (algorithm 1) (Grade 1B). (See 'Enfortumab vedotin plus pembrolizumab' above.)

•However, some patients may decline, lack access to, or be poor candidates for enfortumab vedotin plus pembrolizumab, including those with poorly controlled neuropathy or autoimmune disease. In such cases, appropriate alternatives include nivolumab plus gemcitabine and cisplatin, or cisplatin-based chemotherapy followed by maintenance immunotherapy for patients without disease progression. The optimal sequencing of chemotherapy and immunotherapy for initial therapy (concurrent versus sequential) is not established. (See 'Nivolumab plus gemcitabine plus cisplatin' above and 'Cisplatin-based chemotherapy' above.)

Options for cisplatin-based chemotherapy include:

-Methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) (table 5)

-Dose-dense MVAC (table 6)

-Gemcitabine plus cisplatin (GC) (table 7)

-Paclitaxel, gemcitabine, and cisplatin (PGC) (table 8).

•Other alternatives to enfortumab vedotin plus pembrolizumab include gemcitabine plus carboplatin or single-agent pembrolizumab (table 9) (See 'Gemcitabine plus carboplatin' above and 'Pembrolizumab' above.)

●Subsequent-line therapy

•For patients who progress on enfortumab vedotin plus pembrolizumab, we suggest cisplatin-based chemotherapy (Grade 2C), with gemcitabine plus carboplatin as a reasonable alternative. For patients whose tumors harbor a fibroblast growth factor receptor (FGFR) alteration, erdafitinib is also a reasonable alternative. (See 'Prior pembrolizumab plus enfortumab vedotin' above.)

•For patients with advanced or metastatic UC who progress on both platinum-based chemotherapy and immunotherapy, or for those who are ineligible for these options, our approach is as follows (see 'Prior platinum and immunotherapy' above):

-FGFR mutation positive – For patients with metastatic UC and an FGFR 3 or 2 genetic alteration, we suggest erdafitinib (Grade 2C). Enfortumab vedotin (if not already administered) and sacituzumab govitecan are acceptable alternatives. (See 'FGFR mutation positive' above.)

-FGFR mutation negative – For patients with metastatic UC lacking an FGFR 3 or 2 genetic alteration, options include enfortumab vedotin (if not already administered), sacituzumab govitecan, or single-agent chemotherapy. (See 'FGFR mutation negative' above.)

•Later-line therapy includes single-agent chemotherapy agents, eg, vinflunine (where available), pemetrexed, taxanes, gemcitabine, ifosfamide, and oxaliplatin. (See 'Ineligible for targeted therapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Gary R MacVicar, MD, who contributed to earlier versions of this topic review.