INTRODUCTION — Bladder cancer is the most common malignancy involving the urinary system. Urothelial (transitional cell) carcinoma is the predominant histologic type in the United States and Europe, where it accounts for 90 percent of all bladder cancers. 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" and "Urethral cancer" and "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder", section on 'Epidemiology'.)
Approximately 25 percent of patients will have muscle-invasive disease and either present with or later develop metastases. Systemic chemotherapy is the standard approach for the initial treatment of patients with inoperable locally advanced or metastatic urothelial malignancies. Although initial response rates are high, the median survival with multiagent chemotherapy is approximately 15 months [1,2]. While this is superior to the estimated six-month survival with metastatic disease prior to the development of modern chemotherapy regimens, the five-year survival rate is approximately 15 percent with contemporary regimens [2,3]. Second-line chemotherapy has had only a limited role, but checkpoint inhibitor immunotherapy offers an additional option for patients progressing after their initial systemic therapy.
The approach to systemic treatment for metastatic urothelial carcinoma arising in the renal pelvis or ureter is based on results from trials composed primarily of patients with urothelial carcinoma of the bladder.
Systemic therapy for metastatic urothelial cancer is reviewed here. The use of neoadjuvant or adjuvant chemotherapy in conjunction with cystectomy and as part of a multimodality approach to preserve the bladder is discussed separately. (See "Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer" and "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder".)
PROGNOSTIC FACTORS — A number of clinical and molecular characteristics are correlated with survival. An appreciation of these prognostic factors is important for the interpretation of clinical trial results and for determining which patients may benefit from therapy. (See 'Defining eligibility for systemic therapy' below.)
Clinical factors — A poor performance status and the presence of visceral (ie, pulmonary, liver, bone) metastases correlate with shortened survival in clinical trials. This was illustrated by an Intergroup trial that compared cisplatin alone with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) (table 1) in patients with metastatic disease [4,5].
●The presence of bone or liver metastases and a poor performance status were most predictive of poor response and survival. The presence of these unfavorable features was associated with a median survival of four months, compared with 18 months in those patients without these features [4].
●No patients with liver or bone metastases, and only one patient with a Karnofsky Performance Status <80 percent survived past six years (table 2) [5].
Several subsequent reports confirmed the relationship between shortened survival and poor performance status or the presence of visceral metastases [2,6-10]. Similar to the first-line setting, the presence of liver metastases, a poor performance status, and a low hemoglobin level appear to predict a worse outcome in the second-line setting [11]. Shorter time from prior chemotherapy may enhance prognostic classification independent of the factors above, particularly in the setting of second-line therapy for advanced urothelial cancer [12].
Molecular factors — Molecular abnormalities are also being studied as prognostic/predictive factors, with the goal of using the molecular characteristics of an individual tumor to help select treatment and to predict outcome.
The presence of either a fibroblast growth factor receptor (FGFR) 3 or 2 genetic alteration predicts response to the FGFR inhibitor erdafitinib after progression on a platinum-based chemotherapy regimen. A US Food and Drug Administration (FDA)-approved companion diagnostic test using reverse transcription polymerase chain reaction (RT-PCR) can be used to assess for the presence of FGFR-specific genomic alterations in advanced urothelial tumors. Other genomic platforms can also be used [13]. (See 'Erdafitinib' below.)
The following factors have also been assessed, but none of these has been validated, and they should not be used to make clinical decisions:
●The role of mutations in the p53 gene has been extensively studied but remains uncertain. Multiple studies have suggested that such mutations are associated with resistance to MVAC chemotherapy and a poor prognosis [14-18]. In contrast, at least one report found that tumors with p53 mutations have a worse tumor-specific prognosis but with potentially increased sensitivity to the MVAC or equivalent regimen, at least in the adjuvant setting [19]. In an analysis of another trial, the presence of p53 mutations was neither predictive nor prognostic [20].
●The ERCC1 gene is involved in DNA repair and may mediate resistance to alkylating-agent chemotherapy. In a study of 57 patients with advanced bladder cancer who were treated with a cisplatin-based regimen, the median survival was significantly longer in patients with low ERCC1 levels (25 versus 15 months in those with high ERCC1 expression) [21].
●Other potential markers of chemotherapy resistance include the multidrug resistance p-glycoprotein, multidrug resistance-associated protein, glutathione, and metallothionein [22-26].
●Emerging data in the neoadjuvant setting have shown that mutations in the ERCC2 gene and in other DNA repair genes can be predictors of cisplatin chemotherapy response [27,28].
There is hope that molecular characterization will help to better inform the genomic alterations in urothelial cancers that can be targeted for novel therapies [29]. (See 'Investigational agents' below.)
FIRST-LINE THERAPY — A cisplatin-based combination chemotherapy regimen is the preferred initial therapy for patients with metastatic urothelial cancer of the bladder and urinary tract who are cisplatin candidates (algorithm 1). Importantly, a small proportion of patients with distant metastases in the nodes or lung may be cured by combination chemotherapy.
As described below, cisplatin-based combination chemotherapy results in superior survival when compared with single-agent cisplatin. However, cisplatin-related toxicity is a concern for many patients. In addition, not all patients with urothelial cancer are appropriate candidates for cisplatin therapy.
Defining eligibility for systemic therapy — All patients who are candidates for systemic therapy (either chemotherapy or immunotherapy) 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).
Patients being evaluated for cisplatin-based chemotherapy should also undergo assessment of renal 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 renal 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 being evaluated for immunotherapy should also undergo assessment for autoimmune conditions, infectious disorders, and previous exposure to immunomodulating agents (ie, steroids) and antibiotics. (See "Principles of cancer immunotherapy" and "Toxicities associated with checkpoint inhibitor immunotherapy".)
An assessment that incorporates physiologic and biologic considerations can stratify patients into medically "fit" and "frail" populations, which are used to determine treatment options. The treatment options based on ability to tolerate cisplatin are discussed below.
We agree with the use of criteria published by a consensus working group that defined medically frail patients in whom the decision to treat with a cisplatin-based regimen should be balanced with consideration of the increased risks of toxicity [30]:
●World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status 2 or greater (table 3) or a Karnofsky Performance Status of 60 to 70 percent or less (table 2)
●Creatinine clearance less than 60 mL/min
●Hearing loss (measured at audiometry) of 25 dB at two contiguous frequencies
●Grade 2 or greater peripheral neuropathy (ie, sensory alteration or paresthesia, including tingling, but not interfering with activities of daily living)
●New York Heart Association class III or greater heart failure (table 4)
For medically fit patients (who do not have any of the criteria described above), we recommend initial treatment using cisplatin-based combination chemotherapy. (See 'Cisplatin-based regimens' below.)
For patients who are unable to receive cisplatin due to medical frailty or comorbidities, options include a carboplatin-based regimen (carboplatin plus gemcitabine, or carboplatin, gemcitabine, and paclitaxel) or a non-platinum-based combination (eg, paclitaxel plus gemcitabine) or even monotherapy (eg, gemcitabine). For those who are cisplatin-ineligible and whose tumors express programmed cell death ligand-1 (PD-L1), checkpoint inhibitor immunotherapy with atezolizumab is a reasonable alternative. (See 'Ineligible for cisplatin-based regimens' below and 'Atezolizumab' below.)
For patients who are not eligible for any platinum-containing chemotherapy, we offer checkpoint inhibitor immunotherapy. (See 'Ineligible for any platinum-based regimens' below.)
A decision regarding treatment should take into account the patient's performance status and the clinician's medical judgment as to the patient's ability to tolerate chemotherapy:
●For patients with a good performance status (ie, ECOG performance status <2) who are otherwise candidates for combination chemotherapy, we suggest a carboplatin-based regimen (eg, carboplatin plus gemcitabine). However, a non-platinum-based combination (eg, paclitaxel plus gemcitabine) would be a reasonable alternative. (See 'Carboplatin-based regimens' below and 'Non-platinum regimens' below.)
●For patients with a poor performance status who are not candidates for combination chemotherapy, single-agent chemotherapy is a reasonable option. The choice of a specific treatment is based on patient and provider preference. (See 'Non-platinum regimens' below and 'Single-agent chemotherapy' below.)
Preferred options
Cisplatin-based regimens — Regimens used in the treatment of metastatic urothelial carcinoma include the following:
●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 5). 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.
●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 1).
●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).
●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.
The data to support these recommendations are reviewed below.
MVAC — Methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) (table 1) is a standard first-line option based on the results of randomized clinical trials demonstrating improved survival outcomes [4,31]. This 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 [4]. Compared with cisplatin, MVAC resulted in:
●A significant improvement in the overall response rate (ORR; 39 versus 12 percent)
●A significant increase in median progression-free survival (PFS; 10 versus 4 months)
●A significant improvement in median overall survival (OS; 13 versus 8 months)
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 [32,33]. Although dose-intense treatment probably does not result in a clinically meaningful difference in OS, increased experience has suggested a reduction in toxicity. There is no consensus, and thus, both standard MVAC and dose-dense MVAC (table 6) are used frequently in clinical practice. The National Comprehensive Cancer Network (NCCN) recommends dose-dense MVAC, but this recommendation remains controversial [34].
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 [35]. Furthermore, toxicity-related deaths have been reported in most trials evaluating MVAC for advanced urothelial cancer [4,36]. The use of hematopoietic growth factor support may ameliorate some of these toxicities, especially myelosuppression and mucositis [37,38].
GC — The combination of gemcitabine plus cisplatin (GC) (table 5) has similar efficacy and less toxicity compared with MVAC (table 1). This was demonstrated in a phase III trial in which 405 patients were randomly assigned to either GC or MVAC [1]. Compared with MVAC, GC resulted in:
●Similar ORR (49 versus 46 percent).
●Similar time to progression (seven months in each arm).
●Similar OS (14 versus 15 months). At five years, there was also a similar five-year survival rate (13 and 15 percent) [2].
●Similar quality of life, though patients experienced less weight loss, a better performance status, and less fatigue.
●Less serious (grade 3/4) toxicity, including neutropenia (71 versus 82 percent), neutropenic sepsis (2 versus 14 percent), and mucositis (1 versus 22 percent) [1].
This trial was designed to assess if GC is superior and was not powered to demonstrate equivalency between the two regimens, but given the similar efficacy and lesser toxicity, many consider GC rather than MVAC to be the standard first-line regimen for patients with advanced urothelial carcinoma of the bladder.
Alternate dosing schedules with the GC regimen have used a three-week instead of four-week schedule [39-41]. 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 [42].
PGC (paclitaxel plus GC) — The triplet combination of paclitaxel, gemcitabine, and cisplatin (PGC) is another option for patients with metastatic urothelial carcinoma. This was demonstrated in the European Organization for the Research and Treatment of Cancer (EORTC) study 30987, which enrolled 626 patients with advanced urothelial carcinoma (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 [43]:
●An increase in the ORR (56 versus 44 percent).
●A trend towards an improvement in PFS (median 8.3 versus 7.6 months, hazard ratio [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).
These results suggest that PGC is a treatment option for patients with metastatic urothelial carcinoma and suggest it should be used for those with the bladder as primary origin.
Ineligible for cisplatin-based regimens
Carboplatin-based regimens — For patients who are otherwise candidates for combination chemotherapy but are unable to receive cisplatin (eg, due to renal dysfunction, neuropathy, severe hearing loss, or heart failure), we suggest the combination of gemcitabine plus carboplatin. We also use gemcitabine plus carboplatin in these patients with symptomatic or bulky disease, in whom immediate treatment with cytotoxic chemotherapy is necessary [44].
The benefit of carboplatin-based therapy was demonstrated in the EORTC trial 30986 of 238 chemotherapy-naïve patients with impaired renal function (glomerular filtration rate <60 but >30 mL/min) and/or a poor performance status (ECOG ≥2) were randomly assigned to treatment with carboplatin and gemcitabine, or methotrexate, carboplatin, and vinblastine (MCAVI) [44]. Compared with MCAVI, treatment with carboplatin plus gemcitabine resulted in:
●A higher ORR (41 versus 30 percent, respectively) that did not reach statistical significance.
●No difference in median OS (nine versus eight months, HR for death 0.94, 95% CI 0.72-1.22).
●No difference in median PFS (six versus four months, HR for progression 1.04, 95% CI 0.80-1.35).
●Less serious (grade 3/4) toxicity overall (9 versus 21 percent), including neutropenia (52 versus 63 percent) and febrile neutropenia (5 versus 15 percent). However, it was associated with a higher rate of serious thrombocytopenia (47 versus 18 percent).
The final results of this trial suggest that the combination of gemcitabine and carboplatin is as effective as MCAVI, with a better toxicity profile, and support its use in patients with impaired renal function or a poor performance status (ECOG ≥2) who are otherwise candidates for combination chemotherapy.
However, it is important to ascertain the basis for renal dysfunction prior to selecting a regimen. When simple and reversible causes, such as urinary obstruction by a primary tumor, are the basis for reduced renal function, they should be corrected first; this may allow the use of standard MVAC (table 1) or GC regimens (table 5).
Several other randomized trials have compared carboplatin-based chemotherapy regimens with cisplatin-based combinations [45-47]. However, neither efficacy nor toxicity could be evaluated due to the small number of patients enrolled.
Non-platinum regimens — Regimens that combine gemcitabine with a taxane (either paclitaxel or docetaxel) rather than a platinum are options for initial therapy in patients with advanced urothelial cancer. For patients who are candidates for combination chemotherapy but are ineligible for platinum-based regimens, we offer gemcitabine with either paclitaxel or docetaxel.
●The combination of paclitaxel plus gemcitabine results in objective response rates (ORRs) of 54 to 70 percent and median survival of 13 to 16 months [48-51]. 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 [50].
●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 [52,53].
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 [54].
Atezolizumab (PD-L1 positive tumors) — Systemic immunotherapy with atezolizumab is one option for initial therapy for patients with advanced urothelial carcinoma who are ineligible for cisplatin-based chemotherapy and whose tumors express PD-L1. Another potential option is a non-cisplatin-based chemotherapy regimen. When choosing between these two options in such patients, we typically prefer immunotherapy in patients with indolent disease limited to lymph nodes and without autoimmune conditions. For others, we prefer chemotherapy. Further data on atezolizumab in this population are discussed below. (See 'Atezolizumab' below.)
Ineligible for any platinum-based regimens
Systemic immunotherapy — Systemic immunotherapy is appropriate for patients who are ineligible for any platinum-based (ie, cisplatin or carboplatin) combination chemotherapy regimens. Options include pembrolizumab (table 7) or atezolizumab (algorithm 1). (See 'Pembrolizumab' below and 'Atezolizumab' below.)
Patients not eligible for immunotherapy may be candidates for single-agent chemotherapy and/or best supportive care. (See 'Alternative options' below.)
Although direct comparative phase III data are not available for first-line immunotherapy in this setting, phase II data support its use and tolerability [55,56]. Additionally, the toxicity of these agents in the first-line setting is similar to that seen when used after cisplatin-based chemotherapy or in other indications. (See 'Second-line therapy (immunotherapy)' below and "Toxicities associated with checkpoint inhibitor immunotherapy".)
The role of neoadjuvant checkpoint inhibitor immunotherapy in those with advanced urothelial bladder cancer is discussed separately. (See "Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer", section on 'Is there a role for neoadjuvant immunotherapy?'.)
Pembrolizumab
●Ineligible for platinum-based chemotherapy – In the phase II KEYNOTE-052 study, 370 patients with advanced urothelial carcinoma who were not eligible for a cisplatin-based regimen received initial systemic therapy with pembrolizumab at 200 mg every three weeks for up to two years (table 7) [56,57]. 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 renal impairment.
In preliminary results, 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 [57,58]. 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 11.3 months and three-year OS was 22 percent.
Based on these data, the United States granted full (regular) approval for pembrolizumab as initial therapy in patients who are not eligible for any platinum-containing chemotherapy [59]. The use of pembrolizumab in those who have progressed on platinum-based chemotherapy is discussed below. (See 'Pembrolizumab' below.)
●Is there a role for combining pembrolizumab and platinum-based chemotherapy? – There is no established role for the addition of pembrolizumab to platinum-based chemotherapy as initial treatment. 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 — Atezolizumab has been evaluated both as a single agent and in combination with platinum-based chemotherapy.
In a multicenter, single-arm phase II study, atezolizumab (total dose 1200 mg every three weeks) was used as first-line therapy in 119 patients with advanced or metastatic urothelial carcinoma of the bladder or upper urinary tract who were not eligible for treatment with a cisplatin-based regimen [55]. At a median follow-up of 17 months, objective responses were observed in 27 patients (23 percent), including 11 (9 percent) with a complete response. Median duration of response had not been reached, and 19 of 27 continued to respond at the time of analysis. The median OS for the entire cohort was 16 months.
Based on these data, single-agent atezolizumab was granted conditional approval by the US Food and Drug Administration (FDA) as initial therapy for patients who are not candidates for platinum-based chemotherapy and for those who are cisplatin ineligible and whose tumors express PD-L1 [61]. (See 'Atezolizumab (PD-L1 positive tumors)' above.)
There is no established role for the addition of atezolizumab to platinum-based chemotherapy as initial treatment. In a randomized phase III trial (IMvigor130) of 1213 patients with treatment-naïve metastatic urothelial carcinoma, the addition of atezolizumab to gemcitabine- and platinum-based chemotherapy improved PFS (eight versus six months, HR 0.82, 95% CI 0.70-0.96) [62]. At the interim analysis, median OS was similar between the two groups (16 versus 13 months, HR 0.83, 95% CI 0.69-1.00), as the difference in OS was not statistically significant. We await further follow-up of OS in this study before offering this approach as an option for initial therapy.
Other agents — Other immunotherapy-based regimens either remain investigational or do not have an established role as first-line therapy in patients with metastatic urothelial carcinoma.
●Enfortumab vedotin plus pembrolizumab – The combination of enfortumab vedotin and pembrolizumab remains investigational as first-line therapy for cisplatin-ineligible patients with advanced or metastatic urothelial carcinoma, and further randomized studies are necessary.
Enfortumab vedotin plus pembrolizumab was evaluated in a phase Ib/II trial (EV-103; KEYNOTE-869) with 45 patients with advanced or metastatic urothelial cancer who were ineligible for cisplatin-based regimens. At median follow-up of 20 months, objective responses were seen in 33 patients (73 percent), including a complete response in seven patients (16 percent) [63]. Median duration of response and OS were approximately 26 months each.
●Nivolumab plus ipilimumab – The combination of nivolumab plus ipilimumab is being investigated as first-line therapy versus standard-of-care chemotherapy in an ongoing phase III trial (NCT03036098). The use of this combination in the second-line setting is discussed below. (See 'Nivolumab plus ipilimumab' below.)
●Avelumab – In a single-arm phase II trial (ARIES), avelumab demonstrated clinical activity in patients with PD-L1 positive metastatic urothelial carcinoma who are cisplatin ineligible [64]. At median follow-up of 10 months, objective and complete response rates were 24 and 9 percent, respectively.
Alternative options
Single-agent chemotherapy — A number of chemotherapy drugs have single-agent activity in patients with metastatic urothelial carcinoma, either in the first-line setting or in previously treated patients. These include platinum compounds (cisplatin, carboplatin), gemcitabine, vinca alkaloids (vinblastine, vinflunine), anthracyclines (doxorubicin, epirubicin), methotrexate, taxanes (paclitaxel, docetaxel, and nanoparticle albumin-bound paclitaxel [nabpaclitaxel]), and ifosfamide [65-74]. Responses to single-agent chemotherapy are generally of short duration, and no consistent improvement in survival has been demonstrated in first-line therapy. However, the activity with various single agents led to the development of combination regimens, most of which are cisplatin-based and discussed above. (See 'Cisplatin-based regimens' above.)
MAINTENANCE THERAPY
Avelumab — For patients with advanced bladder cancer (regardless of PD-L1 tumor status) who do not progress (ie, achieve an objective response or stable disease) following platinum-based chemotherapy and are eligible to receive checkpoint inhibitor immunotherapy, we suggest maintenance avelumab, rather than best supportive care alone, as this approach improved overall survival (OS) and progression-free survival (PFS) in a phase III trial [75,76]. 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 best supportive care 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 best supportive care (BSC) or BSC alone [75]. The study included a subset of 358 patients (51 percent) with PD-L1 positive tumors identified using a specific assay [77,78].
In preliminary results, at median follow-up of approximately 39 months, the addition of avelumab to BSC improved OS in the entire study population (three-year OS 36 versus 30 percent, median 24 versus 15 months, HR 0.76, 95% CI 0.63-0.92) and in those with PD-L1 positive tumors (three-year OS 45 versus 35 percent, median 31 versus 19 months, HR 0.69, 95% CI 0.52-0.90) [76]. Avelumab also improved PFS over BSC in both groups (three-year PFS 16 versus 5 percent, median 6 versus 2 months, HR 0.54, 95% CI 0.46-0.65 in the entire study population; three-year PFS 22 versus 6 percent, median 8 versus 3 months, HR 0.46, 95% CI 0.36-0.59 in those with PD-L1 positive tumors). OS benefit from maintenance avelumab was still maintained despite a high proportion of patients treated with BSC receiving subsequent therapy (72 percent), most commonly PD-1 or PD-L1 inhibitors (53 percent).
Maintenance avelumab also improved survival regardless of the platinum-based chemotherapy regimen received. In preliminary results of a subgroup analysis, the addition of avelumab to best supportive care improved OS in patients treated with gemcitabine plus cisplatin (25 versus 17 months, HR 0.69, 95% CI 0.51-0.94) and gemcitabine plus carboplatin (20 versus 13 months, HR 0.66, 95% CI 0.47-0.91) [79]. Preliminary data also suggest that avelumab has an OS benefit independent of the number of chemotherapy cycles received (between four and six cycles) [80].
Long-term treatment with maintenance avelumab was well tolerated. In all patients, grade ≥3 toxicity rates were higher for maintenance avelumab than BSC (47 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) [79]. 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 urothelial carcinoma that has not progressed on initial platinum-based chemotherapy [81].
Other agents — The role of other agents, such as pembrolizumab [82], vinflunine [73,83], and rucaparib for tumors with a DNA repair deficiency phenotype [84], is not established in the maintenance setting, as they have demonstrated PFS but not OS benefit in randomized phase II trials.
SECOND-LINE THERAPY (IMMUNOTHERAPY)
Rationale — Research into immunotherapy has led to important advances in the treatment of melanoma, non-small cell lung cancer, and other malignancies using checkpoint inhibition, particularly with antibodies directed against the programmed cell death 1 protein (PD-1) or its ligand (PD-L1). The following immunotherapy agents have efficacy in patients who have progressed during or after platinum-based therapy and have not received prior immunotherapy (algorithm 1). (See "Principles of cancer immunotherapy".)
Pembrolizumab — In patients with metastatic urothelial carcinoma who have progressed during or after platinum-based chemotherapy, pembrolizumab (table 7) prolongs overall survival (OS) with less toxicity and better quality of life compared with further lines of chemotherapy.
In the phase III KEYNOTE-045 trial, 542 patients 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 chemotherapy (paclitaxel, docetaxel, or vinflunine) [85-87]. Patients were enrolled regardless of the level of PD-L1 expression.
After a median follow-up of approximately 28 months, pembrolizumab, relative to chemotherapy, demonstrated the following:
●Improved OS (median 10.1 versus 7.3 months, hazard ratio [HR] 0.70, 95% CI 0.57-0.85; one-year OS 44 versus 30 percent; two-year OS 27 versus 14 percent).
●Similar median progression-free survival (PFS; median 2.1 versus 3.3 months, HR 0.96, 95% CI 0.79-1.16).
●Improved response rate (21 versus 11 percent) and improved duration of response lasting ≥12 months (68 versus 35 percent).
●Less frequent grade ≥3 treatment-related adverse events (17 versus 50 percent). Adverse events due to pembrolizumab were consistent with those observed in other malignancies also treated with pembrolizumab. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)
●Longer time to health-related quality of life deterioration (3.5 versus 2.3 months, HR 0.72) [86].
Based on these data, the US Food and Drug Administration (FDA) granted regulatory approval for pembrolizumab in patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy [59].
Nivolumab — Nivolumab (table 8) is a PD-1 inhibitor that is indicated for the treatment of advanced urothelial carcinoma that has progressed during or after previous platinum-based chemotherapy either for metastatic disease or for progressive disease less than 12 months after adjuvant or neoadjuvant chemotherapy. Nivolumab (240 mg intravenously every two weeks) has regulatory approval by the FDA; subsequently, an alternative schedule of nivolumab 480 mg every four weeks was approved based on clinical pharmacology analyses and safety assessments [88].
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 urothelial carcinoma [89,90].
In the larger of the two published phase II studies, 270 patients were treated with nivolumab (3 mg per kilogram every two weeks) [90]. The overall objective response rate (ORR) was 19.6 percent, and responses were seen at all levels of PD-L1 expression, with no differences between more or less than 5 percent positivity. At seven months of follow-up, OS for the entire cohort was 8.7 months; for those with PD-L1 expression <1 and ≥1 percent, median OS durations were 6.0 and 11.3 months, respectively.
Nivolumab plus ipilimumab — Combination immunotherapy with nivolumab and ipilimumab in locally advanced or metastatic urothelial carcinoma remains an active area of investigation [91,92], and further studies with longer follow-up are needed.
In the CheckMate 032 open-label phase II study, 274 patients with advanced or metastatic urothelial carcinoma and with progression 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 [93].
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 or higher 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.
Avelumab — Avelumab, a PD-L1 inhibitor, was approved in May 2017 for the treatment of advanced urothelial carcinoma that progressed during or after platinum-based chemotherapy, based on the results of two phase I expansion cohorts. In a combined analysis of these studies, 161 patients were treated with avelumab after platinum therapy and were followed for at least six months [94].
●The ORR for the entire cohort was 17 percent, including 6 percent with a complete response and 11 percent with a partial response; 23 percent had stable disease. The ORR was higher in patients with PD-L1 positive tumors compared with those with PD-L1 negative tumors (24 versus 14 percent).
●The most frequent treatment-related adverse events were infusion-related reaction (29 percent; all grade 1 to 2) and fatigue (16 percent). Grade 3 or worse treatment-related adverse events occurred in 8 percent, the most common of which were fatigue in 2 percent. One treatment-related death occurred (pneumonitis).
While these data appear robust, it is important to note that they are drawn from expansion cohorts of phase I trials, and phase III studies will be required to confirm these early data sets.
Agents no longer used
●Durvalumab – We do not offer durvalumab to patients with metastatic urothelial carcinoma who are either treatment-naïve or refractory to platinum-based chemotherapy. While durvalumab was initially granted accelerated regulatory approval by the FDA based on clinical activity in early phase I/II clinical trials as second-line therapy [95,96], a phase III trial (DANUBE) in treatment-naïve patients did not confirm an OS benefit over platinum-based chemotherapy, either as a single agent or in combination with the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitor tremelimumab [97]. Based on these data, regulatory approval for durvalumab in second-line was voluntarily withdrawn in the United States only, specifically for advanced or metastatic urothelial carcinoma that has progressed on platinum-based chemotherapy [98].
●Atezolizumab – We do not offer atezolizumab to patients with metastatic urothelial carcinoma refractory to platinum-based chemotherapy. Based on data from early phase I/II clinical trials [99,100], atezolizumab was initially granted accelerated approval by the FDA for treatment of locally advanced or metastatic urothelial carcinoma that had progressed during or after platinum-based chemotherapy, or within 12 months of adjuvant or neoadjuvant chemotherapy. However, it did not confer an OS benefit over chemotherapy in a randomized phase III trial (IMvigor211) conducted in 931 patients with metastatic urothelial carcinoma treated with prior platinum-based chemotherapy [101,102], leading to withdrawal of regulatory approval of atezolizumab for this particular indication in the United States only as second-line therapy [103].
The use of atezolizumab in patients with treatment-naïve metastatic urothelial carcinoma not eligible for platinum-based chemotherapy is discussed above. (See 'Atezolizumab' above.)
LATER-LINE THERAPY — Although a significant number of patients have an objective response to first-line therapy, most eventually progress and require subsequent-line therapy. Subsequent management is based on multiple clinical factors including prior therapies received, specific tumor molecular alterations (ie, FGFR status), as well as patient comorbidities, preferences, and treatment goals.
Prior treatment with platinum and immunotherapy — For patients who relapse following treatment with a platinum-based regimen and immunotherapy, targeted agents are available (algorithm 1).
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 rather than chemotherapy as a third-line option, 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, an antibody targeting the cell adhesion molecule nectin-4 linked to a microtubule inhibitor conjugate (monomethyl auristatin E), improved both OS and progression-free survival (PFS) over chemotherapy in a randomized phase III trial [104]. The use of this agent in patients with an FGFR alteration is discussed below. (See 'FGFR mutation positive' below.)
Based on previous results from phase I and II trials [105,106], enfortumab vedotin was evaluated in a phase III clinical trial (EV-301) of 608 patients with locally advanced unresectable or metastatic urothelial carcinoma (including those with squamous differentiation or mixed cell types) previously treated with platinum-based chemotherapy and PD-1/PD-L1 inhibitor [104]; 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 11 months, compared with chemotherapy, enfortumab vedotin improved OS (median 13 versus 9 months, HR 0.70, 95% CI 0.56-0.89), PFS (median 6 versus 4 months, HR 0.62, 95% CI 0.51-0.75) and overall response rates (41 versus 18 percent).
Grade ≥3 toxicity rates for any adverse event were similar between the two treatment arms (51 versus 50 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) [107,108], 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 "Ocular side effects of systemically administered chemotherapy", section on 'Antibody-drug conjugates' and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae" and "Neurologic complications of cancer treatment with molecularly targeted and biologic agents", section on 'Enfortumab vedotin'.)
Enfortumab vedotin has regulatory approval from the US Food and Drug Administration (FDA) in patients with locally advanced or metastatic urothelial carcinoma who have progressed on both platinum-based chemotherapy and immunotherapy [109].
The efficacy of enfortumab vedotin in patients who are ineligible for cisplatin-based chemotherapy and have progressed on immunotherapy is discussed below. (See 'Ineligible for cisplatin as initial therapy, immunotherapy-refractory' below.)
Sacituzumab govitecan — Sacituzumab govitecan is an antibody-drug conjugate that targets Trop-2, a transmembrane glycoprotein highly expressed in most urothelial carcinomas, 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 urothelial carcinoma previously treated with platinum-based chemotherapy or immunotherapy (either with a PD-1 or PD-L1 inhibitor) received sacituzumab govitecan [110]. In this study, objective and complete response rates were 27 and 5 percent, respectively. Median OS and PFS were 5 and 11 months, respectively [110].
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.
Based on these data, the FDA granted accelerated approval for sacituzumab govitecan for patients with locally advanced or metastatic urothelial cancer who have previously received a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor [111]. However, this approval remains contingent on further randomized data confirming survival benefit and acceptable toxicity for this agent.
FGFR mutation positive — For patients with a susceptible FGFR 3 or 2 genetic alteration, we suggest either the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib or the antibody-drug conjugate enfortumab vedotin, rather than further lines of chemotherapy. However, randomized trials directly comparing erdafitinib with enfortumab vedotin in patients with FGFR alterations are needed to direct the appropriate sequencing of these two drugs. (See 'Enfortumab vedotin' above.)
Sacituzumab govitecan is also an available potential alternative in this patient population. Sacituzumab govitecan has also not been specifically tested in patients with FGFR alterations, and further data are necessary to confirm an OS benefit. (See 'Sacituzumab govitecan' above.)
Erdafitinib — The FDA granted accelerated approval for the FGFR inhibitor erdafitinib for patients with locally advanced or metastatic urothelial carcinoma 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 [112-116]. However, our typical approach for patients whose tumors harbor a susceptible FGFR3 or FGFR2 genetic alteration is to offer erdafitinib after progression has occurred on both platinum-containing chemotherapy and on immunotherapy, typically as a third-line option. Patients should be selected for therapy based on the FDA-approved companion diagnostic test using reverse transcription polymerase chain reaction (RT-PCR) [13,112]. Tumors may be assessed either at the initial onset of metastatic disease or upon progression after initial lines of systemic therapy.
Erdafitinib demonstrated efficacy in an open-label, nonrandomized phase II trial (BLC2001). This study was conducted in 101 patients with locally advanced or metastatic urothelial carcinoma harboring certain FGFR3 gene mutations or FGFR2/FGFR3 gene fusions, with a majority progressing on or after at least one prior chemotherapy regimen (either in the metastatic setting or within 12 months of the neoadjuvant or adjuvant setting) [113,115].
At a median follow-up of 24 months, the objective response rate (ORR) was 40 percent [115]. Median progression-free survival (PFS) and overall survival (OS) were 6 and 11 months, respectively. Grade ≥3 toxicities included hyponatremia (11 percent), stomatitis (14 percent), and asthenia (8 percent). Approximately 3 percent of patients discontinued therapy due to detachment of the retinal pigment epithelium. The most common adverse events included hyperphosphatemia, a known class effect of FGFR inhibitors (78 percent); stomatitis (35 percent); diarrhea (54 percent); and dry mouth (46 percent) [117]. (See "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Molecularly targeted agents and immunotherapies", section on 'FGFR inhibitors'.)
This is the first time that a gene-targeted therapy has been approved for bladder cancer. It is important to consider that the approval of erdafitinib is based on the response rate observed in a single-arm phase II study. The benefit of erdafitinib versus chemotherapy or immunotherapy is being explored in an ongoing randomized phase III trial (NCT03390504). Further studies comparing erdafitinib with the targeted agent enfortumab vedotin are also needed to inform appropriate sequencing of these agents.
Ineligible for cisplatin as initial therapy, immunotherapy-refractory — For patients who are ineligible for cisplatin-based chemotherapy and have progressed on immunotherapy, options include enfortumab vedotin or chemotherapy not previously received (algorithm 1).
Enfortumab vedotin — Enfortumab vedotin is active in patients with metastatic urothelial carcinoma 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 [108]. In this study, enfortumab vedotin had an ORR 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 FDA in patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-based chemotherapy and have previously received one or more prior lines of therapy [109]. 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 — Single-agent chemotherapy is a reasonable alternative to enfortumab vedotin in patients with treatment-refractory disease who are ineligible for cisplatin-based chemotherapy. 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 — A number of contemporary chemotherapy agents have clinical activity after patients have progressed despite methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) (table 1) or gemcitabine plus cisplatin (GC) (table 5). However, none of these agents (except for vinflunine) has been approved for use in patients with metastatic urothelial carcinoma. Vinflunine has regulatory approval in Europe, as this agent demonstrated survival benefit in a phase III trial [118].
These agents include vinflunine (not approved in the United States) [118,119], pemetrexed, paclitaxel [67,120], nanoparticle albumin-bound paclitaxel (nabpaclitaxel) [74], docetaxel [70], gemcitabine [71], ifosfamide [66,121], and oxaliplatin [49]. Reported response rates with single agents in the larger series have generally been 10 to 25 percent. Although these drugs have also been combined with either each other or other agents, no one regimen is considered to be the standard second-line therapy [122-128].
Vinflunine — Vinflunine is approved in Europe for second-line treatment of urothelial cancer based on one phase III trial that showed a survival benefit over best supportive care. However, vinflunine is not approved in the United States.
In the phase III trial, 370 previously treated patients were randomly assigned to either vinflunine or best supportive care [118]. Compared with best supportive care, vinflunine resulted in a 9 percent ORR and improved survival (6.9 versus 4.6 months, hazard ratio [HR] 0.88, 95% CI 0.69-1.12). Imbalances in prognostic factors may have accounted for the lack of statistical significance in the primary analysis, with 10 percent more patients in the best supportive care arm than in the vinflunine arm having a better performance status (performance status was 0 in 38.5 versus 28.5 percent, respectively).
Pemetrexed — Antifolates are known to be active in advanced bladder cancer, with a number of regimens incorporating methotrexate (including MVAC (table 1)). Pemetrexed, a multitargeted antifolate, has shown activity in previously treated patients. As an example, in one study of 47 previously treated patients receiving single-agent pemetrexed, the ORR was 28 percent, including three complete responses (6 percent) [129]; median OS was 10 months. However, in another phase II study, minimal response to pemetrexed was observed [130].
Taxanes — Paclitaxel and nanoparticle albumin-bound paclitaxel (nabpaclitaxel) have both demonstrated activity as subsequent-line therapy in patients with metastatic urothelial cancer [74,131]. In a randomized phase II trial of 199 patients with platinum-refractory metastatic urothelial carcinoma, 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 ORR (22 versus 25 percent) [74].
Is there a role for antiangiogenic agents? — There is no defined role for agents that target the vascular endothelial growth factor (VEGF) pathway in patients with advanced or metastatic bladder cancer. Examples are as follows:
●Ramucirumab – The combination of the VEGF pathway inhibitor ramucirumab plus docetaxel does not have an established treatment role in those with urothelial carcinoma refractory to platinum-based therapy. In a randomized phase III trial (RANGE), the addition of ramucirumab improved PFS but not OS [132,133].
●Bevacizumab – The VEGF inhibitor bevacizumab also does not have an established role in the treatment of metastatic urothelial carcinoma. In a randomized phase III trial, the addition of bevacizumab to gemcitabine and cisplatin improved PFS but not OS [134].
●Cabozantinib (with or without immunotherapy) – Cabozantinib, an inhibitor of multiple kinases including VEGF receptors, remains an investigational agent in platinum-refractory metastatic urothelial carcinoma, both as a single agent and in combination with immunotherapy [135-137]. As examples, in a phase II trial, single-agent cabozantinib demonstrated an objective response rate of 19 percent in this patient population [135]. In a separate phase I trial, cabozantinib in combination with checkpoint inhibitor immunotherapy (nivolumab alone or nivolumab plus ipilimumab) demonstrated an ORR of approximately 39 percent among patients with pretreated metastatic urothelial carcinoma [136].
INVESTIGATIONAL AGENTS — Various agents remain under investigation in the treatment of patients with treatment-refractory metastatic urothelial cancer. 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 urothelial carcinoma that recurred or progressed on platinum-based chemotherapy [138]. At median follow-up of 23 months, in the entire study population the objective response rate (ORR) was 37 percent and median overall survival (OS) was 15 months. Among patients whose tumors expressed EphrinB2, the target of sEphB4-HSA, the ORR and complete response rates 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 FGFR1 or FGFR3-positive (based on RNA overexpression) urothelial carcinoma previously treated with platinum-based chemotherapy [139]. At median follow-up of 11 months, in the entire study population, rogaratinib did not improve ORR or OS compared with investigator's choice of chemotherapy (docetaxel, paclitaxel, or vinflunine). In a retrospective exploratory analysis, the ORR 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).
ROLE OF SURGERY — Definitive resection of all sites of residual metastases is an option for select patients who have a good partial response to systemic therapy (chemotherapy, immunotherapy) for metastatic disease [140,141]. Although some patients may remain disease free following metastasectomy, proper patient selection is critical if surgery is contemplated. Features to be considered include good performance status, age of the patient, anticipated length of life expectancy, paucity of metastases (lung in particular), and limited nodal site(s) of involvement. Careful restaging prior to consideration of surgery is crucial to confirm paucimetastatic disease.
In patients with good responses to systemic therapy, other alternatives to metastasectomy have also been explored and are available, such as radiation therapy for patients who are ineligible for surgery or maintenance therapy for those treated with platinum-based chemotherapy. (See 'Maintenance therapy' above.)
NON-UROTHELIAL BLADDER CANCER — Urothelial carcinomas constitute the majority of 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".)
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 1), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. These and recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
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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
●Prognosis of advanced urothelial carcinoma – Advances in the management of advanced urothelial (transitional cell) carcinoma using cisplatin-based combination chemotherapy have led to a substantial increase in survival. Despite this progress, metastatic disease is associated with a limited life expectancy, and cures are infrequent. (See 'Introduction' above.)
●Approach to systemic therapy – The overall approach to the treatment of metastatic urothelial carcinoma is summarized here (algorithm 1).
●Initial therapy (cisplatin-eligible) – For patients with a good performance status, adequate renal function, and metastatic or inoperable locally advanced urothelial cancer, we recommend initial treatment using cisplatin-based combination chemotherapy (Grade 1A). (See 'First-line therapy' above.)
•Preferred options include methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC (table 1)), dose-dense MVAC (table 6), gemcitabine plus cisplatin (GC (table 5)), and paclitaxel, gemcitabine, and cisplatin (PGC). The choice between them is individualized based on patient and provider preferences. (See 'Cisplatin-based regimens' above.)
•For patients with impaired renal function, reversible causes (eg, urinary tract obstruction secondary to a tumor mass) should be identified and treated prior to initiation of cisplatin-based therapy. (See 'Defining eligibility for systemic therapy' above.)
●Initial therapy (platinum-ineligible) – For patients with advanced urothelial cancer who are not eligible for cisplatin- and/or carboplatin-based chemotherapy, the choice of initial treatment should take into account the patient's performance status and ability to tolerate systemic therapy. (See 'Defining eligibility for systemic therapy' above.)
•Cisplatin-ineligible – For patients with a good performance status (World Health Organization [WHO]/Eastern Cooperative Oncology Group [ECOG] performance status <2) who are cisplatin-ineligible but otherwise candidates for a combination regimen, options include carboplatin-based regimens (eg, gemcitabine plus carboplatin) or a non-platinum-based combination (eg, paclitaxel plus gemcitabine). (See 'Ineligible for cisplatin-based regimens' above.)
For patients who are ineligible for cisplatin-based chemotherapy and whose tumors express PD-L1, either immunotherapy with atezolizumab or non-cisplatin-based combination chemotherapy are options. For those with symptomatic or bulky disease, we suggest chemotherapy rather than immunotherapy (Grade 2C). For others, either option is reasonable.
•Platinum-ineligible – For patients who are ineligible for any platinum-based chemotherapy, we offer immunotherapy with an agent targeting the programmed cell death 1 protein (PD-1) or PD-L1. Options include pembrolizumab or atezolizumab. (See 'Ineligible for any platinum-based regimens' above.)
Patients not eligible for immunotherapy may be candidates for single-agent chemotherapy and/or treatment with best supportive care. The choice between agents should be based on clinical factors, such as the patient's performance status, and his or her values and preferences. (See 'Single-agent chemotherapy' above.)
●Indications for maintenance immunotherapy – For patients who do not progress on initial treatment with platinum-based chemotherapy, we recommend maintenance immunotherapy with avelumab rather than best supportive care alone (Grade 1A). Although this approach was only evaluated in those who received gemcitabine plus platinum-based chemotherapy, we also offer maintenance avelumab to patients without disease progression on other platinum-based chemotherapy regimens. (See 'Maintenance therapy' above.)
●Treatment approach after progression on platinum-based regimens – For patients who relapse following treatment with a platinum-based regimen and have had not received prior treatment with checkpoint inhibitor immunotherapy, we recommend immunotherapy with an agent targeting PD-1 or PD-L1, rather than chemotherapy (Grade 1B). Available agents include pembrolizumab (table 7), nivolumab (table 8), and avelumab. (See 'Second-line therapy (immunotherapy)' above.)
●Subsequent therapy – For patients who relapse following treatment with a platinum-based regimen and immunotherapy, targeted therapy options are available. (See 'Later-line therapy' above.)
•FGFR mutation negative – For patients lacking a susceptible fibroblast growth factor receptor (FGFR) 3 or 2 genetic alteration, we suggest enfortumab vedotin rather than chemotherapy (Grade 2B). Sacituzumab govitecan is also another reasonable alternative, with a different toxicity profile, in this setting. (See 'FGFR mutation negative' above.)
•FGFR mutation positive – For patients with a susceptible FGFR 3 or 2 genetic alteration, we suggest either the FGFR inhibitor erdafitinib or the antibody-drug conjugate enfortumab vedotin, rather than further lines of chemotherapy (Grade 2C). Although erdafitinib is approved after platinum-based chemotherapy, we typically use it after progression on both chemotherapy and immunotherapy. Sacituzumab govitecan is also an alternative option in this setting. (See 'FGFR mutation positive' above.)
•Ineligible for cisplatin as initial therapy, immunotherapy refractory – For patients who are ineligible for cisplatin-based chemotherapy and have progressed on immunotherapy, options include enfortumab vedotin or chemotherapy not previously received. (See 'Ineligible for cisplatin as initial therapy, immunotherapy-refractory' above.)
•Ineligible for targeted therapy – Multiple chemotherapy agents also have modest activity, including gemcitabine, vinflunine, ifosfamide, paclitaxel, nabpaclitaxel, docetaxel, and pemetrexed. These agents may be indicated when a targeted agent or clinical trial is not feasible. (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.
