Post–EV + Pembrolizumab Treatment Advanced Urothelial Carcinoma

Authored by Natalia Gandur, published on 2026-09-23 11:30:49.0

  1. Progression after first-line EV + pembrolizumab
    Adult with unresectable locally advanced or metastatic urothelial carcinoma with confirmed disease progression during or after first-line enfortumab vedotin plus pembrolizumab. This pathway addresses systemic treatment selection after first-line EV + pembrolizumab.
    • Confirm progression and reassess treatment fitness
      Confirm radiographic and/or clinically meaningful disease progression. Reassess: ECOG performance status and frailty disease tempo and symptom burden visceral disease or impending organ compromise renal function marrow reserve hearing impairment residual peripheral neuropathy cardiovascular status persistent EV-related skin toxicity or hyperglycemia unresolved immune-related toxicity prior treatment tolerance patient goals and treatment burden Residual EV-related neuropathy is particularly relevant because clinically significant neuropathy may also affect cisplatin eligibility.
      • Ensure FGFR3 status; review HER2 IHC
        Ensure that FGFR3 genomic status is available before further-line treatment selection. Review or obtain HER2 expression by immunohistochemistry when HER2-directed therapy may become clinically relevant. Use validated testing and do not delay urgent treatment solely to complete nonessential biomarker assessment.
        • Susceptible FGFR3 alteration present?
          Determine whether a susceptible FGFR3 genetic alteration is present. YES: consider FGFR3-directed therapy versus platinum according to clinical fit. NO: proceed to prior platinum exposure and current platinum eligibility.
          • FGFR3-altered disease: choose erdafitinib or platinum
            Erdafitinib is an evidence-supported targeted option after prior PD-1/PD-L1 therapy in patients with susceptible FGFR3-altered urothelial carcinoma. Platinum-based chemotherapy is also a reasonable option after first-line EV + pembrolizumab when the patient has not received platinum for metastatic disease and remains clinically eligible. No randomized trial has established the optimal sequence of erdafitinib versus platinum specifically after EV + pembrolizumab. Consider: disease tempo and need for cytoreduction prior perioperative platinum exposure renal function residual peripheral neuropathy ocular comorbidity and monitoring feasibility oral treatment adherence patient preference and treatment burden access and local regulatory status
            • Erdafitinib
              Use erdafitinib according to the locally approved prescribing information in patients with a susceptible FGFR3 alteration. Before and during treatment: review ocular history perform required ophthalmologic monitoring monitor serum phosphate review clinically relevant drug interactions monitor treatment-related toxicity Continue while clinical benefit is maintained and toxicity remains acceptable.
              • Monitor Erdafitinib
                Monitor serum phosphate and treatment-related toxicity. Perform ophthalmologic surveillance according to the current prescribing information and promptly evaluate new or worsening visual symptoms. Modify, interrupt, or discontinue treatment according to toxicity severity and label guidance. At disease progression or unacceptable toxicity, reassess remaining unused active treatment options.
                • At progression/intolerance: select next unused active mechanism.
                  • At progression or intolerance: is an unused active mechanism available?
                    At progression or intolerance after prior therapy, reassess which evidence-supported options remain unused. Review: susceptible FGFR3 alteration and prior erdafitinib exposure HER2 IHC expression prior platinum exposure clinical-trial availability residual treatment toxicity ECOG performance status and organ function patient goals and treatment burden.
                    • FGFR3 alteration + erdafitinib not previously used
                      If a susceptible FGFR3 alteration is present and erdafitinib has not previously been used, consider erdafitinib according to clinical suitability, local approval and access.
                      • Erdafitinib
                        Initiate erdafitinib according to current prescribing information and apply the monitoring principles described earlier in this pathway.
                    • HER2 IHC3+ and no satisfactory standard alternative
                      In previously treated HER2 IHC3+ disease, consider trastuzumab deruxtecan when no satisfactory standard treatment alternative remains and local regulatory approval/access permits. Activity has also been observed in HER2 IHC2+ bladder cancer, and EAU allows consideration in IHC2+ disease; however, the U.S. tumor-agnostic indication is specifically HER2 IHC3+.
                      • Consider T-DXd; monitor for ILD/pneumonitis
                        Use trastuzumab deruxtecan according to local regulatory approval. Before treatment, review pulmonary history and baseline clinical status. During therapy: actively monitor for cough, dyspnea, fever or other new respiratory symptoms promptly investigate suspected ILD/pneumonitis manage according to current prescribing information permanently discontinue T-DXd for Grade ≥2 ILD/pneumonitis according to the current U.S. label.
                    • No preferred targeted option remains
                      If no preferred evidence-supported targeted option remains, prioritize clinical-trial enrollment whenever feasible. Consider patient fitness, expected benefit, residual toxicity and treatment burden before proceeding to additional cytotoxic therapy.
                      • Prioritize a clinical trial
                        Clinical-trial enrollment should be actively considered in the post-EV + pembrolizumab setting, particularly: after platinum progression in platinum-ineligible patients after biomarker-directed therapy when no preferred evidence-supported standard option remains. Post-EV + pembrolizumab sequencing remains an active area of prospective investigation.
                        • Individualized later-line therapy or supportive care
                          If no preferred targeted therapy or clinical trial is feasible, individualize further treatment. Potential options include: paclitaxel docetaxel vinflunine where available other clinically appropriate chemotherapy best supportive and palliative care when further cancer-directed therapy is unlikely to provide meaningful benefit. Single-agent chemotherapy generally provides modest activity and should not be presented as equivalent to an appropriate biomarker-directed therapy or clinical trial.
            • Classify current platinum eligibility
              Reassess platinum fitness at the current treatment decision. Consider: ECOG performance status renal function hearing impairment peripheral neuropathy cardiac function comorbidities marrow reserve residual toxicity from EV Do not rely solely on historical platinum eligibility.
              • Cisplatin-eligible
                Prefer cisplatin-based chemotherapy when the patient remains cisplatin-eligible. Residual EV-related neuropathy, renal function and hearing status should be incorporated into the current eligibility assessment.
                • Gemcitabine + cisplatin — planned 4–6 cycles
                  Treat with gemcitabine plus cisplatin for a planned finite course, generally 4–6 cycles as clinically appropriate and tolerated. Assess response and cumulative toxicity during therapy. Closely monitor renal function, marrow reserve, hearing and residual neuropathy after prior EV exposure.
                  • Reassess response and toxicity during platinum
                    Reassess clinical benefit, radiographic response and cumulative toxicity during the planned platinum course. Modify, delay or discontinue treatment when clinically significant toxicity outweighs continued benefit.
                    • Complete 4–6 cycles; no routine avelumab maintenance
                      Complete the planned platinum course as tolerated rather than continuing platinum indefinitely. After response or stable disease following platinum administered after first-line EV + pembrolizumab, routine maintenance avelumab is not recommended in unselected patients. Routine single-agent checkpoint-inhibitor rechallenge is also not encouraged without additional supporting evidence. Continue clinical and radiographic surveillance after completion of treatment.
                      • At progression or intolerance: is an unused active mechanism available?
                        At progression or intolerance after prior therapy, reassess which evidence-supported options remain unused. Review: susceptible FGFR3 alteration and prior erdafitinib exposure HER2 IHC expression prior platinum exposure clinical-trial availability residual treatment toxicity ECOG performance status and organ function patient goals and treatment burden.
                        • FGFR3 alteration + erdafitinib not previously used
                          If a susceptible FGFR3 alteration is present and erdafitinib has not previously been used, consider erdafitinib according to clinical suitability, local approval and access.
                          • Erdafitinib
                            Initiate erdafitinib according to current prescribing information and apply the monitoring principles described earlier in this pathway.
                        • HER2 IHC3+ and no satisfactory standard alternative
                          In previously treated HER2 IHC3+ disease, consider trastuzumab deruxtecan when no satisfactory standard treatment alternative remains and local regulatory approval/access permits. Activity has also been observed in HER2 IHC2+ bladder cancer, and EAU allows consideration in IHC2+ disease; however, the U.S. tumor-agnostic indication is specifically HER2 IHC3+.
                          • Consider T-DXd; monitor for ILD/pneumonitis
                            Use trastuzumab deruxtecan according to local regulatory approval. Before treatment, review pulmonary history and baseline clinical status. During therapy: actively monitor for cough, dyspnea, fever or other new respiratory symptoms promptly investigate suspected ILD/pneumonitis manage according to current prescribing information permanently discontinue T-DXd for Grade ≥2 ILD/pneumonitis according to the current U.S. label.
                        • No preferred targeted option remains
                          If no preferred evidence-supported targeted option remains, prioritize clinical-trial enrollment whenever feasible. Consider patient fitness, expected benefit, residual toxicity and treatment burden before proceeding to additional cytotoxic therapy.
                          • Prioritize a clinical trial
                            Clinical-trial enrollment should be actively considered in the post-EV + pembrolizumab setting, particularly: after platinum progression in platinum-ineligible patients after biomarker-directed therapy when no preferred evidence-supported standard option remains. Post-EV + pembrolizumab sequencing remains an active area of prospective investigation.
                            • Individualized later-line therapy or supportive care
                              If no preferred targeted therapy or clinical trial is feasible, individualize further treatment. Potential options include: paclitaxel docetaxel vinflunine where available other clinically appropriate chemotherapy best supportive and palliative care when further cancer-directed therapy is unlikely to provide meaningful benefit. Single-agent chemotherapy generally provides modest activity and should not be presented as equivalent to an appropriate biomarker-directed therapy or clinical trial.
              • Carboplatin-eligible, cisplatin-ineligible
                Use carboplatin when cisplatin is not appropriate but combination platinum chemotherapy remains clinically feasible. Do not substitute carboplatin solely for convenience in a patient who remains cisplatin-eligible.
                • Gemcitabine + carboplatin — planned 4–6 cycles
                  Treat with gemcitabine plus cisplatin for a planned finite course, generally 4–6 cycles as clinically appropriate and tolerated. Assess response and cumulative toxicity during therapy. Closely monitor renal function, marrow reserve, hearing and residual neuropathy after prior EV exposure.
                  • Reassess response and toxicity during platinum
                    Reassess clinical benefit, radiographic response and cumulative toxicity during the planned platinum course. Modify, delay or discontinue treatment when clinically significant toxicity outweighs continued benefit.
                    • Complete 4–6 cycles; no routine avelumab maintenance
                      Complete the planned platinum course as tolerated rather than continuing platinum indefinitely. After response or stable disease following platinum administered after first-line EV + pembrolizumab, routine maintenance avelumab is not recommended in unselected patients. Routine single-agent checkpoint-inhibitor rechallenge is also not encouraged without additional supporting evidence. Continue clinical and radiographic surveillance after completion of treatment.
                      • At progression or intolerance: is an unused active mechanism available?
                        At progression or intolerance after prior therapy, reassess which evidence-supported options remain unused. Review: susceptible FGFR3 alteration and prior erdafitinib exposure HER2 IHC expression prior platinum exposure clinical-trial availability residual treatment toxicity ECOG performance status and organ function patient goals and treatment burden.
                        • FGFR3 alteration + erdafitinib not previously used
                          If a susceptible FGFR3 alteration is present and erdafitinib has not previously been used, consider erdafitinib according to clinical suitability, local approval and access.
                          • Erdafitinib
                            Initiate erdafitinib according to current prescribing information and apply the monitoring principles described earlier in this pathway.
                        • HER2 IHC3+ and no satisfactory standard alternative
                          In previously treated HER2 IHC3+ disease, consider trastuzumab deruxtecan when no satisfactory standard treatment alternative remains and local regulatory approval/access permits. Activity has also been observed in HER2 IHC2+ bladder cancer, and EAU allows consideration in IHC2+ disease; however, the U.S. tumor-agnostic indication is specifically HER2 IHC3+.
                          • Consider T-DXd; monitor for ILD/pneumonitis
                            Use trastuzumab deruxtecan according to local regulatory approval. Before treatment, review pulmonary history and baseline clinical status. During therapy: actively monitor for cough, dyspnea, fever or other new respiratory symptoms promptly investigate suspected ILD/pneumonitis manage according to current prescribing information permanently discontinue T-DXd for Grade ≥2 ILD/pneumonitis according to the current U.S. label.
                        • No preferred targeted option remains
                          If no preferred evidence-supported targeted option remains, prioritize clinical-trial enrollment whenever feasible. Consider patient fitness, expected benefit, residual toxicity and treatment burden before proceeding to additional cytotoxic therapy.
                          • Prioritize a clinical trial
                            Clinical-trial enrollment should be actively considered in the post-EV + pembrolizumab setting, particularly: after platinum progression in platinum-ineligible patients after biomarker-directed therapy when no preferred evidence-supported standard option remains. Post-EV + pembrolizumab sequencing remains an active area of prospective investigation.
                            • Individualized later-line therapy or supportive care
                              If no preferred targeted therapy or clinical trial is feasible, individualize further treatment. Potential options include: paclitaxel docetaxel vinflunine where available other clinically appropriate chemotherapy best supportive and palliative care when further cancer-directed therapy is unlikely to provide meaningful benefit. Single-agent chemotherapy generally provides modest activity and should not be presented as equivalent to an appropriate biomarker-directed therapy or clinical trial.
              • Platinum-ineligible
                Do not force combination platinum chemotherapy when expected toxicity outweighs potential benefit. Move to an unused biomarker-directed option, clinical trial, or individualized later-line strategy according to treatment history, fitness and patient goals.
                • Move to non-platinum options
                  When platinum is not appropriate, select among remaining evidence-supported options according to: unused actionable biomarkers prior systemic therapies disease tempo residual toxicity performance status and organ function clinical-trial availability patient goals and treatment burden.
                  • Proceed to later-line treatment selection
                    Reassess the treatments already received and identify evidence-supported active mechanisms that remain unused. Avoid automatically recycling a previously ineffective mechanism outside a clinical trial.
                    • At progression or intolerance: is an unused active mechanism available?
                      At progression or intolerance after prior therapy, reassess which evidence-supported options remain unused. Review: susceptible FGFR3 alteration and prior erdafitinib exposure HER2 IHC expression prior platinum exposure clinical-trial availability residual treatment toxicity ECOG performance status and organ function patient goals and treatment burden.
                      • FGFR3 alteration + erdafitinib not previously used
                        If a susceptible FGFR3 alteration is present and erdafitinib has not previously been used, consider erdafitinib according to clinical suitability, local approval and access.
                        • Erdafitinib
                          Initiate erdafitinib according to current prescribing information and apply the monitoring principles described earlier in this pathway.
                      • HER2 IHC3+ and no satisfactory standard alternative
                        In previously treated HER2 IHC3+ disease, consider trastuzumab deruxtecan when no satisfactory standard treatment alternative remains and local regulatory approval/access permits. Activity has also been observed in HER2 IHC2+ bladder cancer, and EAU allows consideration in IHC2+ disease; however, the U.S. tumor-agnostic indication is specifically HER2 IHC3+.
                        • Consider T-DXd; monitor for ILD/pneumonitis
                          Use trastuzumab deruxtecan according to local regulatory approval. Before treatment, review pulmonary history and baseline clinical status. During therapy: actively monitor for cough, dyspnea, fever or other new respiratory symptoms promptly investigate suspected ILD/pneumonitis manage according to current prescribing information permanently discontinue T-DXd for Grade ≥2 ILD/pneumonitis according to the current U.S. label.
                      • No preferred targeted option remains
                        If no preferred evidence-supported targeted option remains, prioritize clinical-trial enrollment whenever feasible. Consider patient fitness, expected benefit, residual toxicity and treatment burden before proceeding to additional cytotoxic therapy.
                        • Prioritize a clinical trial
                          Clinical-trial enrollment should be actively considered in the post-EV + pembrolizumab setting, particularly: after platinum progression in platinum-ineligible patients after biomarker-directed therapy when no preferred evidence-supported standard option remains. Post-EV + pembrolizumab sequencing remains an active area of prospective investigation.
                          • Individualized later-line therapy or supportive care
                            If no preferred targeted therapy or clinical trial is feasible, individualize further treatment. Potential options include: paclitaxel docetaxel vinflunine where available other clinically appropriate chemotherapy best supportive and palliative care when further cancer-directed therapy is unlikely to provide meaningful benefit. Single-agent chemotherapy generally provides modest activity and should not be presented as equivalent to an appropriate biomarker-directed therapy or clinical trial.
          • Prior perioperative platinum?
            Review prior neoadjuvant or adjuvant platinum exposure. NO: proceed directly to current platinum eligibility. YES: assess the interval from completion of perioperative platinum to metastatic relapse, together with prior benefit and tolerance.
            • Classify current platinum eligibility
              Reassess platinum fitness at the current treatment decision. Consider: ECOG performance status renal function hearing impairment peripheral neuropathy cardiac function comorbidities marrow reserve residual toxicity from EV Do not rely solely on historical platinum eligibility.
              • Cisplatin-eligible
                Prefer cisplatin-based chemotherapy when the patient remains cisplatin-eligible. Residual EV-related neuropathy, renal function and hearing status should be incorporated into the current eligibility assessment.
                • Gemcitabine + cisplatin — planned 4–6 cycles
                  Treat with gemcitabine plus cisplatin for a planned finite course, generally 4–6 cycles as clinically appropriate and tolerated. Assess response and cumulative toxicity during therapy. Closely monitor renal function, marrow reserve, hearing and residual neuropathy after prior EV exposure.
                  • Reassess response and toxicity during platinum
                    Reassess clinical benefit, radiographic response and cumulative toxicity during the planned platinum course. Modify, delay or discontinue treatment when clinically significant toxicity outweighs continued benefit.
                    • Complete 4–6 cycles; no routine avelumab maintenance
                      Complete the planned platinum course as tolerated rather than continuing platinum indefinitely. After response or stable disease following platinum administered after first-line EV + pembrolizumab, routine maintenance avelumab is not recommended in unselected patients. Routine single-agent checkpoint-inhibitor rechallenge is also not encouraged without additional supporting evidence. Continue clinical and radiographic surveillance after completion of treatment.
                      • At progression or intolerance: is an unused active mechanism available?
                        At progression or intolerance after prior therapy, reassess which evidence-supported options remain unused. Review: susceptible FGFR3 alteration and prior erdafitinib exposure HER2 IHC expression prior platinum exposure clinical-trial availability residual treatment toxicity ECOG performance status and organ function patient goals and treatment burden.
                        • FGFR3 alteration + erdafitinib not previously used
                          If a susceptible FGFR3 alteration is present and erdafitinib has not previously been used, consider erdafitinib according to clinical suitability, local approval and access.
                          • Erdafitinib
                            Initiate erdafitinib according to current prescribing information and apply the monitoring principles described earlier in this pathway.
                        • HER2 IHC3+ and no satisfactory standard alternative
                          In previously treated HER2 IHC3+ disease, consider trastuzumab deruxtecan when no satisfactory standard treatment alternative remains and local regulatory approval/access permits. Activity has also been observed in HER2 IHC2+ bladder cancer, and EAU allows consideration in IHC2+ disease; however, the U.S. tumor-agnostic indication is specifically HER2 IHC3+.
                          • Consider T-DXd; monitor for ILD/pneumonitis
                            Use trastuzumab deruxtecan according to local regulatory approval. Before treatment, review pulmonary history and baseline clinical status. During therapy: actively monitor for cough, dyspnea, fever or other new respiratory symptoms promptly investigate suspected ILD/pneumonitis manage according to current prescribing information permanently discontinue T-DXd for Grade ≥2 ILD/pneumonitis according to the current U.S. label.
                        • No preferred targeted option remains
                          If no preferred evidence-supported targeted option remains, prioritize clinical-trial enrollment whenever feasible. Consider patient fitness, expected benefit, residual toxicity and treatment burden before proceeding to additional cytotoxic therapy.
                          • Prioritize a clinical trial
                            Clinical-trial enrollment should be actively considered in the post-EV + pembrolizumab setting, particularly: after platinum progression in platinum-ineligible patients after biomarker-directed therapy when no preferred evidence-supported standard option remains. Post-EV + pembrolizumab sequencing remains an active area of prospective investigation.
                            • Individualized later-line therapy or supportive care
                              If no preferred targeted therapy or clinical trial is feasible, individualize further treatment. Potential options include: paclitaxel docetaxel vinflunine where available other clinically appropriate chemotherapy best supportive and palliative care when further cancer-directed therapy is unlikely to provide meaningful benefit. Single-agent chemotherapy generally provides modest activity and should not be presented as equivalent to an appropriate biomarker-directed therapy or clinical trial.
              • Carboplatin-eligible, cisplatin-ineligible
                Use carboplatin when cisplatin is not appropriate but combination platinum chemotherapy remains clinically feasible. Do not substitute carboplatin solely for convenience in a patient who remains cisplatin-eligible.
                • Gemcitabine + carboplatin — planned 4–6 cycles
                  Treat with gemcitabine plus cisplatin for a planned finite course, generally 4–6 cycles as clinically appropriate and tolerated. Assess response and cumulative toxicity during therapy. Closely monitor renal function, marrow reserve, hearing and residual neuropathy after prior EV exposure.
                  • Reassess response and toxicity during platinum
                    Reassess clinical benefit, radiographic response and cumulative toxicity during the planned platinum course. Modify, delay or discontinue treatment when clinically significant toxicity outweighs continued benefit.
                    • Complete 4–6 cycles; no routine avelumab maintenance
                      Complete the planned platinum course as tolerated rather than continuing platinum indefinitely. After response or stable disease following platinum administered after first-line EV + pembrolizumab, routine maintenance avelumab is not recommended in unselected patients. Routine single-agent checkpoint-inhibitor rechallenge is also not encouraged without additional supporting evidence. Continue clinical and radiographic surveillance after completion of treatment.
                      • At progression or intolerance: is an unused active mechanism available?
                        At progression or intolerance after prior therapy, reassess which evidence-supported options remain unused. Review: susceptible FGFR3 alteration and prior erdafitinib exposure HER2 IHC expression prior platinum exposure clinical-trial availability residual treatment toxicity ECOG performance status and organ function patient goals and treatment burden.
                        • FGFR3 alteration + erdafitinib not previously used
                          If a susceptible FGFR3 alteration is present and erdafitinib has not previously been used, consider erdafitinib according to clinical suitability, local approval and access.
                          • Erdafitinib
                            Initiate erdafitinib according to current prescribing information and apply the monitoring principles described earlier in this pathway.
                        • HER2 IHC3+ and no satisfactory standard alternative
                          In previously treated HER2 IHC3+ disease, consider trastuzumab deruxtecan when no satisfactory standard treatment alternative remains and local regulatory approval/access permits. Activity has also been observed in HER2 IHC2+ bladder cancer, and EAU allows consideration in IHC2+ disease; however, the U.S. tumor-agnostic indication is specifically HER2 IHC3+.
                          • Consider T-DXd; monitor for ILD/pneumonitis
                            Use trastuzumab deruxtecan according to local regulatory approval. Before treatment, review pulmonary history and baseline clinical status. During therapy: actively monitor for cough, dyspnea, fever or other new respiratory symptoms promptly investigate suspected ILD/pneumonitis manage according to current prescribing information permanently discontinue T-DXd for Grade ≥2 ILD/pneumonitis according to the current U.S. label.
                        • No preferred targeted option remains
                          If no preferred evidence-supported targeted option remains, prioritize clinical-trial enrollment whenever feasible. Consider patient fitness, expected benefit, residual toxicity and treatment burden before proceeding to additional cytotoxic therapy.
                          • Prioritize a clinical trial
                            Clinical-trial enrollment should be actively considered in the post-EV + pembrolizumab setting, particularly: after platinum progression in platinum-ineligible patients after biomarker-directed therapy when no preferred evidence-supported standard option remains. Post-EV + pembrolizumab sequencing remains an active area of prospective investigation.
                            • Individualized later-line therapy or supportive care
                              If no preferred targeted therapy or clinical trial is feasible, individualize further treatment. Potential options include: paclitaxel docetaxel vinflunine where available other clinically appropriate chemotherapy best supportive and palliative care when further cancer-directed therapy is unlikely to provide meaningful benefit. Single-agent chemotherapy generally provides modest activity and should not be presented as equivalent to an appropriate biomarker-directed therapy or clinical trial.
              • Platinum-ineligible
                Do not force combination platinum chemotherapy when expected toxicity outweighs potential benefit. Move to an unused biomarker-directed option, clinical trial, or individualized later-line strategy according to treatment history, fitness and patient goals.
                • Move to non-platinum options
                  When platinum is not appropriate, select among remaining evidence-supported options according to: unused actionable biomarkers prior systemic therapies disease tempo residual toxicity performance status and organ function clinical-trial availability patient goals and treatment burden.
                  • Proceed to later-line treatment selection
                    Reassess the treatments already received and identify evidence-supported active mechanisms that remain unused. Avoid automatically recycling a previously ineffective mechanism outside a clinical trial.
                    • At progression or intolerance: is an unused active mechanism available?
                      At progression or intolerance after prior therapy, reassess which evidence-supported options remain unused. Review: susceptible FGFR3 alteration and prior erdafitinib exposure HER2 IHC expression prior platinum exposure clinical-trial availability residual treatment toxicity ECOG performance status and organ function patient goals and treatment burden.
                      • FGFR3 alteration + erdafitinib not previously used
                        If a susceptible FGFR3 alteration is present and erdafitinib has not previously been used, consider erdafitinib according to clinical suitability, local approval and access.
                        • Erdafitinib
                          Initiate erdafitinib according to current prescribing information and apply the monitoring principles described earlier in this pathway.
                      • HER2 IHC3+ and no satisfactory standard alternative
                        In previously treated HER2 IHC3+ disease, consider trastuzumab deruxtecan when no satisfactory standard treatment alternative remains and local regulatory approval/access permits. Activity has also been observed in HER2 IHC2+ bladder cancer, and EAU allows consideration in IHC2+ disease; however, the U.S. tumor-agnostic indication is specifically HER2 IHC3+.
                        • Consider T-DXd; monitor for ILD/pneumonitis
                          Use trastuzumab deruxtecan according to local regulatory approval. Before treatment, review pulmonary history and baseline clinical status. During therapy: actively monitor for cough, dyspnea, fever or other new respiratory symptoms promptly investigate suspected ILD/pneumonitis manage according to current prescribing information permanently discontinue T-DXd for Grade ≥2 ILD/pneumonitis according to the current U.S. label.
                      • No preferred targeted option remains
                        If no preferred evidence-supported targeted option remains, prioritize clinical-trial enrollment whenever feasible. Consider patient fitness, expected benefit, residual toxicity and treatment burden before proceeding to additional cytotoxic therapy.
                        • Prioritize a clinical trial
                          Clinical-trial enrollment should be actively considered in the post-EV + pembrolizumab setting, particularly: after platinum progression in platinum-ineligible patients after biomarker-directed therapy when no preferred evidence-supported standard option remains. Post-EV + pembrolizumab sequencing remains an active area of prospective investigation.
                          • Individualized later-line therapy or supportive care
                            If no preferred targeted therapy or clinical trial is feasible, individualize further treatment. Potential options include: paclitaxel docetaxel vinflunine where available other clinically appropriate chemotherapy best supportive and palliative care when further cancer-directed therapy is unlikely to provide meaningful benefit. Single-agent chemotherapy generally provides modest activity and should not be presented as equivalent to an appropriate biomarker-directed therapy or clinical trial.
            • Relapse ≥12 months after perioperative platinum?
              Use the platinum-free interval as one factor when considering platinum re-exposure. A relapse interval ≥12 months is a pragmatic threshold historically used to distinguish later relapse from early platinum-refractory recurrence. The optimal cutoff for platinum rechallenge specifically after first-line EV + pembrolizumab has not been prospectively validated. Also consider prior response, prior toxicity, current organ function and residual neuropathy.
              • Consider platinum rechallenge if eligible
                If the platinum-free interval is prolonged and prior benefit and tolerance were favorable, platinum re-exposure may be considered if the patient remains clinically eligible. Reassess current platinum fitness rather than relying on historical eligibility.
                • Classify current platinum eligibility
                  Reassess platinum fitness at the current treatment decision. Consider: ECOG performance status renal function hearing impairment peripheral neuropathy cardiac function comorbidities marrow reserve residual toxicity from EV Do not rely solely on historical platinum eligibility.
                  • Cisplatin-eligible
                    Prefer cisplatin-based chemotherapy when the patient remains cisplatin-eligible. Residual EV-related neuropathy, renal function and hearing status should be incorporated into the current eligibility assessment.
                    • Gemcitabine + cisplatin — planned 4–6 cycles
                      Treat with gemcitabine plus cisplatin for a planned finite course, generally 4–6 cycles as clinically appropriate and tolerated. Assess response and cumulative toxicity during therapy. Closely monitor renal function, marrow reserve, hearing and residual neuropathy after prior EV exposure.
                      • Reassess response and toxicity during platinum
                        Reassess clinical benefit, radiographic response and cumulative toxicity during the planned platinum course. Modify, delay or discontinue treatment when clinically significant toxicity outweighs continued benefit.
                        • Complete 4–6 cycles; no routine avelumab maintenance
                          Complete the planned platinum course as tolerated rather than continuing platinum indefinitely. After response or stable disease following platinum administered after first-line EV + pembrolizumab, routine maintenance avelumab is not recommended in unselected patients. Routine single-agent checkpoint-inhibitor rechallenge is also not encouraged without additional supporting evidence. Continue clinical and radiographic surveillance after completion of treatment.
                          • At progression or intolerance: is an unused active mechanism available?
                            At progression or intolerance after prior therapy, reassess which evidence-supported options remain unused. Review: susceptible FGFR3 alteration and prior erdafitinib exposure HER2 IHC expression prior platinum exposure clinical-trial availability residual treatment toxicity ECOG performance status and organ function patient goals and treatment burden.
                            • FGFR3 alteration + erdafitinib not previously used
                              If a susceptible FGFR3 alteration is present and erdafitinib has not previously been used, consider erdafitinib according to clinical suitability, local approval and access.
                              • Erdafitinib
                                Initiate erdafitinib according to current prescribing information and apply the monitoring principles described earlier in this pathway.
                            • HER2 IHC3+ and no satisfactory standard alternative
                              In previously treated HER2 IHC3+ disease, consider trastuzumab deruxtecan when no satisfactory standard treatment alternative remains and local regulatory approval/access permits. Activity has also been observed in HER2 IHC2+ bladder cancer, and EAU allows consideration in IHC2+ disease; however, the U.S. tumor-agnostic indication is specifically HER2 IHC3+.
                              • Consider T-DXd; monitor for ILD/pneumonitis
                                Use trastuzumab deruxtecan according to local regulatory approval. Before treatment, review pulmonary history and baseline clinical status. During therapy: actively monitor for cough, dyspnea, fever or other new respiratory symptoms promptly investigate suspected ILD/pneumonitis manage according to current prescribing information permanently discontinue T-DXd for Grade ≥2 ILD/pneumonitis according to the current U.S. label.
                            • No preferred targeted option remains
                              If no preferred evidence-supported targeted option remains, prioritize clinical-trial enrollment whenever feasible. Consider patient fitness, expected benefit, residual toxicity and treatment burden before proceeding to additional cytotoxic therapy.
                              • Prioritize a clinical trial
                                Clinical-trial enrollment should be actively considered in the post-EV + pembrolizumab setting, particularly: after platinum progression in platinum-ineligible patients after biomarker-directed therapy when no preferred evidence-supported standard option remains. Post-EV + pembrolizumab sequencing remains an active area of prospective investigation.
                                • Individualized later-line therapy or supportive care
                                  If no preferred targeted therapy or clinical trial is feasible, individualize further treatment. Potential options include: paclitaxel docetaxel vinflunine where available other clinically appropriate chemotherapy best supportive and palliative care when further cancer-directed therapy is unlikely to provide meaningful benefit. Single-agent chemotherapy generally provides modest activity and should not be presented as equivalent to an appropriate biomarker-directed therapy or clinical trial.
                  • Carboplatin-eligible, cisplatin-ineligible
                    Use carboplatin when cisplatin is not appropriate but combination platinum chemotherapy remains clinically feasible. Do not substitute carboplatin solely for convenience in a patient who remains cisplatin-eligible.
                    • Gemcitabine + carboplatin — planned 4–6 cycles
                      Treat with gemcitabine plus cisplatin for a planned finite course, generally 4–6 cycles as clinically appropriate and tolerated. Assess response and cumulative toxicity during therapy. Closely monitor renal function, marrow reserve, hearing and residual neuropathy after prior EV exposure.
                      • Reassess response and toxicity during platinum
                        Reassess clinical benefit, radiographic response and cumulative toxicity during the planned platinum course. Modify, delay or discontinue treatment when clinically significant toxicity outweighs continued benefit.
                        • Complete 4–6 cycles; no routine avelumab maintenance
                          Complete the planned platinum course as tolerated rather than continuing platinum indefinitely. After response or stable disease following platinum administered after first-line EV + pembrolizumab, routine maintenance avelumab is not recommended in unselected patients. Routine single-agent checkpoint-inhibitor rechallenge is also not encouraged without additional supporting evidence. Continue clinical and radiographic surveillance after completion of treatment.
                          • At progression or intolerance: is an unused active mechanism available?
                            At progression or intolerance after prior therapy, reassess which evidence-supported options remain unused. Review: susceptible FGFR3 alteration and prior erdafitinib exposure HER2 IHC expression prior platinum exposure clinical-trial availability residual treatment toxicity ECOG performance status and organ function patient goals and treatment burden.
                            • FGFR3 alteration + erdafitinib not previously used
                              If a susceptible FGFR3 alteration is present and erdafitinib has not previously been used, consider erdafitinib according to clinical suitability, local approval and access.
                              • Erdafitinib
                                Initiate erdafitinib according to current prescribing information and apply the monitoring principles described earlier in this pathway.
                            • HER2 IHC3+ and no satisfactory standard alternative
                              In previously treated HER2 IHC3+ disease, consider trastuzumab deruxtecan when no satisfactory standard treatment alternative remains and local regulatory approval/access permits. Activity has also been observed in HER2 IHC2+ bladder cancer, and EAU allows consideration in IHC2+ disease; however, the U.S. tumor-agnostic indication is specifically HER2 IHC3+.
                              • Consider T-DXd; monitor for ILD/pneumonitis
                                Use trastuzumab deruxtecan according to local regulatory approval. Before treatment, review pulmonary history and baseline clinical status. During therapy: actively monitor for cough, dyspnea, fever or other new respiratory symptoms promptly investigate suspected ILD/pneumonitis manage according to current prescribing information permanently discontinue T-DXd for Grade ≥2 ILD/pneumonitis according to the current U.S. label.
                            • No preferred targeted option remains
                              If no preferred evidence-supported targeted option remains, prioritize clinical-trial enrollment whenever feasible. Consider patient fitness, expected benefit, residual toxicity and treatment burden before proceeding to additional cytotoxic therapy.
                              • Prioritize a clinical trial
                                Clinical-trial enrollment should be actively considered in the post-EV + pembrolizumab setting, particularly: after platinum progression in platinum-ineligible patients after biomarker-directed therapy when no preferred evidence-supported standard option remains. Post-EV + pembrolizumab sequencing remains an active area of prospective investigation.
                                • Individualized later-line therapy or supportive care
                                  If no preferred targeted therapy or clinical trial is feasible, individualize further treatment. Potential options include: paclitaxel docetaxel vinflunine where available other clinically appropriate chemotherapy best supportive and palliative care when further cancer-directed therapy is unlikely to provide meaningful benefit. Single-agent chemotherapy generally provides modest activity and should not be presented as equivalent to an appropriate biomarker-directed therapy or clinical trial.
                  • Platinum-ineligible
                    Do not force combination platinum chemotherapy when expected toxicity outweighs potential benefit. Move to an unused biomarker-directed option, clinical trial, or individualized later-line strategy according to treatment history, fitness and patient goals.
                    • Move to non-platinum options
                      When platinum is not appropriate, select among remaining evidence-supported options according to: unused actionable biomarkers prior systemic therapies disease tempo residual toxicity performance status and organ function clinical-trial availability patient goals and treatment burden.
                      • Proceed to later-line treatment selection
                        Reassess the treatments already received and identify evidence-supported active mechanisms that remain unused. Avoid automatically recycling a previously ineffective mechanism outside a clinical trial.
                        • At progression or intolerance: is an unused active mechanism available?
                          At progression or intolerance after prior therapy, reassess which evidence-supported options remain unused. Review: susceptible FGFR3 alteration and prior erdafitinib exposure HER2 IHC expression prior platinum exposure clinical-trial availability residual treatment toxicity ECOG performance status and organ function patient goals and treatment burden.
                          • FGFR3 alteration + erdafitinib not previously used
                            If a susceptible FGFR3 alteration is present and erdafitinib has not previously been used, consider erdafitinib according to clinical suitability, local approval and access.
                            • Erdafitinib
                              Initiate erdafitinib according to current prescribing information and apply the monitoring principles described earlier in this pathway.
                          • HER2 IHC3+ and no satisfactory standard alternative
                            In previously treated HER2 IHC3+ disease, consider trastuzumab deruxtecan when no satisfactory standard treatment alternative remains and local regulatory approval/access permits. Activity has also been observed in HER2 IHC2+ bladder cancer, and EAU allows consideration in IHC2+ disease; however, the U.S. tumor-agnostic indication is specifically HER2 IHC3+.
                            • Consider T-DXd; monitor for ILD/pneumonitis
                              Use trastuzumab deruxtecan according to local regulatory approval. Before treatment, review pulmonary history and baseline clinical status. During therapy: actively monitor for cough, dyspnea, fever or other new respiratory symptoms promptly investigate suspected ILD/pneumonitis manage according to current prescribing information permanently discontinue T-DXd for Grade ≥2 ILD/pneumonitis according to the current U.S. label.
                          • No preferred targeted option remains
                            If no preferred evidence-supported targeted option remains, prioritize clinical-trial enrollment whenever feasible. Consider patient fitness, expected benefit, residual toxicity and treatment burden before proceeding to additional cytotoxic therapy.
                            • Prioritize a clinical trial
                              Clinical-trial enrollment should be actively considered in the post-EV + pembrolizumab setting, particularly: after platinum progression in platinum-ineligible patients after biomarker-directed therapy when no preferred evidence-supported standard option remains. Post-EV + pembrolizumab sequencing remains an active area of prospective investigation.
                              • Individualized later-line therapy or supportive care
                                If no preferred targeted therapy or clinical trial is feasible, individualize further treatment. Potential options include: paclitaxel docetaxel vinflunine where available other clinically appropriate chemotherapy best supportive and palliative care when further cancer-directed therapy is unlikely to provide meaningful benefit. Single-agent chemotherapy generally provides modest activity and should not be presented as equivalent to an appropriate biomarker-directed therapy or clinical trial.
              • Prefer a non-platinum strategy
                Prefer a non-platinum strategy when early relapse after perioperative platinum, poor prior platinum tolerance, current platinum ineligibility, or another clinical factor makes platinum re-exposure unattractive. Prioritize an unused biomarker-directed treatment or clinical trial when appropriate.
                • Proceed to later-line treatment selection
                  Reassess the treatments already received and identify evidence-supported active mechanisms that remain unused. Avoid automatically recycling a previously ineffective mechanism outside a clinical trial.
                  • At progression or intolerance: is an unused active mechanism available?
                    At progression or intolerance after prior therapy, reassess which evidence-supported options remain unused. Review: susceptible FGFR3 alteration and prior erdafitinib exposure HER2 IHC expression prior platinum exposure clinical-trial availability residual treatment toxicity ECOG performance status and organ function patient goals and treatment burden.
                    • FGFR3 alteration + erdafitinib not previously used
                      If a susceptible FGFR3 alteration is present and erdafitinib has not previously been used, consider erdafitinib according to clinical suitability, local approval and access.
                      • Erdafitinib
                        Initiate erdafitinib according to current prescribing information and apply the monitoring principles described earlier in this pathway.
                    • HER2 IHC3+ and no satisfactory standard alternative
                      In previously treated HER2 IHC3+ disease, consider trastuzumab deruxtecan when no satisfactory standard treatment alternative remains and local regulatory approval/access permits. Activity has also been observed in HER2 IHC2+ bladder cancer, and EAU allows consideration in IHC2+ disease; however, the U.S. tumor-agnostic indication is specifically HER2 IHC3+.
                      • Consider T-DXd; monitor for ILD/pneumonitis
                        Use trastuzumab deruxtecan according to local regulatory approval. Before treatment, review pulmonary history and baseline clinical status. During therapy: actively monitor for cough, dyspnea, fever or other new respiratory symptoms promptly investigate suspected ILD/pneumonitis manage according to current prescribing information permanently discontinue T-DXd for Grade ≥2 ILD/pneumonitis according to the current U.S. label.
                    • No preferred targeted option remains
                      If no preferred evidence-supported targeted option remains, prioritize clinical-trial enrollment whenever feasible. Consider patient fitness, expected benefit, residual toxicity and treatment burden before proceeding to additional cytotoxic therapy.
                      • Prioritize a clinical trial
                        Clinical-trial enrollment should be actively considered in the post-EV + pembrolizumab setting, particularly: after platinum progression in platinum-ineligible patients after biomarker-directed therapy when no preferred evidence-supported standard option remains. Post-EV + pembrolizumab sequencing remains an active area of prospective investigation.
                        • Individualized later-line therapy or supportive care
                          If no preferred targeted therapy or clinical trial is feasible, individualize further treatment. Potential options include: paclitaxel docetaxel vinflunine where available other clinically appropriate chemotherapy best supportive and palliative care when further cancer-directed therapy is unlikely to provide meaningful benefit. Single-agent chemotherapy generally provides modest activity and should not be presented as equivalent to an appropriate biomarker-directed therapy or clinical trial.
      • Urgent cytoreduction needed?
        If rapid symptomatic progression, impending organ compromise, or another oncologic emergency requires urgent cytoreduction, prioritize an immediately available active therapy. Do not delay clinically necessary treatment solely to complete nonessential testing. Integrate appropriate local or supportive interventions when clinically indicated.
  2. Consider a clinical trial at every treatment decision
    Consider clinical-trial enrollment throughout the pathway, especially after platinum progression, in platinum-ineligible patients, after exhaustion of validated biomarker-directed options, or whenever evidence for sequencing is limited.
tosprivacyEuropean Association of Urology. EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Metastatic Disease. Current 2026 versionPowles T, Bellmunt J, Compérat E, et al. ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma. Ann Oncol. 2024;35:485-490.U.S. FDA. Erdafitinib approval for susceptible FGFR3-altered locally advanced/metastatic UC.U.S. FDA. Tumor-agnostic T-DXd approval for HER2 IHC3+ solid tumors.Loriot Y, Matsubara N, Park SH, et al. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023;389:1961-1971. doi:10.1056/NEJMoa2308849.ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinomaCurrent BALVERSA prescribing informationNCI. Historical platinum-refractory definition including relapse within 12 months after perioperative platinum.Sternschuss M, et al. Platinum-based chemotherapy after EV + pembrolizumab. ESMO Open. 2026;11(8):108318.Jung KH, Oh DY, Doroshow DB, et al. Final bladder cohort results from DESTINY-PanTumor02. J Clin Oncol. 2026;44(7_suppl):734. doi:10.1200/JCO.2026.44.7_suppl.734.Galsky MD, Drakaki A, Basu A, et al. TROPION-Urothelial03. Future Oncol. 2026;22:1387-1396.