Urothelial carcinoma (UC) is the predominant histologic subtype of malignancies arising in the urinary tract, accounting for more than 90% of cases^[1]. Despite advances in detection and management, outcomes for advanced disease remain poor^[2]. In the first-line setting for locally advanced or metastatic UC (la/mUC), cisplatin-based combination chemotherapy remains the backbone of systemic therapy^[3,4]. However, durable disease control remains limited because of intrinsic and acquired treatment resistance^[5,6]. This resistance often manifests clinically as early progression and limited long-term benefit. Moreover, up to half of patients are ineligible for cisplatin because of renal dysfunction or comorbidities^[4,7]. These patients often receive less effective carboplatin-based regimens, highlighting the need for more effective first-line strategies.

In recent years, immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) and its ligand (PD-L1) have reshaped the treatment landscape of UC. Multiple PD-1/PD-L1 inhibitors have received regulatory approval in the second-line setting and as first-line options for cisplatin-ineligible patients, supporting a transition beyond chemotherapy-only strategies^[8-10].

With the advent of ICIs, multiple large phase III randomized controlled trials (RCTs), such as IMvigor130^[11], KEYNOTE-361^[12], DANUBE^[13], and CheckMate 901^[14], have evaluated the role of ICIs alone or in combination with chemotherapy in the first-line setting. Although these studies did not consistently demonstrate overall survival (OS) superiority in the intention-to-treat population, they provided comparative evidence across major treatment strategies. More recently, the EV-302 trial showed that enfortumab vedotin (EV) plus pembrolizumab significantly improved OS and progression-free survival (PFS) compared with chemotherapy^[15]. These findings contributed to updated guideline endorsements and reshaped expectations for first-line treatment. Collectively, these trials reflect the increasing evaluation of ICI-based combinations in the first-line setting. However, the durability of benefit remains variable across regimens. In addition, treatment outcomes may differ across biological subgroups. In FGFR-altered UC, selective pan-FGFR inhibitors may yield higher objective response rates (ORRs) than ICI or chemotherapy^[16]. However, they have not shown a survival benefit and may be associated with more grade ≥ 3 adverse events (AEs). Recent evidence also suggests that FGFR3-mutated tumors display an immunosuppressive microenvironment and diminished response to checkpoint blockade^[17]. These observations further highlight the biological heterogeneity underlying treatment outcomes. Accordingly, an updated synthesis incorporating recent randomized trials and a broader comparative evidence framework remains clinically relevant.

Despite these advances, direct head-to-head comparisons across the full spectrum of available first-line systemic therapies remain lacking. Traditional pairwise meta-analyses are limited when most regimens have not been compared directly. Previous network meta-analysis (NMA) have evaluated first-line systemic therapy for metastatic UC^[18], but important evidence gaps remain. In this context, we conducted a systematic review and NMA of RCTs evaluating first-line systemic therapies for patients with advanced or metastatic UC.

This NMA synthesized evidence from 13 RCTs evaluating 10 first-line regimens for advanced or metastatic UC. Across the overall population, ICI+ADC demonstrated the most consistent and substantial benefit in OS, PFS, and ORR, ranking first in nearly all analyses. ICI+Chemo also showed significant but more modest improvements, while ICI+ICI provided variable benefit without statistical superiority. In contrast, ICI monotherapy and TKI-based combinations failed to outperform chemotherapy. Safety analysis indicated that ICI monotherapy had the most favorable toxicity profile, though at the cost of limited efficacy, whereas combination regimens, especially ICI+ADC and ICI+Chemo, were associated with higher rates of grade ≥ 3 AEs. Compared with previous published meta-analyses, the present study incorporates a more contemporary first-line evidence base, including ADC-era randomized trials such as EV-302 and other recently reported studies. We also evaluated outcomes separately in cisplatin-eligible and cisplatin-ineligible patients and included an exploratory cross-endpoint consistency analysis to jointly interpret efficacy and safety signals. These additions may provide more clinically relevant information for treatment selection in current practice.

The advantage of ICI+ADC is consistent with the EV-302 trial, which established EV plus pembrolizumab as a key first-line option. Our results extend this evidence by showing consistent benefit in both cisplatin eligible and cisplatin ineligible subgroups. Similar patterns were observed across age, ECOG performance status, and PD-L1 strata. The signal in cisplatin ineligible and PD-L1 low patients is clinically relevant because durable benefit is often limited in these settings. The ICI+ADC strategy is also supported by the RC48-C016 trial^[31]. This study enrolled HER2 positive patients and evaluated disitamab vedotin plus toripalimab. The observed survival benefit provides additional support for ICI+ADC combinations across different ADC platforms.

ICI+Chemo showed meaningful benefit in several subgroups, including PD-L1 high and ECOG 1 or higher patients, which is consistent with signals reported in IMvigor130. In contrast, ICI+ICI did not provide clear benefit in the overall population, which is in line with the negative DANUBE results. ICI monotherapy ranked low across most endpoints, supporting its limited role as first-line treatment in unselected patients. These patterns also fit a resistance framework. Single agent ICI may fail to control early treatment failure in tumors with primary immune resistance. Combination strategies may reduce early nonresponse by adding a nonoverlapping antitumor component, but they increase toxicity.

These findings inform first-line treatment selection in advanced UC. ICI+ADC showed the strongest efficacy profile and can be considered the preferred option when available. However, the real-world adoption of ICI+ADC combinations may be constrained by higher treatment costs, reimbursement barriers, and limited accessibility in some healthcare settings. Therefore, although these regimens showed the most favorable efficacy profile, financial toxicity and availability remain important considerations in routine clinical decision-making. This is relevant to the scope of cancer drug resistance because early progression and short-lived responses represent resistance related treatment failure in routine care. Regimens that improve both PFS and ORR are more likely to delay early treatment failure at the population level. ICI+Chemo remains an appropriate alternative when ADCs are unavailable or unsuitable. This may be most relevant in groups with higher risk of early failure, such as patients with ECOG 1 or higher or PD-L1 high tumors. ICI+ICI may be considered for selected patients, but current evidence does not support broad use. ICI monotherapy showed the most favorable safety profile, but it ranked low for efficacy outcomes. Its role may be limited to patients who cannot tolerate combination therapy or who prioritize safety. Treatment decisions should balance efficacy and toxicity. They should also consider the goal of delaying resistance related treatment failure.

We further evaluated agreement across OS, PFS, ORR, and grade ≥ 3 AEs using the previously described framework. Agreement across endpoints may support a more consistent overall benefit–risk pattern, whereas inconsistency across endpoints may indicate efficacy–safety trade-offs. In our NMA, ICI+ADC and ICI+Chemo showed consistently favorable directions across endpoint pairs, in line with their leading SUCRA ranks. Chemo+Chemo showed partial agreement across endpoints, whereas ICI monotherapy and TKI-containing combinations showed greater inconsistency across endpoints. When we required CrIs to exclude the null, agreement scores decreased, but the overall hierarchy remained similar, with ICI+ADC and ICI+Chemo remaining top ranked. This framework complements SUCRA and league tables by summarizing whether efficacy and safety endpoints move in the same direction, but it does not account for effect size, baseline risk, or patient utility. Future work should incorporate patient-reported outcomes (PROs) and individual participant data (IPD) with explicit utility weighting to better reflect clinical value and resistance-related treatment failure.

Several limitations merit consideration. First, we included only RCTs, but heterogeneity in trial design, eligibility criteria, and patient characteristics may introduce bias and weaken the transitivity assumption of the NMA. In addition, several included studies were phase II trials with relatively small sample sizes. Although these trials were randomized and helped improve network coverage across currently available first-line strategies, their inclusion may have increased uncertainty in some comparisons and treatment rankings. Differences in PD-L1 assays, cutoffs, and endpoint definitions or assessment methods across trials may also affect comparability and represent an additional source of clinical heterogeneity. Second, most regimens were not compared directly, and the HRs for EV-103 cohort K were estimated from the published Kaplan–Meier curves rather than directly reported, which may reduce precision. In addition, KEYNOTE-672 had a short median follow-up of 64 days because enrollment was discontinued early. However, this trial contributed only ORR and grade ≥ 3 AE data and was not included in the OS or PFS analyses. Third, subgroup analyses were constrained by available reporting and should be interpreted cautiously.

Future head-to-head trials are needed to compare leading regimens, particularly ICI+ADC vs. ICI+Chemo. Precision oncology approaches that incorporate PD-L1, tumor mutational burden (TMB), molecular subtypes, and immune gene signatures may improve patient selection. Real-world evidence and IPD are likely to be important to validate these findings and inform sequencing. Further work should also examine mechanisms of resistance to ICI, ADC, and combination regimens, as well as optimal treatment duration. Emerging modalities such as bispecific antibodies and cellular therapies may further expand options.

In conclusion, this NMA suggests that ICI+ADC was associated with the most consistent improvement in OS, PFS, and ORR in advanced UC, including cisplatin-eligible and cisplatin-ineligible patients. ICI+Chemo also improves outcomes and remains a practical option when ADCs are unavailable. ICI monotherapy shows limited efficacy despite favorable safety and may be reserved for patients unfit for combination regimens. Further head-to-head trials and biomarker-based approaches are needed to refine first-line selection.