Systemic therapy for urothelial cancer: platinum defeated?

Platinum-based chemotherapy has been the mainstay of systemic therapy for decades [1, 2]. Treatment choice was mainly determined by cisplatin eligibility, with eligible patients generally receiving cisplatin in combination with gemcitabine, whereas ineligible patients were offered carboplatin with gemcitabine. Whilst clinical trials historically have struggled to accrue, the past decade has seen a multitude of successfully completed large randomized trials, thoroughly changing the treatment paradigm for advanced urothelial cancer [3].

The first indication that PD-L1 blockade showed anti-tumor activity in metastatic UC was obtained from phase I–II trials with atezolizumab in heavily pre-treated patients [4]. Surprisingly, the phase III IMvigor 211 study did not demonstrate the anticipated benefit of second-line atezolizumab compared to non-platinum chemotherapy (paclitaxel, docetaxel, or vinflunine) [5]. The Keynote 045 trial was the first positive phase III trial with second-line PD‑1 blockade in metastatic UC [6], demonstrating an overall survival (OS) benefit of 2.9 months following pembrolizumab versus non-platinum chemotherapy. Based on Keynote 045, pembrolizumab has become standard of care as treatment option in metastatic UC patients who relapsed upon frontline chemotherapy [7].

Following the success of PD‑1 blockade as second-line treatment for metastatic UC, the phase III JAVELIN100 trial assessed whether resistance to frontline chemotherapy could be prevented by maintenance therapy with avelumab (anti-PD-L1) following first-line chemotherapy [8]. Compared to best-supportive care, maintenance avelumab resulted in a benefit in median OS of 7.1 months (HR for death 0.69, p = 0.001), which led to the approval of maintenance avelumab in metastatic UC patients who achieved at least stable disease upon 4–6 cycles platinum-based chemotherapy.

Atezolizumab and pembrolizumab as frontline therapy received registration by the EMA for cisplatin ineligible patients with PD-L1 positive tumors, based on single-arm trials [9, 10]. Both drugs were subsequently tested in multi-arm studies. In the phase III IMvigor 130 trial, cisplatin-eligible- and ineligible patients were randomized to atezolizumab plus platinum-based chemotherapy (group A), atezolizumab alone (group B) or placebo plus platinum-based chemotherapy (group C). Because the OS comparison of group A versus C as primary endpoint did not cross the pre-specified significance boundary, the comparison of group B versus group C became exploratory. Atezolizumab showed a numerically better OS in PD-L1 positive tumors (HR for OS: 0.68; 95% CI 0.43–1.08) [11].

The phase III Keynote 361 study evaluated overall survival for frontline pembrolizumab with or without platinum-based chemotherapy versus chemotherapy alone in both cisplatin-eligible and -ineligible patients [12]. The primary endpoint was not met, as pembrolizumab plus chemotherapy failed to show prolonged (progression-free) survival compared to chemotherapy alone. The study design precluded a formal comparison of pembrolizumab versus chemotherapy; the PD-L1 positive cisplatin-ineligible subgroup showed an OS HR of 0.82 for pembrolizumab versus carboplatin plus gemcitabine, with the KM curves largely overlapping [12]. European guidelines do not recommend frontline pembrolizumab or atezolizumab as the first choice, though these therapies are mentioned as a potential alternative for cisplatin ineligible patients with a PD-L1 positive tumor upon careful consideration [7].

Several studies aimed to show a benefit of combining chemotherapy with anti-PD-(L)1 therapy. The IMvigor 130 and Keynote 361 trials, mentioned above, both enrolled patients regardless of cisplatin eligibility. The choice of platinum was up to the investigator, and the majority of patients received carboplatin/gemcitabine as the chemotherapy backbone. Exploratory analyses showed a potential benefit in the subpopulation receiving cisplatin, suggesting that cisplatin could have more potent immune-inducing effects. The phase III Checkmate 901 trial tested this hypothesis and showed a progression-free survival (PFS) and OS benefit following frontline gemcitabine-cisplatin plus nivolumab, compared to gemcitabine-cisplatin (HR for death 0.78; 95% CI 0.63–0.96; p = 0.02; HR for progression or death 0.72; 95% CI 0.59–0.88; p = 0.001) [13]. Based on these results, frontline nivolumab plus cisplatin/gemcitabine acquired FDA- and EMA approval.

Several studies aimed to show a benefit of combining anti-CTLA‑4 with anti-PD-(L)1 therapy. The phase III DANUBE trial compared frontline chemotherapy to durvalumab and to durvalumab plus tremelimumab [14]. DANUBE was considered a negative trial, as neither durvalumab alone, nor durvalumab plus tremelimumab improved survival compared to chemotherapy in the PD-L1 positives and in the intention-to-treat population (ITT), respectively. However, even though durvalumab was not formally compared to durvalumab plus tremelimumab, the objective response rate (ORR) was numerically higher upon durvalumab plus tremelimumab (36% vs. 26%), and this ORR difference was more pronounced in PD-L1 positive patients (47% vs. 28%). The OS HR for tremelimumab plus durvalumab vs. chemotherapy was 0.82 (0.72–1.02) in the ITT population and the HR was 0.74 (0.59–0.93) for the PD-L1+ population [14].

Recently, the final results of the comparison between combination ICB and carboplatin-based chemotherapy in the phase III Checkmate 901, were reported (ASCO Annual Meeting 2025). In cisplatin ineligible, previously untreated patients with unresectable or metastatic UC, median OS was 19.1 months upon ipilimumab plus nivolumab and 13.2 months following carboplatin and gemcitabine (HR 0.79; p = 0.0245). As the OS difference did not meet the pre-specified boundary for significance (p < 0.0173), the trial was considered negative. Given the OS difference in the tail of the KM curve, together with a longer duration of response (DOR) following combination ICB (median DOR 7.4 months upon carboplatin gemcitabine vs. 25.0 months upon combination ICB), one could argue that combination ICB in frontline metastatic UC may have benefit in terms of durability of response compared to chemotherapy, which is not adequately captured by commonly used trial designs.

In conclusion, multiple multicenter trials have aimed to replace platinum-based chemotherapy as the frontline standard of care in advanced UC (for an overview, see Tab. 1). Unfortunately, many of these trials failed to reach their (statistical) endpoint, with the Checkmate 901 trial being the exception, showing an OS benefit with the addition of nivolumab to cisplatin-gemcitabine. However, this situation of modest incremental improvements changed with the development of enfortumab vedotin, especially when combined with ICB (see below).

Enfortumab vedotin (EV; an antibody drug conjugate (ADC) targeting nectin‑4, with monomethyl auristatin E as the payload drug) was developed in advanced UC. In the phase 3 EV301 trial, EV was compared to non-platinum single agent chemotherapy in advanced UC patients who had progressed to platinum-based chemotherapy and immune checkpoint inhibitors. EV showed a significantly improved OS with a HR of 0.70 (95% CI 0.56–0.89) and a median OS benefit of 12.8 versus 9.0 months [15]. The response rate was approximately 40%. EV is associated with a specific toxicity spectrum, which can be serious, challenging to treat and even lethal. Specific toxicities of interest include skin reactions (which may include Stevens Johnson Syndrome), peripheral neuropathy, hyperglycaemia, pulmonary complications and metabolic acidosis. Based on the results in this study, EV has become the standard of care in patients with progression of disease after first-line chemotherapy and immunotherapy (including maintenance avelumab).

Preclinical data suggested that EV may have immune-enhancing effects, making the combination of EV with pembrolizumab (EVP) particularly efficacious. In the phase Ib/II multi-cohort EV-103 study, EVP was investigated in first- or second-line settings in patients with advanced UC. Results from the dose escalation/Cohort A conducted in 45 patients with la/mUC cisplatin-ineligible patients treated in first line demonstrated a confirmed ORR of 73.3% with a complete response rate of 15.6%. The median PFS was 12.3 months, the median OS was 26.1 months. A recent update of the data with a median follow-up of 62 months showed a 5-year PFS of 38.2% and a 5-year OS of 41.5%, suggesting exceptional long-term outcomes in comparison with historical data for chemotherapy.

In the landmark phase 3 EV302 trial, EVP was tested against platinum-based chemotherapy in previously untreated patients with advanced urothelial cancer. The results showed EVP to have a remarkable benefit in OS (HR 0.47; 95% CI 0.38–0.58; p < 0.00001) and PFS (HR 0.45; 95% CI 0.38–0.54; p < 0.00001), in comparison to standard chemotherapy [16]. In follow-up analyses, the results were consistent across various clinically important subgroups or relevant biomarkers. This trial has firmly established EVP as the preferred first-line treatment in international guidelines [3].

Several other ADCs have been tested for urothelial cancer. Sacituzumab Govetecan (SG) is an ADC directed at TROP2, with a topoisomerase inhibitor payload. Despite encouraging response rates in therapy-refractory advanced urothelial cancer, a randomized phase 3 trial failed to show an OS benefit for SG compared to non-platinum chemotherapy [17], possibly due to higher-than-expected rates of fatal neutropenic sepsis. Multiple other ADCs have shown promising response rates in single-arm studies in advanced UC and development in the changing treatment landscape is ongoing.

In conclusion, the development of ADCs, especially the combination of EV plus pembrolizumab, has led to a significant improvement in OS in the advanced UC setting. Novel ADCs, with multiple combinations of targets and payloads, are currently being developed in clinical trials.

Mutations in the FGFR3 gene have long been recognized as important drivers of a subset of urothelial cancers and a potential therapeutic target. Erdafitinib is a selective FGFR inhibitor, that can be used in patients with an aberrant FGFR2 or FGFR3 gene in human cancers [18]. Mutations or fusions in the FGFR genes are present in 15–20% of patients with bladder urothelial cell carcinoma, and more frequently in upper tract urothelial cell carcinoma. These are usually activating mutations in the FGFR3 gene, the most common hotspot mutations include R248C, R249C, G370C and Y373C; activating gene fusions involving TACC3 or BAIAP2L1 also occur in a small percentage.

In the recently published randomized phase 3 Thor trial (cohort 1), patients having advanced urothelial carcinoma with an FGFR2 or FGFR3 mutation were randomized to receive either erdafitinib or non-platinum chemotherapy (docetaxel or vinflunine) after at least one prior treatment with a PD-(L)1 checkpoint inhibitor [19]. Although patients having FGFR2 mutations were eligible, only patients with FGFR3 mutations were enrolled. OS, the primary endpoint of the trial, was statistically significantly better for erdafitinib than for chemotherapy (HR 0.64; 95% CI 0.47–0.88; p < 0.005), with a median survival of 12.1 months (95% CI 10.3–16.4) with erdafitinib and 7.8 months (95% CI 6.5–11.1) with chemotherapy. PFS (secondary endpoint) was also significantly better in the erdafitinib group (HR: 0.58; 95% CI 0.44–0.78; p < 0.001). The objective response rate was 45.6% for erdafitinib, compared to 11.5% for chemotherapy [19]. A large majority of patients (89.1%) had previously received platinum-based chemotherapy. At the time of the study, EV was not yet available and the best therapy sequence for EV or erdafitinib after platinum chemotherapy and anti-PD-(L)1 cannot be made based on the current data. In the Thor study, 14% and 10% of patients treated with erdafitinib or chemotherapy, respectively, received subsequent treatment with EV.

EMA registration for erdafitinib has been obtained for patients with advanced urothelial carcinoma who had previously been treated with anti-PD-(L)1. This would offer the possibility of treatment with erdafitinib after a checkpoint inhibitor alone, or EVP, before treatment with platinum chemotherapy. However, the number of patients in this situation was limited in the THOR trial (10.9%), and the control arm consisted of docetaxel or vinflunine, which is not a common control arm for patients who can receive platinum chemotherapy. The results of cohort 2 of the THOR trial showed no improvement for erdafitinib against pembrolizumab for patients who had previously received platinum-based chemotherapy, despite improving response rates, urging caution against the use of erdafitinib in earlier lines of therapy.

In recent years, three randomized phase 3 trials with adjuvant checkpoint inhibition in high-risk urothelial cancer have reported disease-free survival (DFS) outcomes. In the IMVIGOR010 trial, 800 high-risk urothelial cancer patients were randomized to adjuvant atezolizumab (anti-PD-L1) for 1 year, or observation. This trial did not show a difference in DFS (HR 0.89) or OS (HR 0.85) [20]. PD-L1 as a biomarker could not select for clinical benefit of adjuvant therapy. The Checkmate 274 trial investigated adjuvant nivolumab (anti-PD-1) for 1‑year versus placebo in 709 high risk muscle-invasive urothelial cancers (including upper tract cancers), and showed a median DFS in the ITT of 20.8 months with nivolumab and 10.8 months with placebo (HR 0.70) [21], which led to FDA approval. An improved benefit was found for the PD-L1 positive subgroup. Based on data from Checkmate 274, adjuvant nivolumab is registered only for patients with PD-L1 positive tumors in the EU. Finally, a third trial, AMBASSADOR, investigated adjuvant pembrolizumab (anti-PD-1) compared to observation in the same population. This trial also showed a positive result for DFS, with a HR of 0.73 (95% CI 0.59 to 0.90; two-sided p = 0.003) [22]. PD-L1 (by CPS) did not select for improved benefit in this trial and there was no OS benefit in the initial analysis, although follow-up for OS is still immature.

Cisplatin-based combination chemotherapy has dominated neoadjuvant therapy for decades, based on a modest survival benefit in a meta-analysis of randomized trials [23]. Recent developments include a clinical trial, VESPER, which was negative for the primary endpoint in the combined neoadjuvant and adjuvant population, but suggested a benefit of using six cycles of ddMVAC instead of four cycles cisplatin/gemcitabine in the neoadjuvant setting [24].

Given the observed efficacy of ICB in metastatic UC and based on data indicating that ICB may be even more potent when applied in the pre-operative setting, trials with ICB in non-metastatic UC were initiated. In the phase II PURE-01 trial, 50 MIBC patients were treated with three cycles pembrolizumab followed by surgery, which resulted in a pCR rate of 42% [25]. The phase II ABACUS trial evaluated the efficacy of two cycles pre-operative atezolizumab in 95 patients with MIBC and demonstrated that a pCR could be achieved in 31% of the patients [26]. Even though these two trials showed compelling anti-tumor efficacy following PD-(L)1 blockade as monotherapy, more than half of the patients did not respond to single-agent ICB, highlighting the need to further improve ICB treatment strategies.

Based on the hypothesis that immune-priming is insufficient in non-responders to anti-PD-(L)1 and that immune-priming could be enhanced by combining PD-(L)1 blockade with CTLA‑4 blocking agents, the NABUCCO trial was initiated. In this phase Ib trial, 54 patients with locally advanced stage III UC (cT3-4aN0M0 or cT1-4aN1-3M0) were treated with pre-operative ipilimumab plus nivolumab in different dosing regimens, which resulted in a pCR rate of 45% upon ipilimumab 3 mg/kg plus nivolumab and 7% upon ipilimumab 1 mg/kg plus nivolumab [27]. Gao and colleagues evaluated pre-operative durvalumab plus tremelimumab in 28 cisplatin-ineligible MIBC patients and observed a pCR rate of 37.5% [28].

Given the efficacy of cisplatin-based chemotherapy and ICB, combining these agents in the neoadjuvant setting was tested in multiple trials in MIBC. The combination of pre-operative durvalumab and gemcitabine plus cisplatin followed by adjuvant durvalumab was evaluated in a single-arm phase II trial (n = 57) [29], demonstrating an event-free survival (EFS) at two years of 76%, thereby meeting its primary endpoint. A formal comparison of peri-operative durvalumab and gemcitabine plus cisplatin versus neo-adjuvant gemcitabine plus cisplatin in the phase III NIAGARA trial showed a clear EFS benefit at two years in MIBC patients who were treated in the combination arm (67.8% vs. 59.8%; HR 0.68; p < 0.001) [30]. Importantly, the trial also reported a benefit in OS. Results obtained from the NIAGARA trial led to FDA and EMA approval of peri-operative durvalumab and gemcitabine plus cisplatin for MIBC patients.

Given the highly positive trial results with EVP in the advanced UC setting, several randomized phase 3 clinical trials are now testing EV + checkpoint inhibition in the pre-operative setting. The KEYNOTE-905/EV-303 study evaluates efficacy and safety of perioperative pembrolizumab monotherapy versus EVP versus radical cystectomy plus pelvic lymph node dissection alone in cisplatin-ineligible patients with MIBC [31]. The KEYNOTE-B15/EV-304 (NCT04700124) study investigates the efficacy and safety of perioperative EVP versus neoadjuvant chemotherapy using gemcitabine/cisplatin in cisplatin-eligible patients with MIBC. Finally, the VOLGA trial studies the efficacy and safety of durvalumab + tremelimumab + enfortumab EV or durvalumab + EV for neoadjuvant treatment in cisplatin-ineligible MIBC (NCT04960709).