For advanced or metastatic bladder cancer, the platinum-free combo is now the standard
If your cancer has spread (metastatic) or is locally advanced, the old first-line standard—cisplatin-based chemotherapy—has been dethroned. The EV-302 study, a major trial, showed that combining enfortumab vedotin (EV, an antibody-drug conjugate that delivers chemotherapy directly to cancer cells) with pembrolizumab (an immune checkpoint inhibitor that helps your immune system attack the tumor) works better than chemotherapy as the first treatment [1]. This is a landmark shift: it's the first time a platinum-free regimen has beaten chemotherapy in this setting, and it's now the standard of care [1].
This matters because platinum chemotherapy is toxic and many patients can't tolerate it. The EV-302 result means that even patients who are not eligible for cisplatin now have a highly effective option that doesn't rely on platinum [1]. The old approach—giving cisplatin-based chemo first, then switching to immunotherapy later—is being replaced by this upfront combination for advanced disease.
For muscle-invasive bladder cancer (before or after surgery), cisplatin is still the standard—but alternatives are emerging
If your cancer is muscle-invasive but hasn't spread (nonmetastatic), the picture is different. The standard of care is still cisplatin-based chemotherapy before surgery (neoadjuvant) followed by radical cystectomy (bladder removal) [3][4]. This is because neoadjuvant chemo improves survival, and no platinum-free regimen has yet proven superior in this setting [3][4].
However, more than half of patients with muscle-invasive bladder cancer are not eligible for cisplatin due to kidney problems, frailty, or other health issues [5]. For these patients, there is an unmet need. Recent trials are exploring alternatives: neoadjuvant immune checkpoint inhibitors alone have shown encouraging pathologic complete response rates (meaning no cancer found at surgery) in cisplatin-ineligible patients [3]. The combination of EV plus pembrolizumab is also being tested in the perioperative setting, with phase 3 data supporting its use [3]. Another approach is TAR-200, an intravesical (into the bladder) sustained-release gemcitabine, combined with systemic PD-1 blockade, which has shown promising activity in early studies [3]. So, while cisplatin remains the standard for eligible patients, the field is actively moving toward platinum-free options for those who can't take it.
Immunotherapy alone doesn't work for everyone—and that's why combinations matter
Immune checkpoint inhibitors (ICIs) like pembrolizumab and nivolumab have been approved for bladder cancer, but they only work in about 30% of patients with metastatic disease [2]. That means most patients don't respond to ICI alone. This is why combining ICIs with other agents, like antibody-drug conjugates (EV) or even antiandrogens, is so promising—it aims to boost the response rate.
Research also shows that bladder cancer can evade the immune system through other checkpoints. For example, a 2022 study found that an alternative immune checkpoint axis involving NKG2A and HLA-E can limit the effectiveness of PD-1/PD-L1 blockade [6]. This suggests that adding NKG2A blockade to existing immunotherapies could help more patients, especially those with high HLA-E expression [6]. Similarly, a 2022 study in mice suggested that combining antiandrogen therapy (enzalutamide) with immunotherapy could improve response rates in male patients, potentially because sex hormones affect the immune response [7]. These are early-stage findings, but they highlight that the future of bladder cancer treatment is likely to be combination therapy, not single agents.
About These Sources
This answer is built on 7 peer-reviewed studies — published from 2021 to 2026, 2 from 2024 or later, 5 in Q1 journals, collectively cited 812 times — selected as the most relevant from 7 studies that passed quality screening, drawn from 35 papers retrieved from a database of over 500 million.
Sources used in this answer
Changing landscape of first-line treatment for locally advanced or metastatic urothelial carcinoma: the progression from platinum-based chemotherapy to platinum-free therapy
Reviews the shift in first-line treatment for advanced urothelial carcinoma, concluding that the EV-302 trial's success with enfortumab vedotin plus pembrolizumab has made this platinum-free combination the new standard of care, replacing platinum-based chemotherapy.
Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer
Reviews immune checkpoint inhibitors in bladder cancer, noting that about 30% of patients with metastatic disease respond to ICI monotherapy, and that PD-L1 expression may predict response; also covers approvals for cisplatin-ineligible patients and second-line settings.
Neoadjuvant Therapy in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer: Recent Progress, Challenges, and Future Directions in the Era of TAR-200 and Enfortumab Vedotin Plus Pembrolizumab
Reviews perioperative therapy for cisplatin-ineligible muscle-invasive bladder cancer, highlighting that neoadjuvant ICIs show encouraging pathologic complete response rates, and that EV plus pembrolizumab and TAR-200 plus PD-1 blockade are emerging platinum-free strategies, though not yet standard.
Bladder cancer
Provides a comprehensive overview of bladder cancer, stating that for muscle-invasive disease, radical cystectomy with neoadjuvant chemotherapy (cisplatin-based) remains the standard of care, while immune checkpoint inhibitors have demonstrated benefit across non-muscle-invasive, muscle-invasive, and metastatic settings.
Emerging perioperative therapeutic approaches in muscle invasive bladder cancer
Reviews perioperative approaches in muscle-invasive bladder cancer, noting that more than 50% of patients are ineligible for cisplatin-based therapy, and that immune checkpoint inhibitors are improving outcomes, with nivolumab approved in the adjuvant setting and ADCs like enfortumab vedotin in trials.
NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer
Identifies an alternative immune checkpoint axis in bladder cancer involving NKG2A and HLA-E, showing that NKG2A blockade can restore T-cell function in an HLA-E-dependent manner, suggesting a potential combination strategy with PD-1/PD-L1 blockade.
Combining Antiandrogens with Immunotherapy for Bladder Cancer Treatment
In a mouse model of bladder cancer, combining the antiandrogen enzalutamide with anti-PD-1 or BCG+poly(I:C) immunotherapy improved response rates in male mice, suggesting that antiandrogen therapy may potentiate immunotherapy in male patients.