Perioperative durvalumab for muscle invasive bladder cancer: the start of a new chapter

Approximately 50% of patients with muscle invasive bladder cancer (MIBC) will relapse with a significant proportion of patients dying of their disease, making it a lethal cancer and area of unmet need [1]. Neoadjuvant cisplatin-based chemotherapy has proven to be associated with higher pathological complete response (pCR) rates and a significant reduction in the risk of death, however there is lack of clarity regarding the optimal regimen. Original trials explored CMV (cisplatin, methotrexate, vinblastine) combination. Following this, other regimens have been adopted including dose dense MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) and gemcitabine and cisplatin (GC) which are both considered a standard [2,3]. Adjuvant chemotherapy in MIBC has never shown survival benefit in a randomized phase 3 trial and is not widely recommended, nor is perioperative carboplatin-based chemotherapy [4].

Immune checkpoint inhibitors (ICI) were first explored in metastatic bladder cancer a decade ago. They were associated with durable remissions in a subset of patients [5]. Subsequently, ICIs have moved into first line metastatic setting and shown significant overall survival (OS) benefit when combined with enfortumab vedotin (EV) or GC [6]. Neoadjuvant ICIs have been explored in the ABACUS and PURE-01 single arm phase 2 trials with relevant single agent activity displaying pCR rates of 29% and 42%, respectively [7,8].

The combination of neoadjuvant GC and durvalumab was explored in a single arm phase 2 trial with relevant efficacy and acceptable toxicity [9]. Therefore, a randomized phase 3 (NIAGARA NCT03732677) investigating 4 cycles of neoadjuvant GC plus durvalumab followed by cystectomy and 8 cycles of adjuvant durvalumab versus neoadjuvant GC and surgery alone was performed [10]. Over 1000 patients were enrolled into this two-arm trial. The study recruited patients who were cisplatin-eligible, including those with a creatinine clearance above 40 mL/min, owing to the use of split-dose cisplatin. Dual primary endpoints were pCR and event free survival (EFS). OS was a key secondary endpoint with pre-specified alpha allocation.

The addition of durvalumab was associated with a significant reduction in EFS compared to chemotherapy alone (HR 0.68, 95% CI: 0.56–0.82, p < 0.0001). At 24 months the EFS rate in the durvalumab group and the control arm was 67.8% (95% CI: 63.6%-71.7%) versus 59.8% (95% CI: 55.4–64.0%) respectively. The benefit seen with durvaluamb was broadly across all sub groups of patients irrespective of tumor stage, PD-L1 expression and nodal status. pCR rate increased by 10% in the durvalumab arm; 37% versus 27% in control arm, but this pCR endpoint was not statistically significant. Exploratory analysis showed that benefit with durvalumab occurred irrespective of pCR status. OS data also significantly favored addition of durvalumab with a 25% reduction in risk of death compared to chemotherapy alone (HR 0.75, 95% CI 0.59–0.93). The shape of the Kaplan Meier curves highlighted the potential long-term benefit of ICI. The surgical safety and adverse event (AE) profile revealed no major issues in the study arm, with more patients proceeding to cystectomy in this arm and no significant delays or surgical complications. The adjuvant durvalumab period appeared tolerable with most treatment related AEs occurring during the neoadjuvant period.

This trial has led to neoadjuvant GC plus perioperative durvalumab being recommended by the National Comprehensive Cancer Network (NCCN) and is now also incorporated into treatment guidelines by European Association of Urology (EAU). As of March 2025, durvalumab approval was granted by the Food and Drug Administration (FDA) based on the results of NIAGARA [11].

NIAGARA was the first perioperative ICI study to show a significant OS advantage in MIBC. Adjuvant ICI in MIBC has also been explored. CheckMate274 was a randomized phase 3 trial which evaluated efficacy of adjuvant nivolumab in patients with high risk MIBC following cystectomy. In this study adjuvant nivolumab significantly delayed disease-free survival (DFS) versus placebo (HR 0.70, 98% CI 0.55–0.90). Whilst OS data looks promising, the study has not yet shown statistical significance in survival benefit [12]. Data for adjuvant pembrolizumab showed similar DFS results without significant improvement in OS. Adjuvant ICI is attractive for patients not eligible for neoadjuvant chemotherapy. However, in those that are cisplatin eligible, neoadjuvant GC plus durvalumab has advantages. Earlier exposure to ICI, particularly in the presence of a higher antigen load enhances the likelihood of generating a sustained immune response. Moreover, the proven survival benefit as a result of NIAGARA make it a new standard of care.

The prognostic value of circulating tumor DNA (ctDNA) has also been explored in NIAGARA using the personalized Signatera assay [13]. 57%, 22% and 9% of patients were ctDNA positive at baseline, pre-cystectomy and post cystectomy respectively. ctDNA clearance rate from baseline to pre-surgery in positive patients was 13% higher with addition of durvalumab (70% vs 57%). ctDNA positivity post-surgery strongly correlated with poorer outcomes. Perioperative durvalumab appeared to improve outcomes regardless of ctDNA status at all the time points explored, including ctDNA negative patients post-surgery [14].

A key outstanding question is whether the additional adjuvant ICI period is necessary in all patients, particularly in those that have had a complete pathological response or ctDNA clearance. The data from NIAGARA suggests benefit is not confined to a positive or negative subgroup. Ultimately, a 3^rd arm in the study with neoadjuvant GC and durvalumab alone would be needed to determine this. The feasibility of doing a much larger study than NIAGARA with multiple arms was questioned. Future trials may address this issue with additional arms and ctDNA analysis.

ctDNA is also being explored prospectively in the adjuvant setting (IMvigor011 NCT04660344). Retrospective analyses have demonstrated that ctDNA positivity following surgery is strongly prognostic and potentially predictive of response to adjuvant atezolizumab [15]. ctDNA shows promise as a biomarker that could outperform conventional imaging in the early detection of relapsed disease. Importantly, ctDNA status in the neoadjuvant and adjuvant setting reflect distinct biological contexts; whilst preoperative ctDNA originates from the primary tumor, postoperative ctDNA represents minimal residual disease (MRD). These differences highlight the need for caution when interpreting results across these time points.

It is likely that cisplatin-based chemotherapy will be challenged by future perioperative trials. The survival benefit and 30% CR rate demonstrated with EV and pembrolizumab in the metastatic setting suggests potential efficacy in the perioperative MIBC setting [6]. This is supported by the pilot data from the neoadjuvant EV, duravlumab and tremelimumab trial [16]. Randomised phase 3 trials such as VOLGA (NCT04960709) and KEYNOTE-B15 (NCT04700124) are currently evaluating the combinations of antibody-drug conjugates (ADCs) and ICI in the perioperative setting [17,18]. These studies may replicate the impressive outcomes seen with EV-302 in the metastatic setting and potentially establish a new standard of care in MIBC. Should pCR rates exceed 50%, bladder sparing strategies may become an increasingly attractive options for selected patients and multiple trials are being planned to explore this. ctDNA is likely to play a key role in this space, helping to refine patient selection and guide bladder-preserving treatment pathways.

In conclusion the NIAGARA study starts a new chapter in MIBC. A positive neoadjuvant trial indicates that early intervention with ICI offers a survival benefit without additional toxicity or surgical complications. With work underway to explore novel ICI combinations along with earlier detections of disease and response there is hope to further improve outcomes for patients.

Funding Statement

This paper was not funded.

Author contributions

Elizabeth Nally: Drafting the article and overall review of the content of the manuscript.

Thomas Powles: Oversight of the writing and revision of the manuscript and responsibility for the overall content as guarantor.

Disclosure statement

Thomas Powles has received travel expenses and research funding from Roche, Pfizer, MSD, AstraZeneca, Ipsen, BMS, Merck, Exelixis, Novartis, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson and Eisai, and has received honoraria from Roche, Pfizer, MSD, AstraZeneca, Ipsen, BMS, Merck, Exelixis, Novartis, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson and Eisai.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed

No writing assistance was utilized in the production of this manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.