FDA Approves Durvalumab for Muscle Invasive Bladder Cancer

On March 28, 2025, the Food and Drug Administration approved durvalumab (Imfinzi, AstraZeneca) with gemcitabine and cisplatin as neoadjuvant treatment, followed by single agent durvalumab as adjuvant treatment following radical cystectomy, for adults with muscle invasive bladder cancer (MIBC).

What is Bladder cancer?

Bladder cancer is the sixth most common cancer in the United States and ranks fourth in men and twelfth in women. Bladder cancer arises in the urothelial lining (transitional epithelium) of the urinary tract, which includes the renal pelvis, ureters, bladder, and proximal urethra. Over 90% of bladder cancers are transitional cell carcinomas (urothelial carcinomas). Other histologic types include squamous cell carcinoma, adenocarcinoma, small cell carcinoma, and sarcomas.

Bladder cancer is classified into:

• Low-grade tumors: Frequently recur but rarely invade or metastasize; seldom cause death.
  
• High-grade tumors: Tend to invade the bladder wall and metastasize; account for most bladder cancer deaths.

It is also categorized as:

• Non–muscle-invasive bladder cancer (NMIBC): Confined to the mucosa or submucosa; often treated with transurethral resection and intravesical therapy.
  
• Muscle-invasive bladder cancer (MIBC): Invades the detrusor muscle; associated with higher metastatic risk and typically requires radical surgery or chemoradiation.
  

The strongest risk factor for bladder cancer is cigarette smoking, which increases risk by 2–4 times and accounts for nearly 50% of cases. 

The most common symptom is painless hematuria (visible or microscopic). Less frequently, patients may present with urinary frequency, urgency, dysuria, or nocturia, especially in cases of carcinoma in situ. Upper tract urothelial carcinomas may present with flank pain or hydronephrosis due to obstruction. 

How Durvalumab Works?

Durvalumab (Imfinzi™) is a fully human monoclonal antibody of the immunoglobulin G1k type developed by AstraZeneca for cancer treatment. It targets programmed cell death ligand-1 (PD-L1), a protein that interacts with receptors programmed cell death-1 (PD-1) and CD80 (B7-1), inhibiting the function of T-cells. Many tumors express high levels of PD-L1 to avoid immune detection, leading to poor patient outcomes. By blocking PD-L1’s interactions with PD-1 and CD80, durvalumab enhances the immune system’s ability to recognize and eliminate cancer cells.

Durvalumab FDA approval history

Intravenous durvalumab was granted accelerated approval by the US FDA in May 2017 for patients with locally advanced or metastatic urothelial carcinoma whose disease progressed either during or after platinum-based chemotherapy or within 12 months of receiving platinum-based chemotherapy in the neoadjuvant or adjuvant setting. This approval was based on observed objective response rate (ORR) and the duration of response in Study 1108 

Study 1108  was a multicentre, multicohort, open-label, phase I/II trial for patients with advanced  bladder cancer. In this  study patients with advanced urothelial carcinoma  who have not responded for the first line treatment were included. 

Patients with urothelial carcinoma (n = 182) treated with durvalumab had an ORR of 17.6% in all patients, 27.4% in the PD-L1-high subgroup (n = 95) and 4.1% in the PD-L1-low/negative subgroup (n = 73)

After the successful results of Study 1108, DANUBE trial started. It evaluated the efficacy of first-line durvalumab (a PD-L1 inhibitor), alone or combined with tremelimumab (a CTLA-4 inhibitor), compared to standard chemotherapy.

In this international, randomized, phase 3 study involving 1032 patients, the primary endpoints were overall survival comparing durvalumab alone versus chemotherapy in patients with high PD-L1 expression, and durvalumab plus tremelimumab versus chemotherapy in the entire study population.

After a median follow-up of 41.2 months, neither durvalumab monotherapy nor the combination with tremelimumab significantly improved overall survival compared to chemotherapy. The median overall survival was:

• Durvalumab alone (high PD-L1 group): 14.4 months vs. chemotherapy: 12.1 months.
  
• Durvalumab plus tremelimumab (overall group): 15.1 months vs. chemotherapy: 12.1 months.

Overall, the trial did not achieve its primary objectives, emphasizing the need for further research to identify patients who may benefit from immune checkpoint inhibitors

In Jan 2021 AstraZeneca announced the voluntary withdrawal of the Imfinzi (durvalumab) indication in the US for previously treated adult patients with locally advanced or metastatic bladder cancer, because it did not meet its primary endpoints by the year 2020.  This decision was made in consultation with the Food and Drug Administration (FDA). The withdrawal is aligned with FDA guidance for evaluating indications with accelerated approvals that did not meet post-marketing requirements, as part of a broader industry-wide evaluation. 

What was the standard treatment of BC before Durvalumab?

Standard treatment for non-metastatic muscle invasive bladder cancer has a multidisciplinary approach. Starting from stage II neoadjuvant chemotherapy with Cisplatin + Gemcitabine followed by cystectomy is recommended.  Also, according to Study 1108 and NIAGARA trial results perioperative/sandwich immunotherapy with neoadjuvant cisplatin-based combination chemotherapy was included in American and European protocols as a preferred treatment option. And patients in adjuvant settings should continue durvalumab. 

Here you can see what is being discussed within the oncology community regarding the 

NIAGARA trial

On September 15, 2024, ​The New England Journal of Medicine published a pivotal study titled “Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer,” which explores the efficacy of integrating durvalumab, an immune checkpoint inhibitor, into the standard treatment regimen for muscle-invasive bladder cancer (MIBC). 

Muscle-invasive bladder cancer (MIBC) poses a significant therapeutic challenge, with a high propensity for progression and recurrence. The current standard of care for cisplatin-eligible patients involves neoadjuvant chemotherapy followed by radical cystectomy. Despite this approach, long-term survival rates remain suboptimal, prompting the exploration of adjunctive therapies to enhance outcomes. Immunotherapy, particularly agents targeting the PD-1/PD-L1 axis, has emerged as a promising avenue in oncology, demonstrating efficacy in various malignancies. Durvalumab, a PD-L1 inhibitor, has shown potential in treating urothelial carcinoma, leading researchers to investigate its role in the perioperative setting for MIBC.​

Study Design

This phase 3, open-label, randomized controlled trial enrolled 1,063 cisplatin-eligible patients with operable MIBC. Participants were randomly assigned in a 1:1 ratio to two groups:​

• Durvalumab Group: Received neoadjuvant durvalumab in combination with gemcitabine–cisplatin every three weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every four weeks for eight cycles.
  

• Comparison Group: Received neoadjuvant gemcitabine–cisplatin alone, followed by radical cystectomy without adjuvant therapy. 

The primary endpoint was event-free survival (EFS), defined as the time from randomization to disease progression, recurrence, failure to undergo radical cystectomy, or death from any cause. Overall survival (OS) served as a key secondary endpoint.​

At the 24-month mark, the estimated EFS was 67.8% in Durvalumab vs 59.8% in the comparison group. The hazard ratio for progression, recurrence, non-performance of radical cystectomy, or death was 0.68 (95% CI, 0.56 to 0.82; P<0.001), indicating a 32% reduction in the risk of these events for the durvalumab group compared to the comparison group.

The 24-month OS rates were 82.2% in Durvalumab group and 75.2% in the comparison group
The hazard ratio for death was 0.75 (95% CI, 0.59 to 0.93; P=0.01), suggesting a 25% reduction in the risk of death for patients receiving durvalumab.​

This trial demonstrates that the addition of perioperative durvalumab to neoadjuvant gemcitabine–cisplatin chemotherapy significantly improves event-free and overall survival in patients with operable muscle-invasive bladder cancer, making it current standard of care. 

You can read the full article here 

Written by Sona Karamyan, MD