FDA Approval of Perioperative Durvalumab Plus Chemo Supports the Efficacy of a Novel MIBC Management Approach

Matthew Galsky, MD

The FDA approval of neoadjuvant durvalumab (Imfinzi) plus cisplatin or carboplatin and gemcitabine, followed by durvalumab monotherapy in the adjuvant setting, for the treatment of adult patients with muscle-invasive bladder cancer (MIBC) marks a significant advancement in the management of this disease, which has had historically limited perioperative progress, according to Matthew Galsky, MD.

On March 28, 2025, the FDA granted approval to this regimen for this indication based on results from the phase 3 NIAGARA trial (NCT03732677), which evaluated the perioperative use of durvalumab in combination with standard chemotherapy.1 The trial randomly assigned patients with clinically localized MIBC to receive either neoadjuvant gemcitabine and cisplatin plus durvalumab followed by radical cystectomy and adjuvant durvalumab, or standard neoadjuvant chemotherapy followed by cystectomy alone.

Findings from the study demonstrated a statistically significant improvement in event-free survival (EFS) with the addition of durvalumab. The median EFS was not reached (NR) in the investigational arm (95% CI, NR-NR) compared with 46.1 months (95% CI, 32.2-NR) in the control arm (HR, 0.68; 95% CI, 0.56-0.82; 2-sided P < .0001). The median overall survival (OS), a key secondary end point, was NR in either arm but favored the durvalumab combination (HR, 0.75; 95% CI, 0.59-0.93; 2-sided P = .0106).1,2 Additionally, the pathological complete response (pCR) rate was 9.8% higher for the perioperative durvalumab group compared with the group that received chemotherapy alone.2

In an interview with OncLive®, Galsky, a professor of medicine at the Icahn School of Medicine at Mount Sinai in New York, New York, as well as the principal investigator of the NIAGARA trial, emphasized that these findings underscore the feasibility and clinical benefit of incorporating immune checkpoint inhibition into the perioperative treatment paradigm for patients with MIBC.

“[Currently], there are multiple studies exploring the perioperative approach with immune checkpoint blockade. NIAGARA is the first to read out in bladder cancer, showing a benefit. There are several [trials] pending results, and viewing all these data in total will be important in understanding how the paradigm shifts in the future,” Galsky explained in the interview.

OncLive: What is the significance of the FDA approval of perioperative durvalumab plus neoadjuvant chemotherapy for the treatment of patients with MIBC?

Galsky: [This] approval represents the first time that a cisplatin-based treatment has improved outcomes and [become standard] in the neoadjuvant setting. This is the first advance in neoadjuvant therapy since neoadjuvant therapies have been shown to be beneficial in bladder cancer.

What were the rationale and design of the NIAGARA trial?

[Immune] checkpoint blockade has changed the landscape of treatment for patients with metastatic urothelial cancer, showing that a subset of patients will achieve durable responses to treatment. Once safety and activity are demonstrated in the metastatic setting, there’s an interest in moving new therapies earlier in the course of disease. We’ve had approvals for immune checkpoint blockade in the adjuvant setting in urothelial cancer, and even in the non-MIBC setting.

[Prior to the FDA approval of durvalumab], the neoadjuvant setting was the only major remaining clinical disease state for which immune checkpoint blockade had not been approved, so that was the rationale to move this treatment even earlier into the neoadjuvant setting. The [NIAGARA] trial used [durvalumab] perioperatively.

The NIAGARA study enrolled patients with clinically localized MIBC. Patients were randomly assigned to receive neoadjuvant gemcitabine and cisplatin plus the PD-L1inhibitor durvalumab for 4 cycles of treatment, followed by cystectomy, followed by 8 additional cycles of single-agent adjuvant durvalumab. [The treatment] approach around cystectomy the control arm was standard neoadjuvant gemcitabine plus cisplatin for 4 cycles followed by cystectomy with no planned adjuvant treatment.

What key efficacy findings from the trial lead to the FDA approval of this regimen?

The primary end points of the NIAGARA study were EFS and pCR rate. OS was a key secondary end point. [The median] EFS was improved with the use of perioperative durvalumab vs the control arm, with a hazard ratio [HR] of 0.68. [The median] OS was also improved with an HR of 0.75. The pCR rate was 9.8% higher in the perioperative durvalumab arm compared with the adjuvant standard gemcitabine/cisplatin alone arm. All the end points [are trending] in the same direction, [which is] suggestive of an overall benefit with this regimen.

What adverse effects (AEs) should oncologists keep in mind when prescribing immune checkpoint blockade?

Immune-related AEs [irAEs] with immune checkpoint blockade occur regardless of the clinical disease state for which we use these drugs. What has been the case in bladder cancer—and other solid tumors—so far is that the severity and frequency of irAEs doesn't change based on the clinical disease state where [immunotherapy agents] are used, nor does it change necessarily [when these agents are used] in combination with chemotherapy.

In the NIAGARA study, the irAEs were similar to what you would see when using immune checkpoint blockade in any other clinical disease states, mostly grade 1 and grade 2. The nature of those [AEs] was not increased in frequency or severity with the use of concurrent cisplatin-based chemotherapy, nor did it seem to be increased in the post-cystectomy period, which we’ve also seen to be the case in other studies with adjuvant immune checkpoint blockade.

What advice would you offer to colleagues who are considering how to integrate this regimen into their patients’ treatment paradigms?

The early integration of immune checkpoint blockade should be considered for clinically low-class MIBC. That could include the perioperative approach of integrating durvalumab into the neoadjuvant setting and then in the adjuvant setting.

[There] are a couple aspects to keep in mind. One is that the NIAGARA study enrolled patients with [bladder] cancer regardless of the percentage of variant histology. That’s a bit different than what we’ve seen in some other studies, where the proportion of [patients with] urothelial cancer had to be greater than 50%. [Those] flexible eligibility criteria translate into the [populations of] patients we see in the clinic [who are eligible to receive the NIAGARA regimen], particularly those with a component of variant histology.

The second thing to keep in mind is that NIAGARA was a study where the control arm was cisplatin-based chemotherapy. That is a regimen for cisplatin-eligible patients. That said, this study included patients with a creatinine clearance of 40 or greater, and in patients with a creatinine clearance of 40 to 60, split-dose cisplatin—meaning 35 mg/m2 of cisplatin given on day 1 to day 8, rather than 70 mg/m2 given on day 1—could be used either in the backbone of the experimental regimen or in the control regimen. That approach has been shown to be safer in some small phase 2 studies, even in patients with mild renal impairment; that was reinforced in this study. That opens the window for [patients to potentially be] eligible for this [perioperative durvalumab] approach based on renal function.

References

1. FDA approves durvalumab for muscle invasive bladder cancer. FDA. March 28, 2025. Accessed May 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-muscle-invasive-bladder-cancer
2. Powles T, Van der Heijden MS, Galsky M, et al. A randomized phase III trial of neoadjuvant durvalumab plus chemotherapy followed by radical cystectomy and adjuvant durvalumab in muscle-invasive bladder cancer (NIAGARA). Ann Oncol. 2024;35(suppl 2):S1271. doi:10.1016/j.annonc.2024.08.2327