NIAGARA Trial Validates Perioperative Durvalumab Approach in MIBC

Petros Grivas, MD, PhD

Practice-changing results with the addition of perioperative durvalumab (Imfinzi) to neoadjuvant chemotherapy have both refined the management of muscle-invasive bladder cancer (MIBC) and raised questions regarding the optimal comparator arms to use in future investigations of immunotherapy in this disease, according to Petros Grivas, MD, PhD.

On March 28, 2025, the FDA approved neoadjuvant durvalumab plus gemcitabine and cisplatin, followed by adjuvant durvalumab monotherapy after radical cystectomy for the treatment of adult patients with MIBC.1 This regulatory decision was supported by data from the phase 3 NIAGARA trial (NCT03732677), in which the median event-free survival (EFS) was not reached (NR; 95% CI, NR-NR) in the durvalumab arm (n = 533) vs 46.1 months (95% CI, 32.2-NR) with neoadjuvant chemotherapy alone (n = 530; HR, 0.68; 95% CI, 0.56-0.82; 2-sided P < .0001).1,2 Furthermore, the median overall survival (OS) was NR in either arm (HR, 0.75; 95% CI, 0.59-0.93; 2-sided P = .0106).1

Furthermore, data from NIAGARA presented at the 2025 Genitourinary Cancers Symposium (ASCO GU) showed that the addition of perioperative durvalumab to neoadjuvant chemotherapy resulted in a 9.8% improvement in pathologic complete response (pCR) rate; the respective pCR rates in these arms were 37.3% (95% CI, 33.2%-41.6%) and 27.5% (95% CI, 23.8%-31.6%).2 Notably, the addition of durvalumab improved EFS and OS regardless of whether patients achieved a pCR with neoadjuvant therapy.

“The data updates from NIAGARA at least inform dialogue and discussion with patients and give an impetus to potentially continue the adjuvant therapy component, regardless of [patients’ pCR status],” Grivas said in an interview with OncLive® following a State of the Science Summit™ on genitourinary cancers, which he co-chaired.

In the interview, Grivas discussed key findings from NIAGARA, how these data support the use of perioperative durvalumab in MIBC clinical practice, and questions that remain regarding the clinical benefit of each portion of the perioperative regimen.

Grivas is a professor in the Clinical Research Division and clinical director of the Genitourinary Cancers Program at Fred Hutchinson Cancer Center in Seattle, Washington. He is also a professor in the Division of Hematology and Oncology at the University of Washington School of Medicine.

OncLive: How was the NIAGARA trial designed?

Grivas: The NIAGARA trial was designed several years ago before the [COVID-19] pandemic and accrued 1063 patients. Kudos to the investigators, patients, and caregivers who participated in the study. This was a trial evaluating the addition of durvalumab—an anti–PD-1 agent—as neoadjuvant and adjuvant therapy. Durvalumab was given with neoadjuvant gemcitabine plus cisplatin for 4 cycles, and then, [following radical] cystectomy, durvalumab was continued for up to 8 monthly doses in the adjuvant setting [in the investigational arm]. The trial compared perioperative durvalumab added to gemcitabine plus cisplatin vs neoadjuvant gemcitabine plus cisplatin alone without planned adjuvant therapy.

What were the key efficacy outcomes from this trial?

The trial showed positive results. It was positive for EFS and OS, favoring the durvalumab addition compared with neoadjuvant gemcitabine plus cisplatin alone. The pCR rate was [37.3%] in the durvalumab arm vs [27.5%] with neoadjuvant gemcitabine plus cisplatin alone, and there was a [9.8%] delta between the [pCR rates with] the triplet vs chemotherapy alone. However, the important point is that the EFS and OS end points were met.

This [trial was] practice changing. [Based on these findings, the FDA approved] durvalumab in the perioperative setting. The trial results were interesting. We saw updates at the 2025 ASCO GU meeting. The authors tried to give granularity about the outcomes of patients who had achieved pCR with the neoadjuvant phase of treatment, vs those who did not achieve pCR with neoadjuvant treatment. [These outcomes were] not definitive, because that analysis may have been underpowered, but the qualitative signal was—at least in the authors’ conclusion—that the addition of durvalumab appeared to benefit patients regardless of pCR achievement with neoadjuvant treatment.

There were different HRs for EFS and OS in those subsets of patients. This can be affected by the number of events in each group. [Patients who achieved] a pCR [with neoadjuvant therapy had a] lower number of recurrence or death events, because pCR is a positive prognostic factor. [However, even though there were] limitations of the trial’s power, sample sizes, and subsets, there seemed to be—based on the conclusion of the authors—benefit for EFS and OS [with the addition of durvalumab], regardless of [whether patients achieved] pCR [with neoadjuvant therapy].

What safety findings are important to note?

Toxicity-wise, the data from NIAGARA showed that the addition of neoadjuvant [durvalumab] to gemcitabine plus cisplatin did not compromise the ability of patients to undergo curative-intent radical cystectomy. That was reassuring. [Additionally], the toxicity profile was similar between the 2 arms and did not generate safety concerns. We need to see more data down the road with longer follow-up—maybe quality of life data and some cost-effectiveness analyses, if available. However, overall, the data from the NIAGARA trial are interesting and practice changing.

How might the NIAGARA regimen be incorporated into clinical practice?

The big question is: What do you do in clinical practice? If a patient achieves a pCR [with neoadjuvant chemotherapy], their chance of recurrence is lower. However, one can argue that you may still need to give [adjuvant] durvalumab to [further] reduce the chance of recurrence in those patients. Traditionally, for patients who achieve pCR with neoadjuvant chemotherapy, the chance of cure is between approximately 10% and 15%. You want to improve that by giving the adjuvant portion.

We do not completely know the full answer, and there is, of course, a risk of overtreatment regarding toxicity, therapy burden, and cost. There is the risk of undertreatment as well. [Additionally], patients may sometimes want to be treated more, depending on their case scenario and the data.

In the absence of accurate, reliable, clinically useful biomarkers, we will have this issue of undertreatment vs overtreatment. [That should ultimately prompt] a discussion with the patient. [Because of] the trial design of NIAGARA, we cannot separate the contributions and effects of neoadjuvant therapy vs adjuvant therapy vs both.

[However], based on the pCR difference [between the 2 NIAGARA arms, and] based on the data we know from other trials, such as the phase 3 CheckMate 274 [NCT02632409] and AMBASSADOR [NCT03244384] trials, there is probably value in the adjuvant phase of the study. That’s why it’s reasonable to at least consider and discuss with the patient the pros and cons of both neoadjuvant and adjuvant checkpoint inhibition based on the NIAGARA design. I would like to see more data in the future, for example, with circulating tumor DNA incorporated in the pCR [analyses] that may further inform this dialogue with the patient of whether they need the adjuvant therapy component.

How might future research address the limitations of the NIAGARA design?

From an academic standpoint, regarding limitations of the trial, in the control arm, there was no planned adjuvant immunotherapy. The NIAGARA trial finished accrual approximately 1 month before adjuvant nivolumab [Opdivo] became FDA approved for the [high-risk urothelial carcinoma] indication. The big question is: if the patients in the control arm had received adjuvant immunotherapy, would that have resulted in a different outcome, where there would have been better EFS and OS performance in the control group? It’s hard to tell. I don’t think we will get the answer.

There are ongoing trials with enfortumab vedotin-hziy [Trodelvy] plus pembrolizumab [Keytruda] or [other forms of] checkpoint inhibition that are ongoing, [as well as trials with] gemcitabine plus or minus nivolumab or plus or minus pembrolizumab. Those trials will inform this dialogue, and we’ll see how many patients receive adjuvant immunotherapy in the control arms of those trials. EFS can be affected by that. OS can also be affected by what therapies may be used in the metastatic disease setting in both arms of a study, [as well as whether we] have access to salvage therapies. [However], overall, despite the caveats, NIAGARA shows important, practice changing data.

References

1. FDA approves durvalumab for muscle invasive bladder cancer. FDA. March 28, 2025. Accessed May 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-muscle-invasive-bladder-cancer
2. Galsky M, Van Der Heijden M, Catto J, et al. Additional efficacy and safety outcomes and an exploratory analysis of the impact of pathological complete response (pCR) on long-term outcomes from NIAGARA. J Clin Oncol 43, 2025 (suppl 5; abstr 659). doi:10.1200/JCO.2025.43.5_suppl.659