NIAGARA interim data support perioperative durvalumab for MIBC

In a preplanned interim analysis of the NIAGARA trial, the addition of durvalumab to neoadjuvant chemotherapy prior to radical cystectomy (RC) and durvalumab monotherapy following surgery confers a survival advantage over chemo alone for muscle-invasive bladder cancer (MIBC).

“NIAGARA is the first phase III perioperative immunotherapy study in MIBC and has demonstrated a statistically significant and clinically meaningful improvement in event-free survival (EFS) and overall survival (OS),” said Dr Thomas Powles from Barts Cancer Institute, Queen Mary University of London, UK, at ESMO 2024.

EFS was significantly longer in the durvalumab vs chemo arm, both in the intention-to-treat cohort after a median EFS follow-up of 42.3 months in censored patients (median not reached [NR] vs 46.1 months; hazard ratio [HR], 0.68; p<0.0001) and on sensitivity analysis after censoring patients who did not undergo RC (median NR vs NR; HR, 0.69). [ESMO 2024, abstract LBA5]

The Forrest plot analysis broadly favoured durvalumab in terms of EFS across all subgroups, with HRs ranging between 0.52 and 0.81.

Regarding pathologic complete response (pCR) rate, the result was nonsignificant in the formal analysis in January 2022 (33.8 percent vs 25.8 percent; odds ratio [OR], 1.49; p=0.0038). In the April 2024 re-analysis, nominal statistical significance was achieved in favour of the durvalumab arm (37.3 percent vs 27.5 percent; OR, 1.60; p_nominal=0.0005).

For OS, after a median follow-up of 46.3 months in censored patients, there was a 25-percent reduction in the risk of death in the durvalumab vs the chemo arm (HR, 0.75; p=0.0106). “This is statistically significant. The Kaplan-Meier curves [separated] early and stayed apart,” noted Powles.

Subgroup analysis for OS also favoured the durvalumab over the chemo arm, aligning with the EFS analysis, which, according to Powles, is reassuring.

Safety profile

During the overall study period, grade 3/4 treatment-related adverse events (TRAEs) occurred in 41 percent of participants in each arm. Compared with the chemo arm, the durvalumab arm had higher rates of serious AEs (62 percent vs 55 percent), AEs leading to discontinuation of study treatment (21 percent vs 15 percent), and any-grade immune-mediated AEs (21 percent vs 3 percent).

In the adjuvant treatment phase, 8 percent of participants in the durvalumab arm had AEs that led to durvalumab discontinuation; none were reported in the chemo arm. Grade 3/4 TRAE rate was also higher in the former vs the latter (6 percent vs 1 percent).

Overall, the most frequently reported grade 3/4 AEs in the durvalumab arm were neutropenia (14.3 percent), urinary tract infection (14.2 percent), and anaemia (13.8 percent).

A potential new standard Tx

Neoadjuvant cisplatin-based chemo followed by RC has been the recommended treatment for MIBC over the last 40 years. [Ann Oncol 2022;33:244-258; J Urol 2024;212:3-10; https://uroweb.org/guidelines/muscle-invasive-and-metastatic-bladder-cancer, accessed September 30, 2024] “Despite this, about half of the patients relapse and die [within 3 years]. Therefore, it is an area of unmet need,” stressed Powles.

“The perioperative approach … has a strong biological rationale and has been explored successfully in other cancers,” he continued. Perioperative durvalumab has shown its efficacy and safety for MIBC in a phase II trial. [J Clin Oncol 2023;41:5131-1539]

Powles and team randomized 1,063 patients (median age 65 years, 82 percent men, 28 percent Asian) 1:1 to neoadjuvant durvalumab 1,500 mg IV Q3W and chemo* Q3W for four cycles followed by RC, then adjuvant durvalumab 1,500 mg IV Q4W for eight cycles, or neoadjuvant chemo alone followed by RC.

“Neoadjuvant durvalumab did not delay surgery or cause surgical problems. Therefore, NIAGARA supports perioperative durvalumab with neoadjuvant chemo as a potential new standard treatment for patients with cisplatin-eligible MIBC,” Powles said.

Practice-changing based on EFS, OS benefit

“NIAGARA is practice-changing for patients with localized MIBC,” said discussant Professor Petros Grivas from the University of Washington and Fred Hutchinson Cancer Center, Seattle, Washington, US, at ESMO 2024. “The trial met its primary endpoint of EFS, while OS was also significantly extended, which is a more difficult endpoint to meet [as] OS can be confounded by access to and effectiveness of rescue or salvage therapies.”

However, Grivas underlined that the contributions of neoadjuvant and adjuvant therapy are unclear. As such, it is imperative to tease out their individual contributions in future trials to determine whether either or both are needed.

He added that it would also be interesting to evaluate exploratory subgroups, disease-free survival, and OS stratified by pCR in future studies and to validate the theoretical reasons supporting neoadjuvant therapy’s relevance in this space.

Grivas also recommended future evaluations looking at the potential of systemic therapy alone to provide a cure for these patients in view of bladder preservation. “The immunotherapy rechallenge remains an open question in this disease, and input from patients and advocates is also important for advancing the field.”