Durvalumab Boosts Survival in Muscle-Invasive Bladder Cancer

BARCELONA — Adding the immune checkpoint inhibitor durvalumab to standard treatment for muscle-invasive bladder cancer (MIBC) significantly improved survival, reducing the risk for death by 25%, according to a preplanned interim analysis of the phase 3 NIAGARA trial.

These results offer practice-changing evidence in an area of unmet need, said lead investigator Thomas Powles, MD, from the Barts Cancer Institute at Queen Mary University of London, London, England, who presented the study here at the European Society for Medical Oncology (ESMO) Annual Meeting 2024. The findings were published simultaneously in the New England Journal of Medicine.

“Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the [current] standard of care and has been the recommended treatment for MIBC for the past 40 years,” said Powles. “Despite this, over half of patients relapse and die.”

Now, “NIAGARA supports perioperative durvalumab with neoadjuvant cisplatin-based chemotherapy as a potential new standard treatment” for patients with cisplatin-eligible disease, he told attendees.

This approach has been shown to be safe and efficacious in a phase 2 study of MIBC; however, NIAGARA is the first phase 3 study to test adding durvalumab to the standard of care. And, with 1063 participants, it is the largest study ever undertaken in MIBC, noted Powles.

The patient population had classic muscle-invasive disease (clinical tumor stage of T2, T3, or T4a, N0 or N1, and M0). To participate in the trial, they had to be medically fit to undergo radical cystectomy, eligible for cisplatin-based chemotherapy, and have a creatinine clearance of ≥ 40 ml/min/1.73 m² of body surface area.

The patients were randomized to receive either four cycles of neoadjuvant gemcitabine/cisplatin-based chemotherapy alone (control group; n = 530) or with the addition of durvalumab (n = 533), followed by radical cystectomy, and then adjuvant durvalumab for those in the experimental arm. The dose for durvalumab was 1500 mg IV every 3 weeks for neoadjuvant use and 1500 mg IV every 4 weeks for adjuvant use.

Baseline characteristics were well-balanced between groups with regard to renal function, tumor stage, and PD-L1 expression, among other things.

Event-free survival and pathological complete response were the two primary endpoints, with overall survival being a key secondary endpoint, Powles explained.

The study showed that the treatment arm had a significantly better pathological complete response rate at 6 months post-surgery (37.3% vs 27.5%; P = .0005) and a significantly better event-free survival at a median follow-up of 24 months (67.8% vs 59.8%; hazard ratio [HR], 0.68; P 

The 2-year overall survival was also significantly better in the treatment arm (82.2% vs 75.2%; HR, 0.75; P = .0106), showing a 25% reduction in the risk for death.

“The addition of perioperative durvalumab to [neoadjuvant chemotherapy] was tolerable and manageable, with no new safety signals,” reported Powles.

Adverse events (AEs) were balanced in both arms, with grade 3 or 4 treatment-related AEs occurring in 41% of patients in both groups in the neoadjuvant phase. In the adjuvant period, only 6% of patients had grade 3 or 4 treatment-related AEs, he added.

Overall, the most frequent AEs reported were nausea, anemia, constipation, and fatigue.

Importantly, neoadjuvant durvalumab did not delay or otherwise impact the ability of patients to undergo/complete surgery, with 88.0% in the durvalumab group and 83.2% in the comparison group having a successful cystectomy.

“We were worried it might be a lower rate than that,” said Powles. “Cystectomy is a massive undertaking and not for the fainthearted. The most common reason for not having surgery was patient choice.”

Practice Should Be Changed ‘Immediately’

Calling it “one of the most impactful” study results at the meeting, invited discussant Petros Grivas, MD, PhD, said NIAGARA “is it the first trial to show significant event-free survival and overall survival benefit, and I think it should change practice immediately.”

That the high proportion of patients who underwent radical cystectomy was not lower in the experimental group lends support to the idea that the addition of durvalumab did not compromise the ability of patients to undergo a curative intent radical surgery, said Grivas, who is director of the Genitourinary Cancer Program at University of Washington and Seattle Cancer Care Alliance in Seattle. This is very important, he added.

“We see that toxicity seems to be similar within the two arms, especially in the neoadjuvant phase,” he elaborated, during a press conference at the meeting, adding that this raises another question.

“The trial design does not differentiate between the impact of neoadjuvant or adjuvant therapy: Do we need either, or both? Future trials may be able to dissect that.”

The trial was funded by AstraZeneca. Powles disclosed financial interests with AstraZeneca, Bristol Myers Squibb, Exelixis, Incyte, Ipsen, Merck, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, and MSD (personal, advisory board); Roche, Pfizer, MSD, AstraZeneca, and Ipsen (personal, other, travel/accommodation/expenses); Mashup Co Ltd (personal, other, sponsorship for Uromigos Podcast); Gilead Sciences (institutional, other, honoraria); and AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, Merck, MSD, Seattle Genetics, Novartis, Pfizer, Merck Serono, Astellas, Johnson & Johnson, and Eisai (institutional, research grant).

Grivas disclosed receiving research funding (institutional) from Acrivon Therapeutics, ALX Oncology, Bristol Myers Squibb, Merck KGaA, MSD, Genentech, Gilead Sciences, G1 Therapeutics, Mirati Therapeutics, and QED Therapeutics and consulting fees from Aadi Bioscience, Abbvie, AstraZeneca, Asieris Pharmaceuticals, Astellas Pharma, Bicycle Therapeutics, Briston Myers Squibb, CG Oncology, Daiichi Sankyo, Fresenius Kabi, G1 Therapeutics, Gilead Sciences, ImmunityBio, Janssen, Merck KGaA, MSD, Pfizer, Roche, Strata Oncology, and Replimune.