EAU 2025: Discussant: NIAGARA - Surgical Outcomes and Neoadjuvant Safety with Perioperative Durvalumab for Muscle-Invasive Bladder Cancer

(UroToday.com) The 2025 EAU annual meeting featured a game changer session and a discussant presentation by Dr. Geraldine Pignot. Dr. Pignot discussed Dr. Catto’s presentation “NIAGARA - Surgical outcomes and neoadjuvant safety with perioperative durvalumab for muscle-invasive bladder cancer.” The NIAGARA trial is the first randomized phase 3 trial of neoadjuvant durvalumab plus chemotherapy followed by radical cystectomy and adjuvant durvalumab in muscle invasive bladder cancer.¹

Perioperative durvalumab plus neoadjuvant chemotherapy led to a significant improvement in overall survival as compared with neoadjuvant chemotherapy alone. Importantly, the addition of perioperative durvalumab to neoadjuvant chemotherapy was tolerable with no new safety signals. At EAU 2025, Dr. Catto presented, for the first time, surgical data and postoperative complications from the NIAGARA trial.

Dr. Pignot notes that cystectomy remains the cornerstone of management of localized muscle invasive bladder cancer in a multidisciplinary team setting:
There are several important points regarding cystectomy as the cornerstone of management of localized muscle invasive bladder cancer. The first is that neoadjuvant treatment should not delay surgery or impact the ability of the patients to undergo surgery, and an expeditious care pathway is an important part of the patient’s prognosis. There should be excellent urology and medical oncology coordination during this phase of the treatment. Indeed, the proportion of radical cystectomies performed and the time to surgery are very relevant secondary endpoints of any neoadjuvant therapy trial. In NIAGARA, durvalumab had no impact on a patient’s ability to undergo a cystectomy: 88% of patients in the durvalumab arm versus 83% in the comparator arm underwent radical cystectomy. When comparing neoadjuvant trials, the rate of unperformed cystectomies in NIAGARA, VESPER,² and COXEN³ is as follows:

When looking at reasons not to perform a cystectomy, toxicity was much more common in VESPER than it was in NIAGARA:
Additionally, neoadjuvant durvalumab did not delay surgery, as there was no difference in time to cystectomy between the study arms:

• The median time from last dose of neoadjuvant therapy to cystectomy was 5.6 weeks (range: 1.1-16.9) for the durvalumab arm versus 5.4 weeks (range: 1.7-47.6) for the comparator arm
• The median time from randomization to radical cystectomy was 16.3 weeks (IQR 14.7-18.4) for the durvalumab arm versus 16.1 weeks (IQR 14.3-18.3) for the comparator arm
• Patients undergoing cystectomy within 56 days after the last dose of neoadjuvant therapy included 90% in the durvalumab arm and 90% in the comparator arm
• Patients undergoing cystectomy within 70 days after the last dose of neoadjuvant therapy included 96% in the durvalumab arm and 95% in the comparator arm

The second point regarding cystectomy as the cornerstone of management of localized muscle invasive bladder cancer is that postoperative complications after cystectomy should not preclude patients from receiving adjuvant therapy. As such, postoperative complication rate is also a very relevant secondary endpoint of phase 3 neoadjuvant trials. Dr. Pignot notes that the rates of surgical complication rates in NIAGARA by Clavien-Dindo classification were similar between study arms:
In comparison with other series of cystectomies, the results from NIAGARA are comparable:
Looking at the surgical characteristics of NIAGARA, there is evidence of guideline recommended adoption of sex-sparing surgeries:

Dr. Pignot emphasized that the ~25% blood transfusion rate during surgery may be notable in NIAGARA. She highlighted that this is higher than contemporary cystectomy series, and previous work suggests that for each unit of blood transfused, there is a 7% increase in the risk of death from bladder cancer. This may be linked, in part, to the anemia induced by neoadjuvant chemotherapy, suggesting the importance of prehabilitation with preoperative correction of anemia. This may also be reduced by minimally invasive approaches, suggesting there may be a more important role for implementing robot-assisted surgery. Finally, this may be an indirect marker of surgical difficulty post-immunotherapy, emphasizing the importance of recording intra-operative complications. Published in 2020, there is a new intraoperative adverse incident classification system (EAUiaiC),⁴ which can facilitate and standardize the reporting of surgical difficulties. Previously, surgical complications have been reporting post-immunotherapy in the nephrectomy. In work from Dr. Pignot’s group,⁵ in 66% of cases, surgeons reported intraoperative complexity, especially after partial nephrectomies (85%), with a conversion rate to radical nephrectomy in 10% of cases. Surgical difficulties were associated with increased blood loss, but was not associated with increased postoperative complications.

With regards to pathological complete response rate, the following figure highlights results from the neoadjuvant therapy trials:
Notably, in NIAGARA, 37% of patients were ypT0, which raises the question regarding over treating these patients with adjuvant durvalumab. Certainly, there is a need for better selection of patients who will benefit from adjuvant treatment, with promising biomarkers including ctDNA and PDL1+ status. 

Dr. Pignot concluded her discussant presentation of NIAGARA with the following take home points:

• The addition of durvalumab to neoadjuvant chemotherapy had no impact on the rate or timing of radical cystectomy and did not increase the rate of surgical complications
• Despite certain limitations (gemcitabine + cisplatin and not MVAC in the comparator arm, no adjuvant treatment in the comparator arm, all patients in the experimental arm receiving adjuvant immunotherapy), the absence of negative impact on surgical outcomes in the NIAGARA trial supports perioperative durvalumab with neoadjuvant chemotherapy as a potential new standard treatment
• We are waiting on further phase III trials assessing the “sandwich” approach in the treatment of cisplatin eligible localized muscle invasive bladder cancer (Keynote-866, EV-304)

Presented by: Geraldine Pignot, MD, Paoli-Calmettes Institute, Marseille, France 

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the European Association of Urology (EAU) 2025 Annual Meeting, Madrid, Spain, Fri, Mar 21 – Mon, Mar 24, 2025. 

References:

1. Powles T, Catto JWF, Galsky MD, et al. Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer. N Engl J Med. 2024 Nov 14;391(1):1773-1786.
2. Pfister C, Gravis G, Flechon A, et al. Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin or gemcitabine and cisplatin as perioperative chemotherapy for patients with nonmetastatic muscle-invasive bladder cancer: Results of the GETUG-AFU V05 VESPER trial. J Clin Oncol. 2022 Jun 20;40(18):2013-2022.
3. Flaig TW, Tangen CM, Daneshmand S, et al. Long-term outcomes from a phase 2 study of neoadjuvant chemotherapy for muscle-invasive bladder cancer (SWOG S1314; NCT02177695). Eur Urol. 2023 Sep;84(3):341-347.
4. Biyani CS, Pecanka J, Roupret M, et al. Intraoperative adverse incident classification (EAUiaiC) by the European Association of Urology ad hoc Complications Guidelines Panel. Eur Urol. 2020 May;77(5):601-610.
5. Pignot G, Thiery-Vuillemin A, Walz J, et al. Nephrectomy after Complete Response to Immune Checkpoint Inhibitors for Metastatic Renal Cell Carcinoma: A New Surgical Challenge? Eur Urol. 2020 Jun;77(6):761-763.