The NIAGARA trial, which enrolled over 1,000 patients, is the largest conducted trial in this patient population, representing a “paradigm shift” in the management of localized muscle-invasive bladder cancer (MIBC). It is impressive to see such a large trial conducted in this therapy setting and patient population, while we have seen challenges in the accrual of randomized trials in the past, for example evaluating adjuvant chemotherapy. It is noteworthy that the trial’s accrual period included the COVID-19 pandemic, which introduced major challenges and barriers in conducting clinical research globally.
Bladder cancer accounts for many thousands of global deaths annually, representing a major cause of mortality, morbidity, and economic burden in healthcare systems worldwide. The conventional standard of care for MIBC involves neoadjuvant cisplatin- based chemotherapy (in fit patients) followed by radical cystectomy and pelvic lymph node dissection in patients who pursue the surgical approach (not the bladder preservation strategy). However, this approach has been associated with relatively high recurrence rates, underlining a significant and major need in this curable patient population. As we get more effective systemic therapies in the metastatic disease setting, “moving” those combinations in the localized disease setting is attractive, interesting, and logical.
Durvalumab is an anti-PD-L1 agent with approved indications in other cancer types (its previous indication in metastatic urothelial carcinoma was withdrawn). The perioperative (neoadjuvant and adjuvant) strategy has a robust biological rationale and has shown positive results in other cancer types, for example breast and lung cancers, aiming to eradicate micro-metastases and the primary tumor, and, thus, reduce the risk of recurrence and death.
The NIAGARA trial was a randomized phase III trial involving over 1,000 patients with localized muscle-invasive bladder cancer (clinical stage T2–T4aN0–N1). Patients were randomized to either four cycles of gemcitabine/cisplatin neoadjuvant chemotherapy followed by radical cystectomy (standard of care) or four cycles of gemcitabine/cisplatin neoadjuvant chemotherapy combined with durvalumab followed by radical cystectomy, followed by adjuvant durvalumab for up to eight monthly doses. Primary endpoints were event-free survival (EFS) and pathologic complete response rate. EFS was defined as the time from randomization to cancer recurrence, progression or death from any cause (patients who did not undergo cystectomy were counted as having an event regarding the EFS endpoint).
NIAGARA showed a significant improvement in EFS with durvalumab, which translated to a significant reduction in the risk of cancer recurrence, progression, or death (HR 0.68). At the two-year landmark, EFS rates were 68% for durvalumab arm vs 60% for standard of care arm. Overall survival (OS) also showed a significant benefit, with a significant reduction in the risk of death (HR 0.75); the two-year OS rates were 82% for durvalumab arm vs 75% for standard of care arm.
Pathologic complete response rates were numerically higher with durvalumab (37% vs 27%). Although this did not reach statistical significance in the primary analysis due to alpha allocation in the statistical analysis plan and a clerical error in the initial analysis (59 cases were not appropriately analyzed); this trend implied increased rate of primary tumor eradication with durvalumab added to chemotherapy. The benefit with added durvalumab was consistent across patient subgroups with likely different degrees/magnitudes of benefit.
The toxicity profile was similar between the arms without notable additional toxicity from durvalumab. Grade 3-4 adverse events occurred in 69% of patients in the durvalumab arm vs 68% in the standard of care arm. Treatment-related grade 3-4 adverse events were observed in 41% of patients in each arm, while adverse events leading to death were really rare, occurring in < 1% of patients in each arm. In the adjuvant phase, only 6% of patients experienced grade 3-4 treatment- related adverse events, with a similarly low proportion of patients discontinuing adjuvant durvalumab due to toxicity. Notably, the addition of durvalumab did not delay curative intent surgery or lower the prospect of patients undergoing radical cystectomy (approximately 85% of patients in each arm successfully underwent cystectomy). Interestingly, ‘patient choice’ was the most common reason for not proceeding to the planned radical cystectomy.
The NIAGARA trial opens new paths for the treatment of muscle-invasive bladder cancer, while we wait the results of two additional phase III trials evaluating other checkpoint inhibitors (pembrolizumab or nivolumab) combined with gemcitabine/cisplatin as well as three trials evaluating checkpoint inhibitors plus the antibody drug conjugate, enfortumab-vedotin.
While the NIAGARA trial is practice-changing, there are several very important questions that remain unanswered:
- The individual contribution of the neoadjuvant vs adjuvant phase of therapy is not certain. Do we need either or both? Future three-arm or four-arm clinical trial designs, despite being complex, long, costly, and challenging, can help clarify these questions.
- The impact of pathologic stage on survival needs further exploration; an exploratory analysis of disease-free and overall survival in each arm stratified by pathologic stage can provide useful insights. There is concern about over-treatment and under-treatment; therefore, adding granular data in key patient subsets can help inform this dialogue.
- The potential impact of prior systemic checkpoint inhibitor given in non–muscle invasive bladder cancer setting, as well as the potential of rechallenge with a checkpoint inhibitor in cases of later recurrence, remain unanswered urgent questions.
- The impact of potential adjuvant checkpoint inhibitor, example nivolumab, in the standard-of-care arm, as well as access to effective salvage therapies upon cancer recurrence / progression can affect the performance of the control arm and, therefore, the results of this trial regarding EFS and OS. That is an inherent limitation of NIAGARA also based on the timing of the accrual period (prior to adjuvant nivolumab regulatory approval).
- Upper tract urothelial carcinoma (UTUC) is a separate, major unmet need. Results from the ongoing ECOG ACRIN 8192 phase II/III trial will help answer that question; therefore, accrual in that trial is critical and highly encouraged across the U.S. centers.
- The role of accelerated or dose-dense (dd) MVAC is a relevant question since many experts use this regimen in the neoadjuvant setting. While gemcitabine/cisplatin is the most commonly used neoadjuvant regimen and is a very reasonable and acceptable control arm in NIAGARA trial, results from the AURA phase II trial, among others, raise the interesting hypothesis whether ddMVAC may be a preferred partner for checkpoint inhibitors. This question is being asked in the ECOG ACRIN 8192 phase II/III trial in UTUC.
- There is significant interest in viewing health-care utilization, patient-reported outcomes and quality- of-life data in future analyses from the NIAGARA trial. There is also a considerable curiosity regarding tissue-based molecular biomarkers, example DNA repair genes, and circulating tumor DNA, which could possibly inform the discussions on decision-making about adjuvant therapy and potentially help avoid both over- and under- treatment.
Written by: Petros Grivas, MD, PhD, Associate Professor, Department of Medicine, Division of Oncology, Clinical Director, Genitourinary Cancers Program, Fred Hutch Cancer Center, University of Washington Medicine, Seattle, WA
Adapted from the International Bladder Cancer Group (IBCG) Newsletter 2024 Vol 3