The addition of the PD-L1 inhibitor durvalumab to standard neoadjuvant gemcitabine/cisplatin chemotherapy has demonstrated statistically significant and clinically meaningful improvements in survival compared with neoadjuvant chemotherapy in cisplatin-eligible patients with muscle-invasive bladder cancer, according to data presented at the European Society for Medical Oncology (ESMO) Congress 2024 and simultaneously published in The New England Journal of Medicine.^1,2

‘Major Step Forward’

The groundbreaking results of the phase III NIAGARA trial showed that perioperative durvalumab combined with neoadjuvant chemotherapy improved both event-free survival and overall survival vs chemotherapy alone, without compromising the ability to complete curative-intent radical cystectomy. The addition of durvalumab to standard chemotherapy was associated with a 32% reduction in the risk of cancer recurrence, disease progression, or death. Authors of the study reported that the NIAGARA trial, which enrolled more than 1,000 patients, is the largest ever conducted in this specific patient population and represents a “major step forward in the field of genitourinary oncology.”

Thomas Powles, MBBS, MRCP, MD

“The NIAGARA trial supports perioperative durvalumab with neoadjuvant chemotherapy as a new standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer,” said lead study author Thomas Powles, MBBS, MRCP, MD, Professor of Genitourinary Oncology, University of London, and Director, Barts Cancer Centre at St. Bartholomew’s Hospital, London. “The significant results across multiple endpoints underscore the potential of this approach to improve outcomes for patients with this aggressive type of cancer.”

As Dr. Powles explained, bladder cancer accounts for approximately half a million global deaths annually, making it a significant health concern worldwide, also causing significant morbidity and expense in health-care systems. The current standard of care for muscle-invasive bladder cancer involves neoadjuvant cisplatin-based chemotherapy (in fit patients) followed by radical cystectomy and pelvic lymph node dissection. However, this approach has shown relatively moderate success, with approximately 50% of patients experiencing recurrence within 3 years, highlighting a significant major need in this patient population.

Durvalumab has shown promise in various cancers by enhancing the immune system’s ability to recognize and attack tumor cells. The perioperative approach, combining neoadjuvant and adjuvant therapies, has a strong biological rationale, said Dr. Powles, who noted this strategy has been successful in other cancer types, such as lung and breast, by potentially eliminating micrometastases and reducing the risk of recurrence.

Study Design

The NIAGARA trial was a randomized phase III trial involving more than 1,000 patients with localized muscle-invasive bladder cancer (clinical stage T2–T4aN0–N1). Patients were randomly assigned to receive either four cycles of gemcitabine/cisplatin chemotherapy, followed by radical cystectomy (standard arm) or four cycles of gemcitabine/cisplatin chemotherapy plus durvalumab (anti–PD-L1), followed by radical cystectomy and adjuvant durvalumab for up to eight monthly doses (experimental arm).

The primary endpoints were event-free survival and pathologic complete response rate. Event-free survival was defined as the time from randomization to cancer recurrence or progression, patients not having planned cystectomy, or death from any cause (patients who did not undergo radical cystectomy were counted as having an event toward that endpoint). According to Dr. Powles, the trial design allowed for a “comprehensive evaluation of the impact of adding a checkpoint inhibitor to the standard chemotherapy regimen throughout the entire treatment journey for localized muscle-invasive bladder cancer.”

Significant Survival Benefits and Manageable Safety Profile

As Dr. Powles reported, the study demonstrated a significant improvement in event-free survival with durvalumab, which translated to a 32% reduction in the risk of cancer recurrence, progression, or death (hazard ratio [HR] = 0.68; P < .001). At the 2-year landmark, event-free survival rate was 68% for the durvalumab arm vs 60% for the standard arm, representing an 8% absolute improvement.

Overall survival also showed a significant benefit, with a 25% reduction in the risk of death (HR = 0.75; P = .0106). The 2-year overall survival rate was 82% for the durvalumab arm vs 75% for the standard arm, demonstrating a 7% absolute improvement in overall survival at the data cutoff.

Pathologic complete response rates were higher in the durvalumab arm (37% vs 27%). Although this did not reach statistical significance in the primary analysis due to alpha allocation in the statistical plan and a clerical error in the initial analysis (59 cases were not properly analyzed initially), said Dr. Powles, this trend suggested enhanced tumor elimination with the addition of durvalumab. Of note, the benefits of durvalumab were consistent across various subgroups, including different clinical stages, PD-L1 expression levels, and histologic subtypes, indicating broad applicability of this treatment approach.

The safety profile was also comparable between the two arms, alleviating concerns about potential major added toxicity from immunotherapy. Grade 3 or 4 adverse events occurred in 69% of patients in the durvalumab arm vs 68% in the standard arm. Treatment-related grade 3 or 4 adverse events were observed in 41% of patients in both arms, and adverse events leading to death were rare, occurring in less than 1% of patients in both arms. In the adjuvant phase, 6% of patients experienced grade 3 or 4 treatment-related adverse events, suggesting relatively good tolerability of durvalumab adjuvant therapy.

“Importantly, the addition of durvalumab did not cause delay in surgery or reduce the likelihood of patients undergoing radical cystectomy,” said Dr. Powles, who reported that approximately 85% of patients in both arms successfully underwent radical cystectomy, with patient choice being the most common reason for not proceeding to that surgery.

“The tolerability of this regimen is particularly encouraging,” he added. “This is crucial in a disease where timely intervention can make a significant difference in outcomes.”

According to Dr. Powles, the success of the NIAGARA trial opens new avenues for research in the treatment of muscle-invasive bladder cancer and paves the way for further advancements in patient care. Ongoing trials are exploring combinations of checkpoint inhibitors with antibody-drug conjugates across different patient subgroups, including patients who are ineligible for cisplatin-based chemotherapy.

EXPERT POINT OF VIEW

Petros Grivas, MD, PhD

Invited discussant Petros Grivas, MD, PhD, Professor, Clinical Research Division, Fred Hutch Cancer Center, Seattle, emphasized that NIAGARA is indeed a practice-changing trial, based on the significant event-free and overall survival benefit demonstrated.

“This is the first trial testing a checkpoint inhibitor that shows a clear event-free survival and overall survival benefit in the neoadjuvant and/or adjuvant setting of bladder cancer and represents a significant step forward in the treatment of muscle-invasive bladder cancer,” said Dr. Grivas. “It also opens up new avenues for research and raises important questions about optimizing treatment strategies for individual patients.”

However, Dr. Grivas pointed out several key questions that remain unanswered:

The individual contributions of the neoadjuvant vs adjuvant phases of treatment are not yet clear; future trial designs, though complex, long, costly, and challenging, can be very helpful to tease out these particular differences.

The impact of pathologic stage on outcomes needs further exploration; an exploratory analysis of disease-free and overall survival between the arms stratified by pathologic stage could provide valuable insights, similar to what has been seen in breast cancer trials.

The potential impact of prior checkpoint inhibition given in non–muscle-invasive disease settings, as well as the possibility of rechallenging with a checkpoint inhibitor in cases of later recurrence, remain open questions.

The impact of a potential adjuvant checkpoint inhibitor in the control arm as well as access to effective salvage therapies upon cancer recurrence/disease progression may impact the performance of the control arm and, therefore, the results of this trial.

Upper tract urothelial carcinoma represents a separate unmet need; results from the ongoing ECOG ACRIN 8192 phase II/III trial will help to answer important questions.

Additional Considerations

Dr. Grivas also emphasized the importance of considering health-care utilization, patient-reported outcomes, and quality-of-life data in future analyses. He expressed high interest in seeing data on tissue-based molecular biomarkers and circulating tumor DNA (ctDNA), which could potentially inform decision-making about adjuvant therapy and may help to avoid both over- and undertreatment.

Looking ahead, Dr. Grivas highlighted ongoing relevant trials that may further shape the therapeutic landscape. They include perioperative phase III trials and also studies exploring bladder-preserving approaches with the potential for curing a proportion of patients with systemic therapy alone in the future.

“There are compelling theoretical reasons supporting neoadjuvant and perioperative immunotherapy. NIAGARA is a practice-changing trial and a major step forward in this direction. We also need to address the practical challenges of designing future trials to definitively answer relevant questions and help understand which patients need a particular therapy based on validated biomarkers,” said Dr. Grivas, who stressed the importance of patient input and advocacy in designing trials and advancing the field.

DISCLOSURE: Dr. Powles reported financial relationships with Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Seagen, and Roche. Dr. Grivas reported financial relationships with Acrivon Therapeutics, ALX Oncology, Bristol Myers Squibb, Merck KGaA, MSD, Genentech, Gilead Sciences, G1 Therapeutics, Mirati Therapeutics, QED Therapeutics, Aadi Bioscience, AbbVie, AstraZeneca, Asieris Pharmaceuticals, Astellas Pharma, Bicycle Therapeutics, CG Oncology, Daiichi Sankyo, Fresenius Kabi, G1 Therapeutics, Immunity Bio, Janssen, Pfizer, Roche, Strata Oncology, and Replimune.

REFERENCES

1. Powles T, Van der Heijden MS, Galsky M, et al: A randomized phase III trial of neoadjuvant durvalumab plus chemotherapy followed by radical cystectomy and adjuvant durvalumab in muscle-invasive bladder cancer (NIAGARA). ESMO Congress 2024. Abstract LBA5. Presented September 15, 2024.

2. Powles T, Catto JWF, Galsky MD, et al: Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med. September 15, 2024 (early release online).