NIAGARA Data Raise Questions About the Role of MVAC in Resectable MIBC

Data have demonstrated how the addition of the immunotherapy agent durvalumab (Imfinzi) to neoadjuvant chemotherapy improves long-term outcomes for patients with muscle-invasive bladder cancer (MIBC); however, questions remain about how this regimen compares with dose-dense MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) in eligible patients, according to Waddah Arafat, MD.

"The data are clear: neoadjuvant chemotherapy is better than adjuvant chemotherapy," Arafat said in an interview with OncLive®.

The phase 3 NIAGARA trial (NCT03732677) findings confirm the efficacy of neoadjuvant chemotherapy in patients with resectable MIBC and indicate the potential benefit of adding immunotherapy to this standard regimen, Arafat noted. Data from the trial’s primary analysis showed an estimated 24-month event-free survival rate of 67.8% (95% CI, 63.6%-71.7%) with durvalumab plus gemcitabine and cisplatin (n = 533) vs 59.8% (95% CI, 55.4%-64.0%) with gemcitabine and cisplatin alone (n = 530; HR, 0.68; 95% CI, 0.56-0.82; P < .001).1 Additionally, long-term outcomes demonstrated a pathologic complete response (pCR) benefit with the addition of durvalumab.2 The pCR rate was 37.3% (95% CI, 33.2%-41.6%) in the durvalumab arm vs 27.5% (95% CI, 23.8%-31.6%) in the chemotherapy alone arm (odds ratio, 1.60; 95% CI, 1.23-2.08; nominal P = .0005).

In the interview, Arafat discussed the evolving treatment paradigm for patients with resectable MIBC, unanswered questions regarding the mechanism of the benefit seen with neoadjuvant chemoimmunotherapy in this setting, and patient characteristics that inform eligibility for treatment with dose-dense MVAC.

Arafat is an associate professor of internal medicine and a member of the Division of Hematology and Oncology at the University of Texas (UT) Southwestern Medical Center; as well as medical director of the Clinical Cancer Informatics Program at the UT Southwestern Harold C. Simmons Comprehensive Cancer Center in Dallas.

OncLive: How might data from the NIAGARA trial change the future role of dose-dense MVAC for patients with resectable MIBC?

Arafat: Neoadjuvant chemotherapy data are mostly historical data, but [there is also a] role for adding immunotherapy to the chemotherapy backbone. The NIAGARA trial of durvalumab in addition to the cisplatin and gemcitabine doublet showed encouraging data. The main limitation of [NIAGARA] is that we still don't know whether this triplet therapy outperforms dose-dense MVAC, which was not compared in this setting. That remains an open question: [In] patients who are fit for dose-dense MVAC, is that preferred over the NIAGARA regimen? What we know for sure is that gemcitabine and cisplatin is not the standard of care anymore, because [whichever patients are eligible to] receive dose-dense MVAC might receive it, but if they are [ineligible], they need to receive the triplet therapy that includes durvalumab, unless they have a contraindication.

What is the current role of neoadjuvant chemotherapy in the MIBC treatment paradigm? How has this role evolved with the addition of immunotherapy to the treatment paradigm?

There have been well-documented deficiencies in the United States health system in using neoadjuvant data as they should be [used]. [Circumstances] have improved over the past couple decades, but we continue to see a lot of shortcomings. This might be a case especially in community practices where there's less access to multidisciplinary settings, where the urologists and medical oncologists are sitting in the same practice discussing the patients. Whether [these discussions occur] in an academic institution or in the community setting, the emphasis on multidisciplinary decision-making and prioritizing the use of neoadjuvant chemotherapy continues to be a high priority.

With the addition of durvalumab [to gemcitabine plus cisplatin] based on the NIAGARA data, I don't see a change to the historic challenge. [However, these data] emphasize the importance of administering neoadjuvant therapy so we can achieve better pCRs because [achieving pCR] has been well established as a predictor of better outcomes in the long run. The data are clear. Perioperative chemotherapy improves outcomes, but the benefit is significantly more visible and supported by evidence in the neoadjuvant setting. [However, questions remain regarding] whether that is because of the improved surgical resection of tumors or the opportunity to address micrometastatic disease early on and then administering the definitive therapy with surgery.

What parameters indicate patient eligibility for dose-dense MVAC?

The difference between dose-dense MVAC and doublet chemotherapy [with gemcitabine and cisplatin] is around [patient] performance status, which is what is used by many oncologists to make this decision. There are also secondary considerations that are still important, such as cardiac function, because of the use of [doxorubicin]. There might be contraindications for [doxorubicin] in patients with poor systolic function, but that might also be a challenge [precluding treatment with] cisplatin.

[Therefore], the main difference between [the eligibility criteria for] those 2 regimens is the performance status of the patient. An indirect way of thinking about that is [to consider] the age of the patient. Some oncologists have a certain line in the sand [where for patients of] a certain age, they would not give dose-dense MVAC. Although we try to focus on performance status, age [is still used as a surrogate marker for performance status] by a lot of practicing oncologists.

References

1. Powles T, Catto JWF, Galsky MD, et al. Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med. 2024;391(19):1773-1786. doi:10.1056/NEJMoa2408154
2. Galsky M, Van Der Heijden M, Catto J, et al. Additional efficacy and safety outcomes and an exploratory analysis of the impact of pathological complete response (pCR) on long-term outcomes from NIAGARA. J Clin Oncol. 2025;43(suppl 5):659. doi:10.1200/JCO.2025.43.5_suppl.659