Bladder-Sparing with Systemic Therapy: Insights from RETAIN-2 and Future Directions

A virtual roundtable, hosted by Dr. Petros Grivas of Fred Hutchinson Cancer Center, contextualized the latest bladder cancer research updates and trials of relevancy to come out of the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium. Dr. Grivas was joined by Drs. Guru Sonpavde, Elizabeth Plimack, Christopher Wallis, Terence Friedlander, and Matthew Galsky.

In the fourth segment of the roundtable, the panel shares the NIAGARA trial’s findings, expressing cautious optimism while raising concerns about the universal use of adjuvant therapy, while also highlighting promising results from the RETAIN-2 trial on dose-dense MVAC for bladder preservation. The conversation also covers the potential approval of durvalumab in the neoadjuvant-adjuvant setting, addressing patient selection challenges, and suggesting that immunotherapy may benefit both pathologic complete responders and non-responders.

View the next segment on Utility of ctDNA, Overcoming Barriers to Multidisciplinary Care in Community, Academic Settings.

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Dr. Grivas: Dr. Plimack, you gave a great discussion at ASCO GU on the NIAGARA data and CheckMate 274. You have led trials with dose-dense MVAC. What is your take on that dataset? How do you synthesize the NIAGARA data in your practice? Do you see a role for dose-dense MVAC in PD-L1 inhibition? Some Phase II trials are investigating this. How do you approach your practice moving forward?

Dr. Plimack: NIAGARA was really interesting and a great concept. It is the first of six sandwich-design trials we are about to see in bladder cancer, all of which have a gem-cis control arm. Many chemotherapy combination trials use a gem-cis backbone, so I had hoped this would significantly improve event-free and overall survival. We may see better long-term outcomes with further follow-up, but so far, I was not as impressed with the difference in benefit, particularly given that everyone received eight cycles of adjuvant therapy. Unlike CheckMate 274, which stratifies treatment based on stage, risk, and prognostic factors, NIAGARA treats all patients the same way. Those were the two main considerations that stood out.

Regarding dose-dense MVAC, conducting trials with generic chemotherapy agents is more challenging. Without pharmaceutical support, we lack the same level of funding for trial reimbursements, data cleaning, and querying. However, credit to the COXEN and VESPER trials; they conducted two randomized studies with consistent results, aligning with single-arm Phase II data. We now have a solid understanding of how dose-dense MVAC performs relative to gem-cis. Some clinicians remain hesitant to use it, while others are more comfortable. The question is whether we can combine it with immunotherapy. Unfortunately, most available data focus on gem-cis with immunotherapy, while data on dose-dense MVAC combinations are limited.

That said, the existing data are compelling. In RETAIN-2, which we presented, we combined dose-dense MVAC with three cycles of nivolumab in a bladder preservation approach, similar to Dr. Galsky’s HCRN studies and RETAIN-1. We were pleasantly surprised by the pathologic complete response rates; 40% of patients expected to have residual disease did not. Additionally, the event-free survival rate was 84%, which is better than previous results. Moving forward, investigator-initiated and cooperative group trials will be essential to further explore this approach. If it proves superior, we should pursue it and continue asking these critical questions.

Dr. Grivas: Congratulations on the RETAIN-2 trial, which Dr. Ghatalia presented at ASCO GU. Also, thank you for stopping by our poster on the dose-dense MVAC-pembrolizumab trial for variant histologies, where pathologic complete response approached 60%, again raising this hypothesis. There is also the AURA trial in Europe investigating dose-dense MVAC with avelumab.

Dr. Plimack: That is right.

Dr. Grivas: It is an interesting discussion. Dr. Sonpavde, what is your approach moving forward? Do you anticipate durvalumab receiving approval in the neoadjuvant-adjuvant setting, and if so, how would you incorporate it into practice?

Dr. Sonpavde: Yes, I expect durvalumab combined with gem-cis to be approved. The key argument for its use in all-comers is the improvement in event-free and overall survival, with early separation in event-free survival occurring even before cystectomy. This suggests benefit for a broader patient population.

However, the counterargument is that patients who achieve a pathologic complete response (pathCR) with gem-cis or dose-dense MVAC may not need additional therapy, as their outcomes are already favorable. If we could reliably identify these patients, we might offer them only gem-cis, avoiding unnecessary immune checkpoint blockade pre- or post-treatment. Unfortunately, we do not yet have a robust biomarker for this. DNA damage repair alterations have been studied in bladder-sparing trials, and while ERCC2 appears to be the most promising, more work is needed to refine precision medicine and ensure the right patients receive treatment while avoiding overtreatment.

Dr. Grivas: Absolutely. Overtreatment is a significant concern, not only due to toxicity and cost but also the risk of undertreatment. Dr. Galsky, in this context, you reviewed the NIAGARA updates at ASCO GU, specifically the breakdown of patients with and without pathCR. The data were intriguing regarding the role of durvalumab in different subsets. Can you share your insights on these exploratory analyses?

Dr. Galsky: This exploratory analysis examined outcomes based on pathCR status, stratified by treatment arm, using event-free and overall survival as endpoints. The key finding was that patients who achieved pathCR and received durvalumab had better event-free survival than those in the control arm. Similarly, patients without pathCR also experienced better event-free survival with durvalumab.

Two take-home messages emerge. First, while this was an exploratory analysis and the effect size is debatable, I would challenge the notion that achieving pathCR means a patient is “fine.” If you ask most oncologists, they would estimate a 10% risk of metastatic recurrence in a pathCR patient. That is not insignificant, and we can likely improve outcomes even for those who achieve pathCR. There is also a signal suggesting that immune checkpoint blockade might influence not just the extent of response but also its quality, which we see in the metastatic setting as well.

Second, the benefit seen in non-pathCR patients is equally interesting. This challenges the long-held belief that neoadjuvant therapy must result in pathCR to be effective. Medical oncologists have long observed cases where tumors shrink significantly but do not completely disappear, yet patients remain disease-free after surgery. This suggests that systemic therapy can eradicate micrometastatic disease without fully eliminating the primary tumor, supporting the role of neoadjuvant treatment in a broader subset of patients.

Previously, we lacked the ability to assess this because we only compared surgery to neoadjuvant chemotherapy. Now, with multiple systemic therapy regimens, we can better differentiate these effects. This analysis reinforces the idea that neoadjuvant treatment provides benefit beyond just achieving pathCR.

Dr. Grivas: Excellent. Thank you for that detailed explanation. You raised some really compelling points.