Bladder-Sparing Innovations in MIBC: Dr. Elizabeth Plimack on the RETAIN Approach and Its Future

Dr. Elizabeth Plimack, MD, MS, FASCO, is a Professor of Medical Oncology and the Deputy Director of Fox Chase Cancer Center. A recognized leader in the treatment of genitourinary malignancies, Dr. Plimack’s work primarily focuses on bladder and kidney cancers.

At Fox Chase Cancer Center, Dr. Plimack and her team have pioneered an innovative approach to bladder preservation in patients with muscle-invasive bladder cancer (MIBC). Through clinical trials like RETAIN-1 and RETAIN-2, they are challenging traditional treatment paradigms by exploring systemic therapy-based strategies as alternatives to radical cystectomy and trimodality therapy.

In this exclusive interview with GU Oncology Now, Dr. Plimack discusses the development of the RETAIN approach, from early findings with neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) to the evolution of the concept in the RETAIN-1 and RETAIN-2 trials. She also shares insights into the design of the upcoming RETAIN-3 trial and the ongoing quest to redefine bladder preservation for patients who are candidates for this alternative approach.

Can you provide some background about the importance of bladder-sparing alternatives for patients with MIBC? What are the negatives of radical cystectomy, and why is there increased focus on alternatives to surgery?

Dr. Plimack: The main reason systemic therapy-based bladder preservation has gained traction is that, for decades, our surgeons have been removing bladders that are free of cancer in approximately one-third of patients who receive neoadjuvant chemotherapy. That experience has significantly shaped how we view the procedure. When a cancer-free bladder is removed, the patient is almost certainly cured, which is a positive outcome. However, both surgeons and patients often ask, “If the bladder did not contain any cancer, why did it need to be removed?” That question has largely driven the push toward systemic therapy-based bladder preservation.

I hesitate to speak negatively about cystectomy because it remains a necessary procedure for many patients now and in the future. However, it is a major surgery that removes not only the bladder but also adjacent reproductive organs in both men and women. It is associated with a long recovery, substantial risks—especially when not performed at a high-volume center—and life-altering changes in how the body eliminates urine.

There are different options for urinary diversion after cystectomy. One is an ileal conduit, which involves an ostomy. While it provides the benefit of being relatively leak-free, allowing patients to travel and sleep through the night without interruption, it is still a significant adjustment. Another option, particularly for men, is a neobladder, which must be trained for continence or periodically catheterized. Regardless of the approach, cystectomy fundamentally changes a patient’s daily life.

When considering all the components of curative treatment, surgery has the most profound and lasting impact on a patient’s long-term quality of life.

How does Fox Chase Cancer Center determine which patients are best suited for trimodality therapy versus systemic therapy-based bladder preservation?

Dr. Plimack: Trimodality therapy has been, and remains, a standard of care. In the United States—and certainly at Fox Chase—we tend to use it primarily for patients with clearly localized disease. Specifically, clinical T2 candidates without lymphovascular invasion or lymph node involvement may be better suited for this approach, as the available data focus on a relatively narrow group of patients. However, it is absolutely an option for eligible individuals.

One of the key benefits of trimodality therapy, or chemoradiation, is that it allows patients to retain their bladder. However, a potential drawback is that radiation can impact bladder function. Additionally, as with all bladder-preservation strategies, there is an inherent risk of developing new urothelial cancers. This occurs due to field cancerization, meaning that the urothelium, once predisposed to developing cancer, remains susceptible to future malignancies. This risk applies not only to trimodality therapy but also to systemic therapy-based bladder preservation.

Can you provide an overview of the RETAIN-1 and RETAIN-2 trials and how they fit into Fox Chase Cancer Center’s broader approach to bladder preservation? What led you to pursue this specific alternative bladder-sparing approach?

Dr. Plimack: We conducted two small studies on neoadjuvant chemotherapy regimens. One evaluated dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin MVAC, which was published in JCO¹, and the other examined dose-dense gemcitabine and cisplatin (gem-cis)², though we had to close that study early due to toxicity. In both trials, we found that a significant portion of patients—38% in the dose-dense MVAC group—had no detectable cancer in their bladder when it was removed.

This raised an important question. Many of our patients asked, “If my bladder was cancer-free, did I really need surgery?” That ongoing concern, combined with our own findings on how effective we were at sterilizing bladders, led us to explore whether we could leave the bladder in place for select patients. However, that immediately raised another critical question: How do we know the bladder is truly cancer-free without removing it for pathological evaluation?

To address this, we investigated several methods. One approach involved transurethral resection of bladder tumor (TURBT) with systematic mapping biopsies. Surgeons would carefully examine the bladder after neoadjuvant chemotherapy, taking targeted biopsies of any suspicious areas while also sampling urothelium that appeared benign to check for subclinical residual disease. Our data showed that this method had a specificity of 94%, meaning if the biopsies showed cancer, there was a high likelihood that cancer would be present at cystectomy. However, the sensitivity was only 65%, meaning we often missed subclinical muscle-invasive or urothelial cancer. That was disappointing, as we had hoped TURBT alone might be the gold standard.

We then turned to biomarkers. We identified a four-gene biomarker—ATM, RB1, FANCC, and ERCC2—that, after platinum-based treatment, produced similar predictive results to TURBT. The specificity was 80%, and the sensitivity was 60%. Since both the biomarker and the mapping biopsies provided useful, though imperfect information, we combined them to develop the RETAIN-1 trial.

The RETAIN-1 trial required several key components:

• Standard imaging, including a CT scan, to confirm there was no lymph node involvement or distant spread.
• Mapping biopsies with TURBT to ensure, to the best of our ability, that no cancer remained after neoadjuvant chemotherapy.
• The four-gene biomarker to further refine the group of patients with no detectable cancer on TURBT into an even more select subset.

For this carefully chosen group, we felt comfortable offering active surveillance in place of immediate cystectomy.

The support for this approach was widespread, with buy-in from our surgeons, the broader medical community, and our patients. The consenting process was completely transparent. We made it clear: Cystectomy is the tried-and-true approach for cure. If cure is your primary goal, surgery remains the best option. However, we also acknowledged that some patients prioritize bladder preservation and would be willing to take an informed risk. We explained that our methods represented our best attempt to determine whether it was safe to keep the bladder, but that we could be wrong – choosing surveillance over cystectomy could mean giving up a chance for cure.

Despite this candid discussion, patient enthusiasm for the trial was high. I cannot recall a patient who declined to enroll.

What are the key findings from RETAIN-1 so far, and how have they influenced the design and goals of RETAIN-2?

Dr. Plimack: RETAIN-1 enrolled 70 patients with MIBC, sequencing their tumors during neoadjuvant chemotherapy. Those with a clinical complete response—based on imaging, TURBT mapping biopsies, and predictive mutations—were assigned to active surveillance. Others were directed to intervention (intravesical therapy, chemoradiation, or cystectomy).

The trial met its goal of achieving metastasis-free survival (MFS) comparable to historical cystectomy outcomes. However, only 64% of the surveillance group remained metastasis-free at last follow-up, which was lower than expected for presumed pathologic complete responders. In contrast, cystectomy was appropriately performed, as 85% had residual disease.

Conducted in tandem with an HCRN study on gem-cis plus nivolumab, we launched RETAIN-2, identical in design but adding three doses of nivolumab to dose-dense MVAC. The impact was clear: MFS in the active surveillance group improved from 64% in RETAIN-1 to 82% in RETAIN-2. However, we also removed too many clean bladders; 40% in the cystectomy group had no residual cancer, highlighting the effectiveness of adding immunotherapy to the neoadjuvant regimen.

These results reinforce that systemic therapy, especially with immunotherapy, allows more people to achieve bladder preservation. As treatments improve, this approach may become viable for more patients.

How will the findings from RETAIN-2 shape future clinical trials and improve bladder preservation strategies?

Dr. Plimack: We are building on RETAIN-2 in several ways. First, we believe we have found a highly effective combination—dose-dense MVAC with immunotherapy—which will serve as the systemic therapy backbone in our next trial. While dose-dense MVAC is an older regimen, its combination with immunotherapy is underexplored but has shown strong results in our studies and a few others, including the Aura trial.³

Second, we are refining how we select patients for bladder preservation. RETAIN-2 used standard CT imaging, TURBT biopsies, and a biomarker that is now obsolete in the setting of immunotherapy. In future trials, we plan to incorporate:

• PET scans to detect hidden metastases before enrollment, ensuring we do not perform unnecessary cystectomies in patients who already have systemic disease.
• MRI (VI-RADS scoring) to improve bladder imaging. While promising, its accuracy in predicting complete response is still uncertain, as most validation studies have compared it to TURBT rather than cystectomy.
• ctDNA analysis to help guide treatment decisions, though its interpretation is still evolving. A positive ctDNA result post-chemotherapy suggests residual disease, but we do not yet know if this means circulating metastases or local tumor shedding from the bladder. This raises concerns about overtreatment and unnecessary cystectomies.

We are currently analyzing RETAIN-1 and RETAIN-2 data to evaluate how well ctDNA predicts long-term outcomes. By combining the best systemic therapy with more precise assessment tools, we aim to better identify patients suited for active surveillance while avoiding futile cystectomies, particularly in those with undiagnosed metastatic disease.

What are the primary goals of the RETAIN-3 trial?

Dr. Plimack: RETAIN-3 aims to define what can be achieved with state-of-the-art systemic therapy and response assessment in bladder preservation. It is a single-arm study, so we will not be directly comparing it to a surgery-for-all approach, nor can we randomize patients between bladder preservation and cystectomy.

We also recognize that patient choice plays a major role; regardless of allocation, some patients will opt to keep their bladder, while others may choose surgery. Rather than forcing a rigid approach, RETAIN-3 will serve as a benchmark, demonstrating real-world outcomes when we apply the most advanced treatment and assessment strategies.

The key question is how well this approach works in clinical practice and what level of evidence is needed for broader adoption outside of a trial setting. Since most bladder preservation studies have been single-arm, this data will be crucial in shaping future strategies and helping clinicians determine when it is appropriate to offer bladder preservation as a standard option.

How do you effectively counsel patients on bladder preservation, given the complexity of the decision?

Dr. Plimack: First, I do not assume broad acceptance of this approach. For many patients, the idea of potentially reducing their chance of cure—even if our phase II data suggests otherwise—can be daunting. This strategy will not be for every practice, every surgeon, or every patient.

That said, the conversation with patients can be straightforward. We start with standard neoadjuvant chemotherapy, which improves the chance of cure before surgery. Then we explain that in about a third of cases, we find no residual cancer when the bladder is removed. But once it is gone, we cannot reverse the decision.

Bladder preservation means using the best available tools—MRI, PET scans, ctDNA, and mapping biopsies—to assess the response before deciding on surgery. Patients can make an informed choice with our guidance.

It is also important to emphasize that life after cystectomy is entirely manageable. Through patient-to-patient networks, we connect individuals considering bladder removal with those living full lives after an ileal conduit, neobladder, or Indiana pouch. Advocacy groups like the Bladder Cancer Advocacy Network provide educational resources, videos, and peer support to help patients navigate this choice with confidence.

References

1. Geynisman M, Abbosh H, Ross E, et al. Phase II Trial of Risk-Enabled Therapy After Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer (RETAIN 1). J Clin Oncol. Published online December 16, 2024. doi:10.1200/JCO-24-01214
2. Anari F, O’Neill J, Choi W, et al. Neoadjuvant Dose-dense Gemcitabine and Cisplatin in Muscle-Invasive Bladder Cancer: Results of a Phase 2 Trial. Eur Urol Oncol. 2018;1(1):54-60. doi:10.1016/j.euo.2018.02.007.
3. Chanza N, Soukane L, Barthelemy P, et al. Avelumab as neoadjuvant therapy in patients with urothelial non-metastatic muscle invasive bladder cancer: a multicenter, randomized, non-comparative, phase II study (Oncodistinct 004 – AURA trial). BMC Cancer. 2021;21(1):1282. doi:10.1186/s12885-021-08990-3.