Targeted Therapies and Biomarker-Driven Therapy Advance MIBC Treatment Paradigm

The treatment landscape of muscle-invasive bladder cancer (MIBC) has undergone a dramatic transformation in recent years, moving from decades of stagnation following the establishment of neoadjuvant cisplatin-based chemotherapy to a new era defined by immune checkpoint inhibitors (ICIs), antibody-drug conjugates (ADCs), and biomarker-driven treatment selection, according to Matthew Galsky, MD.

“There [has been] a convergence of better therapies and better diagnostics that are going to impact the way that we treat MIBC moving forward in the nearer term. There are a series of studies using radiation-based bladder-sparing approaches [which are] adding immune checkpoint blockade that we haven't seen the results for yet,” Galsky said in an interview with OncLive®. “That's the next wave of MIBC [care]; phase 3 studies that were launched several years ago that have practice-impacting potential. In the slightly longer term, some larger, more definitive studies have been launched seeking to determine whether there's a path [towards] response-guided bladder-sparing approaches which leverage transurethral resection plus systemic therapy and reassessment as a basis to define the path to bladder sparing.”

Galsky is the director of Genitourinary Medical Oncology, co-director of the Center of Excellence for Bladder Cancer, the deputy director, and a professor of medicine (Hematology and Medical Oncology) at the Mount Sinai Tisch Cancer Center in New York, New York.

In the interview, which took place during Bladder Cancer Awareness Month in May, Galsky discussed the evolution of MIBC treatment, the role of ICIs, and how biomarkers are being developed to inform clinical decision-making.

OncLive: What was responsible for raising the bar past neoadjuvant chemotherapy and concurrent chemoradiation in MIBC?

Galsky: MIBC has traditionally been treated with local therapies, including radiation or radical cystectomy. We know that with local therapy alone, there is unfortunately a high risk of metastatic recurrence. Historically, we have quoted that approximately 50% of individuals with MIBC, considering the difficulty with clinical staging for clinically localized MIBC, face a risk of metastatic recurrence with local therapy alone that is sufficiently high to warrant consideration of integrating systemic therapy.

In the 1980s, cisplatin-based chemotherapy given prior to surgery was shown to potentially be beneficial in terms of tumor downstaging and achieving pathological complete responses [pCRs], ultimately leading to phase 3 trials that established neoadjuvant cisplatin-based chemotherapy as the standard of care prior to radical cystectomy. Subsequent studies demonstrated that concurrent chemotherapy with radiation could also be a bladder-sparing form of definitive local therapy.

Those 2 standards were established, and then there was a period of about 20 years with little progress in the management of MIBC. From a systemic therapy standpoint, there were a number of trials, but drug development activity in bladder cancer was relatively limited compared with some other malignancies. That created something of a vicious cycle in terms of decreased interest among industry funders and investigators, and it was difficult to break that cycle until the era of immune checkpoint blockade in bladder cancer.

How have recent clinical trial data shifted the treatment paradigm toward ICIs?

Immune checkpoint blockade was first shown to have activity as monotherapy in urothelial cancer in the metastatic setting. Single-agent PD-1 or PD-L1 blockade yields responses in about 20% to 30% of patients with metastatic urothelial cancer. But enthusiasm for immune checkpoint blockade in this disease, similar to other malignancies, [stems from the] durable responses that can occur. [Additionally], many patients tolerate immune checkpoint blockade quite well.

[ICIs] are not without adverse effects by any means, but many patients tolerate the therapy well. That, coupled with the fact that there had been really limited demonstration of new mechanisms of action beyond cytotoxic chemotherapy showing benefit in urothelial cancer, led to this landmark transition in interest in bladder cancer. So not only was it important in terms of demonstrating clinical activity and ultimately being integrated into standard clinical care for metastatic urothelial cancer, but it also led to all these additional opportunities in drug development, not only for immune checkpoint blockade, but for other novel mechanisms of action as well.

Once established as potentially beneficial in the metastatic setting, the standard approach in clinical drug development in oncology is to move drugs earlier in the course of the disease, hoping to have a greater impact on outcomes. The first studies that definitively tested the role of immune checkpoint blockade in muscle-invasive urothelial cancer were done in the adjuvant setting, in patients who had undergone radical surgery but were felt to be at high risk for metastatic recurrence. [There, we] tested adjuvant PD-1 or PD-L1 blockade for 1 year vs either placebo or observation. Three phase 3 studies launched around the same time, all designed similarly. Two of them met their primary end points; 1 did not. Two of them could be considered practice changing. [The phase 3] IMvigor010 trial [NCT02450331] did not meet its primary end point, but the other two did. Adjuvant nivolumab [Opdivo], based on data from the [phase 3] CheckMate 274 trial [NCT02632409], received an FDA approval.¹ Pembrolizumab [Keytruda] has also shown a benefit in the phase 3 AMBASSADOR trial [NCT03244384].

In addition to the adjuvant setting, immune checkpoint blockade has now been moved into the neoadjuvant setting, or the perioperative setting. Two sets of studies have had tremendous impact on the field and have changed the standard of care. One is the [phase 3] NIAGARA study [NCT03732677], which added durvalumab [Imfinzi] to gemcitabine and cisplatin chemotherapy in the neoadjuvant setting, demonstrating an improvement in pCR rate, event-free survival [EFS], and overall survival [OS] compared with platinum-based chemotherapy alone.²

More recently, 2 randomized studies integrated enfortumab vedotin-ejfv [Padcev] plus pembrolizumab in the neoadjuvant and adjuvant setting. [The phase 3] KEYNOTE-905/EV-303 trial [NCT03924895] enrolled patients who were cisplatin-ineligible, with radical cystectomy alone as the comparator. Another study, [the phase 3] KEYNOTE-B15/EV-304 trial [NCT04700124] compared perioperative enfortumab vedotin plus pembrolizumab with neoadjuvant gemcitabine and cisplatin, both followed by cystectomy, in patients with MIBC. Both of those studies showed higher pCR rates, higher EFS and higher OS, marking a new era in the treatment of MIBC with a non–platinum-containing systemic therapy regimen.

How are investigators working to fill gaps in the bladder cancer treatment armamentarium?

The introduction of ADC plus immune checkpoint blockade combination regimens has really transformed the way we treat bladder cancer, both in the metastatic setting and now in the muscle-invasive setting. There are still unmet needs related to not only increasing the likelihood of eradicating bladder cancer but doing so while optimally maintaining patients' quality of life and survivorship. Multiple ongoing efforts are aimed at achieving those goals.

One effort is focused on trying to achieve curative outcomes without patients requiring surgical removal of the bladder, and a number of different approaches and trials are testing strategies toward that end. Another major unmet need is that, even though we have much better systemic therapies for urothelial cancer, not all our patients respond well to the available treatments. We therefore need to develop regimens to ensure that everyone is benefiting. Understanding resistance to current regimens and developing novel approaches is certainly an ongoing need.

Late-stage clinical development in urothelial cancer mostly [encompasses the study of] combination regimens, [which aims to determine] whether the addition of a third drug to an enfortumab vedotin plus pembrolizumab-based regimen can further improve outcomes. Another unmet need is addressing the intrinsic biology that drives bladder cancer. Many of the developments we have seen in the past few years have either targeted the tumor microenvironment or leveraged targets on bladder cancer cells for the selective delivery of cytotoxic [therapies] but have not necessarily addressed the underlying biology driving bladder cancers. A number of developments are starting to address that gap, including potentially targeting PPAR-gamma, which is one of the key regulators of luminal-like urothelial cancers.

How are biomarkers being used for clinical decision-making in bladder cancer?

Biomarkers are often separated into prognostic or predictive categories. The way I like to think about biomarkers, particularly in the perioperative setting, which is a bit distinct from the metastatic setting, is to divide them into 2 groups: biomarkers that define who needs treatment and biomarkers that define who benefits from treatment.

Biomarkers to define who benefits from certain drugs have presented some challenges in bladder cancer. We only have a few actionable biomarkers that indicate which patient should receive which drug, including FGFR3 mutations, which are the most notable example, and HER2 overexpression at the protein level, which is another potential example in terms of identifying patients who might benefit from HER2-directed ADCs.

Biomarkers to determine who needs treatment are most applicable right now in the perioperative setting, though examples are also emerging in the advanced setting. What I mean by this is that in the perioperative setting, particularly after definitive radical surgery, many of our patients are already cured. The challenge has been trying to identify who has been cured, so that we do not [administer] systemic therapy to patients who, by definition, cannot benefit from it. Circulating tumor DNA [ctDNA] has shown remarkable progress in recent years in informing those decisions.

In bladder cancer, we now have data establishing the clinical utility of ctDNA testing in the adjuvant setting. The [phase 3] IMvigor011 study [NCT04660344] demonstrated that treating patients with detectable ctDNA after surgery leads to an improvement in OS with immune checkpoint blockade vs placebo.

The biomarkers one would not want to miss in advanced urothelial cancer are FGFR3 mutation testing and HER2 immunohistochemistry testing. Those are the 2 that are impacting practice today in the advanced urothelial cancer setting. In the perioperative setting, ctDNA has established clinical utility. Detectable ctDNA after surgery identifies patients who achieve a survival benefit with adjuvant immune checkpoint blockade. What we do not yet know with certainty is whether, in patients with undetectable ctDNA after surgery, a watch-and-wait approach is noninferior to immediate adjuvant treatment. But we do know that in the setting of detectable ctDNA after surgery, those patients should proceed with adjuvant therapy.

References

1. US Food and Drug Administration approves Opdivo (nivolumab) for the adjuvant treatment of patients with high-risk urothelial carcinoma. News release. Bristol Myers Squibb. August 20, 2021. Accessed May 15, 2026. https://news.bms.com/news/details/2021/U.S.-Food-and-Drug-Administration-Approves-Opdivo-nivolumab-for-the-Adjuvant-Treatment-of-Patients-with-High-Risk-Urothelial-Carcinoma/default.aspx
2. 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