Experts share insights on next-generation NMIBC therapies

Joshua J. Meeks, MD, PhD

On April 28, 2025, in Las Vegas, Nevada, Urology Times® hosted a Clinical Forum program on the topic of bladder-preserving innovations and next-generation therapies for non–muscle invasive bladder cancer (NMIBC). The forum was moderated by Joshua J. Meeks, MD, PhD, the Edward M. Schaeffer, MD, PhD Professor of Urology and associate professor of urology, biochemistry, and molecular genetics at Northwestern University Feinberg School of Medicine in Chicago, Illinois. What follows is a summary of the discussion.

This summary was generated by artificial intelligence and edited by humans for clarity.

The roundtable discussion provided an in-depth overview of current and emerging strategies for managing NMIBC, particularly in patients who are unresponsive to BCG. The participants recognized that the field is rapidly evolving, with ongoing clinical trials and the development of novel therapies aimed at expanding bladder-preservation options and improving patient outcomes. The traditional standard of care for high-risk NMIBC refractory to BCG has been radical cystectomy; however, there has been a notable shift toward exploring bladder-sparing treatments, especially given the limitations related to surgical morbidity, patient preferences, and resource constraints.

One of the core issues discussed revolved around the definition of BCG unresponsiveness. There is ongoing debate about how many BCG doses constitute failure and whether specific recurrences or persistent disease should prompt progression directly to alternative therapies. Such definitional ambiguities influence clinical decision-making and enrollment criteria for clinical trials, affecting the selection of appropriate interventions and the interpretation of results. A consistent framework for identifying BCG-unresponsive disease remains a significant need within the field.

In terms of intravesical treatments, TAR-200 was highlighted as a promising candidate. This sustained-release delivery system aims to provide continuous intravesical chemotherapy, potentially reducing the frequency of re-transurethral resection of the bladder tumor procedures and improving treatment adherence. The panel emphasized that TAR-200 could serve as an effective maintenance therapy, especially during a period of BCG shortages and logistical challenges that compromise current treatment paradigms. Its scalability and manufacturing capabilities were seen as potential advantages, making it a candidate for broader clinical application, particularly during maintenance phases post-initial therapy.

Beyond intravesical therapies, systemic immunotherapies are gaining momentum. Pembrolizumab (Keytruda), a PD-1 checkpoint inhibitor, has shown activity in high-risk and BCG-unresponsive NMIBC, with early-phase trials demonstrating durable responses. Participants discussed trials such as KEYNOTE-676 (NCT03711032), which compared pembrolizumab plus BCG v BCG alone. The familiarity with managing immune-related adverse events is increasing within urology practices, and integrating these agents into earlier treatment lines could significantly alter future standards. However, practical issues such as adverse event management and insurance reimbursement remain barriers to widespread adoption.

Nadofaragene firadenovec (Adstiladrin) is another treatment discussed by the panel. It is an intravesical gene therapy delivering interferon directly into the bladder lining, aiming to stimulate local immune responses against tumor cells. The participants recognized that nadofaragene firadenovec has shown promise in clinical trials as an alternative for patients who have failed BCG, potentially serving as a bladder-preserving option. Nevertheless, its adoption is affected by institutional costs and logistical considerations, such as the need for specific investments from health care providers, which may limit its availability in some settings.

Alongside these therapies, the panel discussed nogapendekin alfa inbakicept-pmln (NAI, Anktiva), which involves intravesical administration of a CpG oligonucleotide designed to activate innate immune pathways within the bladder. Although data on Anktiva are still emerging, its mechanism offers an immunostimulatory approach that could complement other treatments or serve as a maintenance option, especially in CIS or high-grade papillary disease. The discussion noted that the logistical and systemic considerations for using NAI will influence its future role in NMIBC management, but it remains a promising novel immunotherapy.

Most experts agreed that clinical trials are crucial for optimizing treatment pathways. There was a consensus that ongoing trials are broadening the therapeutic landscape and provide the necessary evidence to refine indications for each agent. These studies include combinations of systemic immunotherapy with intravesical agents, long-term maintenance strategies with sustained-release formulations like TAR-200, and novel gene therapies such as nadofaragene firadenovec. Their goal is to find effective bladder-sparing treatments that can delay or prevent cystectomy, maintain quality of life, and reduce health care resource utilization.

Operational challenges and health care logistics were also emphasized. Managing adverse events related to immunotherapies, ensuring patient adherence, and coordinating surveillance protocols are resource-intensive activities. The panel acknowledged that resource limitations, especially in community settings, influence the feasibility of adopting new therapies. Insurance reimbursement and systemic support are critical factors—without adequate coverage, even promising treatments like pembrolizumab, NAI, or nadofaragene firadenovec face significant barriers to widespread use. As systemic therapies become integrated into practice, it is expected that urologists will need to develop expertise in their administration and toxicity management.

The discussion also underscored the importance of aligning treatment strategies with robust clinical trial data. Several speakers emphasized that many of these novel agents are still under investigation, and their optimal placement within treatment algorithms remains to be definitively established. The panel advocated for collaborative efforts to develop standardized treatment pathways, independent of pharmaceutical influences, that include sequencing of therapies based on patient characteristics and disease progression.

In conclusion, the participants reinforced that the landscape of NMIBC treatment is shifting from a reliance on immediate cystectomy toward bladder-sparing approaches supported by innovative therapies. Intravesical sustained-release chemotherapies like TAR-200, systemic immunotherapies such as pembrolizumab, and local gene therapies including nadofaragene firadenovec and emerging agents like NAI, all have the potential to change practice. These advances hinge on the completion and publication of ongoing clinical trials, the development of clear definitions for BCG unresponsiveness, and addressing systemic and operational barriers. The aim is to expand effective options for patients, reduce invasive procedures, and optimize resource utilization—all within a framework guided by solid clinical evidence.