Bladder cancer continues to represent a significant challenge in the US, with an estimated 83,190 new cases in 2024 and growing costs of care.¹ For decades the backbone of bladder cancer treatment has revolved around bacillus Calmette-Guérin (BCG) followed by radical cystectomy for those found to have unresponsive disease. We now find ourselves at the precipice of an exciting era where we can offer several choices to delay or ultimately eliminate the need for radical cystectomy in a cohort of patients. Development of an effective, safe, and durable treatment remains a critically unmet need for this population. Due to the abundance of recent trials and approvals, we will focus on advancements in the nonmuscle-invasive disease space.

Approximately 80% of new bladder cancer diagnoses fall within this space and intermediate-/high-risk treatment begins with transurethral resection followed by BCG.² Recurrence rates remain substantial and up to 50% of those who initially respond will experience relapse.³ Ultimately 20% of patients with high-risk nonmuscle-invasive bladder cancer (NMIBC) will progress to muscle-invasive disease.⁴ These BCG-unresponsive patients traditionally have fallen into the decision between salvage intravesical treatments or radical cystectomy.

Table 1. Current Landscape of Treatments for Bacillus Calmette-Guérin–Unresponsive Nonmuscle-Invasive Bladder Cancer

Table 2. The Next Wave of Clinical Trials in Bladder Cancer

In the first wave of emerging treatments, pembrolizumab monotherapy received Food and Drug Administration approval in 2020 first showing efficacy in KEYNOTE-057, demonstrating 41% complete response (CR) at 3 months in BCG-unresponsive carcinoma in situ (CIS) patients.⁵ Another checkpoint inhibitor, atezolizumab, was investigated in SWOG S1605 and found to have a CR of 27% at 6 months, with 56% of the responses being durable to at least 12 months.⁶ While showing potential for significant clinical impact, the modest efficacy and significant adverse effect profile drove efforts to explore more localized agents that could reduce systemic effects.

This was followed by nadofaragene firadenovec, which is a recombinant adenovirus instilled intravesically that directly delivers interferon alfa-2b protein to urothelial cells, promoting oncolysis. A phase 3 trial (NCT 02773849) in patients with BCG-unresponsive CIS +/− papillary disease demonstrated a CR of 53.4% at 3 months, maintained in 45.5% of patients at 12 months.⁷

Cretostimogene grenadenorepvec (CG-0070) is another oncolytic immunotherapeutic that replicates in retinoblastoma gene pathway-defective cells, present in the majority of urothelial carcinoma. It is currently being investigated in several trials including PIVOT-006, BOND-003, and CORE-001. Preliminary data from BOND-003 were presented at AUA2024, showing that in BCG-unresponsive high-risk NMIBC, 75% of patients achieved CR, and 83% of responders maintained it at 12 months. It also highlighted the importance of multiple treatments on the adaptive immune response, as 54% of those who did not respond to the first treatment, responded to re-induction.⁸

Detalimogene voraplasmid (EG-70) is a novel nonviral intravesical gene therapy that activates a localized innate and adaptive immune response. Investigators boast its ease of use in the clinic space due its simplified preparation and handling. Interim data from the LEGEND phase 1 study were presented at AUA2024, showing CR of 73% at any time point. This study is currently enrolling into its phase 2 trial.⁹

Nogapendekin alfa inbakicept (N803) is another intravesical immunomodulator, acting as an interleukin-15 superagonist. The open-label QUILT 3.032 trial demonstrated a CR in 71% of CIS patients and 55% in papillary disease, with a median duration of response of 26.6 months¹⁰ in BCG-unresponsive patients.

While the above focused on alternative agents to BCG, there have also been efforts to improve delivery of intravesical therapies. The TAR device is a silicone drug delivery system allowing for intravesical release of a desired therapeutic for a period of 21 days, inserted via a catheter delivery system and removed using office cystoscopy. The TAR-200 system which delivers gemcitabine is being investigated in the SunRISe trials. As a monotherapy in BCG-unresponsive NMIBC, it showed a CR of 83%, with CR of 75.7% and 61.9% at 6 and 12 months, respectively (Table 1).¹¹ This system is being further evaluated in muscle-invasive bladder cancer patients undergoing trimodality therapy (SunRISe-2), BCG-naïve NMIBC (SunRISe-3), and neoadjuvantly for muscle-invasive bladder cancer patients not eligible for cisplatin (SunRISe-4).

Several promising local-acting agents target unique aspects of tumor biology, and with the ongoing investigations, the next 10 years have the potential to revolutionize the way we approach NMIBC (Table 2). It will be our role to further elucidate the sequence or combinations of these therapies that will prove most effective for our patients. At this time most outcomes have reported on immediate responses, and therefore the ability to demonstrate that these treatments can not only delay progression or recurrence, but ideally make it an artifact of history.