The ‘Bar Is High’ to Usurp BCG, but Novel Therapies Could Drive Change in Bladder Cancer Management

Within the past 5 years, the bladder cancer space has seen significant shifts, including several FDA approvals and trials showcasing recent developments, improving response rates and durability, and safety, according to Bogdana Schmidt, MD, MPH.

Additionally, coming off the heels of the 2025 AUA Annual Meeting, a variety of trials were presented on novel therapies, such as the phase 2 SunRISe-1 trial (NCT04640623) evaluating TAR-200 monotherapy, which demonstrated a complete response of 82.4% (95% CI, 72.6%-89.8%) in patients with BCG-unresponsive, high-risk non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without papillary tumors, who are ineligible or refuse radical cystectomy.¹

“We recently had the AUA [Annual] Meeting, and there have been updates for a couple treatments. The SunRISe-1 trial was presented, which [evaluated] gemcitabine released in a device form [called TAR-200], and it is administered intravesically every 3 weeks,” Schmidt said in an interview with OncLive® during Bladder Cancer Awareness Month, observed in May. “There are going to be other companies that have drugs in [the BCG-naive] space as well, looking to improve upon BCG, but we're already seeing that the bar is pretty high, so we're all going to be pretty picky about these data.”

During the interview, Schmidt discussed FDA-approved bladder-sparing therapies in BCG-refractory NMIBC and how they fit into the treatment paradigm; emphasized how minimally invasive and robotic approaches have shaped the bladder cancer landscape; and current shifts in the BCG-naive space.

Schmidt is an associate professor in the Division of Urology at the University of Utah Huntsman Cancer Institute in Salt Lake City. In a previous article, Schmidt discussed the role of BCG in bladder cancer and how to navigate BCG shortages.

OncLive: What are the current FDA-approved bladder-sparing therapies, and how do these fit into the treatment paradigm in BCG-refractory NMIBC?

Schmidt: [Among bladder-sparing treatments] that are FDA approved in the BCG-refractory space, pembrolizumab [Keytruda] was the first one approved [in January 2020], and that [therapy is] very familiar to medical oncologists. It had some initial promise and [was initially] very exciting, especially for patients who have quite bad urinary symptoms where they worried about putting more intravesical treatments in the bladder. [Pembrolizumab] bypasses the intravesical lower urinary tract adverse effects [AEs]. Unfortunately, pembrolizumab does have some systemic AEs that you have to be really careful about in this comorbid patient population. It's great that [pembrolizumab is an option]; it really was the first drug approved in the space, but as a monotherapy, it didn't take off as everyone's first choice.

Then, nadofaragene firadenovec-vncg [Adstiladrin] was approved [in December 2022], and it was the first intravesical gene therapy approved in this space. One of the real benefits of this drug is that it is delivered intravesically once every 3 months, and therefore, the patients’ burden is not as significant compared with the schedules that have patients coming in [for multiple visits at different time points]. This is just 1 intravesical treatment every 3 months, which is quite lovely.

Nogapendekin alfa inbakicept-pmln (Anktiva) plus BCG was approved [in April 2024]. That is an IL-15 super agonist that’s co-administered with BCG, and it ramps up the response to BCG in this patient population. The challenge with this one, up until very recently, has been the BCG shortage. You have to co-administer it with BCG. If you don't have BCG, it's hard to use this regimen right now. They're currently working on providing recombinant BCG with it, which [could] increase the uptake of this treatment.

The phase 3 BOND trial [NCT04452591] was also presented [at the AUA Annual Meeting, which evaluated cretostimogene grenadenorepvec (CG0070)]. This was more of a traditional intravesical administration, so via catheter in the clinic, the same way as BCG is administered. It also demonstrated an excellent anytime complete response [rate] at 75.5% [95% CI, 66.3%-83.2%].² One of the highlights of this agent is its incredible tolerability. It was well tolerated by patients, with no grade 4 or 5 [treatment-related AEs] and minimal grade 3 AEs.

How have minimally invasive and robotic modalities continued to shape the treatment paradigm?

[These modalities] help our patients recover faster. There was a randomized trial published a couple of years ago that demonstrated an improvement in overall survival for patients who get a robotic cystectomy. This was based on a decreased risk of death, which most people think is attributable to blood clots because maybe patients are moving around a little bit more and better after robotic surgery. It's not based on oncologic principles that were better [following robotic surgery], but I think from a recovery standpoint, maybe it's a little bit easier on patients. That's the first data we've had in the bladder cancer space that showed a real improvement in using robotic technologies.

We also had a great clinical trial read out a couple years ago—the [phase 3] SWOG S1011 trial [NCT01224665]—looking at the lymph node dissections in bladder cancer. We used to do very extended lymph node dissections because we had a lot of retrospective data showing that if there was a benefit to removing more lymph nodes, maybe we could cure more patients with more extensive dissection. This randomized trial demonstrated that we were wrong. [We learned] that a thorough but anatomically standard template dissection was better than the extended node dissection because it had less morbidity. Patients had fewer blood clots in that space, but it did not really change cancer outcomes. Therefore, we're studying more in this space and learning things that are changing our practice, which is always so important.

How have shifts in the BCG-naive space helped improve outcomes?

The BCG-naive space is growing; the BCG-refractory space has some approvals, but there are now trials looking at agents going head-to-head with BCG, and this is the first time that we've had anything in this space. At the AUA Annual Meeting, the [phase 3] CREST trial [NCT04165317] was presented, which is looking at sasanlimab plus BCG vs BCG alone, and this is the first time they added a systemic PD-1 inhibitor to an intravesical treatment in the BCG-naive space.³

It had very interesting findings. It showed that BCG was quite good, which we already knew. It demonstrated, in a very nice way, that the bar is very high in the space because BCG is a very effective treatment. It also showed that BCG maintenance is very important. You can't just do the first 6 weeks of BCG; it requires the maintenance phase to go out for several years. It also showed that, with the addition of other agents to BCG, we can [obtain better outcomes].

Overall, this was a positive trial, as it also showed that the sasanlimab addition improved upon the reduction of recurrences in BCG-naive disease. Still, it comes at a cost with systemic AEs. Nevertheless, this space will continue to grow. The SunRISe team has trials in this space as well for BCG-naive disease assessing TAR-200 that should read out shortly.

References

1. Johnson & Johnson’s TAR-200 monotherapy demonstrates highest complete response rate with sustained clinical benefits in patients with certain types of bladder cancer. News release. Johnson & Johnson. April 26, 2025. Accessed May 19, 2025. https://www.jnj.com/media-center/press-releases/johnson-johnsons-tar-200-monotherapy-demonstrates-highest-complete-response-rate-with-sustained-clinical-benefits-in-patients-with-certain-types-of-bladder-cancer
2. Tyson M. BOND-003 cohort C- a phase-3, single-arm study of intravesical cretostimogene grenadenorepvec for high-risk BCG-unresponsive NMIBC with CIS. Presented at: American Urological Association Annual Congress; April 26-29, 2025; Las Vegas, NV. P2s.
3. Shore ND, Powles T, Bedke J, et al. Sasanlimab in combination with Bacillus Calmette-Guérin improves event-free survival versus Bacillus Calmette-Guérin as standard of care in high-risk non–muscle-invasive bladder cancer: Phase 3 CREST study results. Presented at: 2025 AUA Annual Meeting; April 26-29, 2025; Las Vegas, NV.