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Sam Chang: Hi, I am Sam Chang. I'm a urologist in Nashville, Tennessee, and we really have both the honor and the pleasure of having Dr. Stephen Williams. I've known Dr. Williams, who's the Chair of Urology at UTMB, for almost 10 years. He's going to give us an update on a trial in progress that was presented at the AUA in 2024, looking at one of the SunRISe trials from Johnson & Johnson. So Steve, thanks so much for spending some time with us and I look forward to your review of one of the ongoing trials.

Stephen Williams: So I want to thank everyone from UroToday, and Sam Chang's a dear friend of mine, so I'm always excited to spend some time with the team. Today I'll be presenting our SunRISe-2 trial, which is a phase three multicenter randomized study evaluating the efficacy of TAR-200 in combination with cetrelimab versus chemoradiotherapy in patients with muscle-invasive bladder cancer. I was really excited to present this data on behalf of my co-authors and the Janssen team in general. These are my disclosures. So, getting right into this, TAR-200 is designed to really address an unmet need in patients with muscle-invasive bladder cancer. As we know, muscle-invasive bladder cancer patients often have a poor prognosis and are at high risk of death. For patients ineligible for or refusing radical cystectomy, chemoradiotherapy is the recommended standard of care. Both chemoradiotherapy and radical cystectomy are associated with high treatment burden, toxicity, and impact on quality of life.

TAR-200 is an intravascular targeted releasing system designed for enabling the sustained release of gemcitabine into the bladder. This delivery system is an in-office procedure, which lasts approximately two to three minutes, and it uses a catheter to instill the device into the bladder. SunRISe-2 is a phase three clinical study designed to evaluate the efficacy and safety of intravascular TAR-200 plus cetrelimab, an investigational agent that is a PD-1 antibody, versus concurrent chemoradiotherapy in patients with muscle-invasive bladder cancer who are ineligible for or refuse radical cystectomy. As we described before, this is an open-label phase three study with inclusion criteria, as mentioned, for muscle-invasive bladder cancer. Those ineligible for or who refuse radical cystectomy must have an ECOG status of less than or equal to two, normal thyroid function, and adequate bone marrow, liver, and renal function.

Exclusion criteria include those with urothelial carcinoma or histological variant at any site outside of the urinary bladder, diffuse CIS based on cystoscopy and biopsy, evidence of clinical stage T4b or N1-3 disease, or M1 disease. In addition, bladder perforation during diagnostic cystoscopy, unless this is healed prior to randomization. Patients will be randomized, with a total of 550 patients, into one of two treatment groups. The first group is a TAR-200 intravascular agent, which is instilled every three weeks for the first 18 weeks and then from week 24 through year three, every 12 weeks, plus cetrelimab.

The second group includes those receiving chemoradiotherapy, which is the investigator's choice of chemotherapy, as well as the investigator's choice of radiation therapy, including conventional or hypofractionated. The primary endpoint will be bladder intact event-free survival, and secondary endpoints include metastasis-free survival, overall survival, overall response rate, and safety and tolerability. SunRISe-2 is currently open and enrolling patients. The SunRISe-2 study opened for enrollment on December 7, 2020, with 770 patients screened to date and 382 patients out of the 550 currently randomized as of April 24, 2024. SunRISe-2 is recruiting patients at 176 sites across 23 countries.

We are very excited that the primary completion is expected in December 2026. I'd like to thank the patients who are participating in the study, their families, the investigators, and clinical research staff from the study centers. Additionally, I would like to thank the AUA for allowing us to present this at the trials in progress, and the study and research team at Janssen as well. Thank you.

Sam Chang: Stephen, that was fantastic. And I'll be honest, I think this trial is not getting enough publicity, and that's one of the reasons why I wanted to highlight it because you are talking about a group of individuals, almost everybody is interested in not having their bladder removed, who are having some type of bladder preservation therapy. You're actually comparing that to a modality where there is no radiation given to these patients. You have an intravascular treatment and a systemic therapy. I want to ask you a question about the primary endpoint of bladder intact event-free survival. What is defined as an event? So a low-grade, non-invasive occurrence would not be an event, correct? What would be an event that would basically then say, "Okay, this is the point where we stop in these two arms"?

Stephen Williams: Certainly, and you're exactly right. So, stage progression to muscle-invasive bladder cancer, in addition to any nodal or metastatic disease, those that go on to radical cystectomy or definitive therapy, of course. Those tend to be the primary influences that we're looking for in bladder intact event-free survival.

Sam Chang: So, in my opinion, we're still a success if you have a patient with a non-invasive recurrence, so that would not count as an event in this study, correct?

Stephen Williams: Correct. Because really, and like you alluded to before, patients want to keep their bladders. The goal of this trial is to maintain that. And the thing I really am excited about as well, like you alluded to, that's all of our goal. Even though you and I take out bladders for a living most of the time, I'm excited about this and even tests. The prior research that I have done showing the unmet need really allows patients to then go on to get definitive therapy. As you and I both know, almost 50%, that's half of patients with muscle-invasive bladder cancer nationally do not undergo definitive therapy, whether that be radical cystectomy, trimodal therapy, or even just radiotherapy or chemotherapy. And that's really frightening because you and I at academic medical centers, before I did this research on a large scale, never understood the magnitude that patients are not receiving definitive therapy.

Sam Chang: Yeah, I mean, I think the words that you stated regarding the lack of definitive therapy given for many different reasons. I mean, you've done research on the disparity in care depending on location, socioeconomic standards, etc. When you look at these two arms, the reason why I'm so excited about this is you talked about the possibility of salvage therapy afterwards. And we all know, although there've been publications regarding salvage cystectomy not having higher complications, etc., etc., we all know that it is really not our preference to remove a bladder after radiation compared to before radiation.

So the possibility of actually... and I think it would be important to evaluate if bladders are removed in either arm of this study. I think there'll be a real difference in terms of possible complications, possible long-term sequelae in a group that had radiation versus a group that did not. So another reason why I find this really very much intriguing in terms of possible future modalities. When you look at this, tell me when you think the accrual is going to finish. You talked about the probable completion of the study at the end of next year. Is that completion of accrual, or is that actually the first readout you think will be available in a year and a half?

Stephen Williams: I know you're eager on this, so yes, I wish we could press the button and get to the final results. So, the primary completion is expected in 2026. What I am very excited about, though, is that we really surged and literally doubled our accrual or randomization of patients in a span of one year versus the last year prior. We hope to have our final enrollment by the end of this year. So, the primary completion of the study is December 2026. As you know, we need to meet certain criteria for events. And something also I pointed to or did not articulate well, bladder intact event-free survival also includes any cause of death. So that is an event we have to understand as a primary endpoint. But also, if patients are able to die with their bladder, and whether or not that's related to bladder cancer, that could be alluded to. I think that is critical.

So, I'm excited not only for the results of this study but really for informing us about bladder-sparing options in general and a new threshold that we need to hold ourselves all accountable for. And I know our European colleagues, I think the one thing I've learned through research is understanding each other. And I have had wonderful conversations with Nick James as well as a number of other thought leaders. We really treat patients differently, whether it be in the UK or in the United States. And I bet if we actually do tailor and offer patients bladder-sparing options that are comparable in oncologic and perhaps functional outcomes or even better, many would choose to have a bladder-sparing option. So I've taken my hat off as being a radical cystectomy-biased and just being maybe patient-biased to understand our patients better, and then hopefully help tailor regimens that provide the oncologic and functional outcomes they deserve.

Sam Chang: I think that's really important, and I think we are starting to get a better understanding of that in the US. I honestly think we're a little bit behind on that. There's no question that there are certain patients that would honestly do better with trimodality bladder-preserving type strategies, and there are definitely patients who really would benefit more probably from bladder removal. But being able to offer all those options, and perhaps now even another option, a combination of an intravesical agent with a novel targeted release system combined with systemic therapy, maybe we have yet another option that we'll be learning about in order to help treat these patients with muscle-invasive bladder cancer. So, Stephen, thank you so much for helping to present this study, and show us these options. We're quite excited to have the early readouts, and promise me that we'll be one of the first to hear from you regarding the primary outcomes here in a year and a half.

Stephen Williams: Well, you always will. And I think the friends here at UroToday have just done a phenomenal job of getting the news out really to all comers, not just academicians, but our community providers and our patients importantly. So, thank you so much for inviting me here this evening.