Bladder Cancer Podcast

Breaking Bladder Cancer Barriers: The Promise of Gene Therapy

Cheryl T. Lee, MD; Stephen A. Boorjian, MD


April 20, 2023

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.

Cheryl T. Lee, MD: Welcome to Medscape InDiscussion for season 2 of our bladder cancer series. I'm Cheryl Lee, and today we'll discuss the latest drug approved by the US Food & Drug Administration (FDA) for bacillus Calmette-Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer. I'm referring to nadofaragene firadenovec-vncg — trade name Adstiladrin. This agent, which was approved by the FDA on December 16, 2022, is the first gene therapy indicated for non–muscle-invasive disease. I'm sure our listeners have many questions about it. Why is this adenoviral vector-based therapy important? What is its mechanism of action? What are the associated complications? How does it compare with other agents on the market? To answer these questions, we're going to speak with Dr Steve Boorjian, one of the leaders of the clinical trial that demonstrated the efficacy of nadofaragene in a large cohort of patients. Dr Boorjian is the Carl Rosen Professor and Chair of the Department of Urology at the Mayo Clinic, where he also directs the Urologic Oncology Fellowship Program. Dr Boorjian is a true thought leader in the field of bladder cancer. He previously served as a member of the National Comprehensive Cancer Network (NCCN) Guidelines Panel for Bladder Cancer, has served on the American Urological Association (AUA) Non-Muscle Invasive Bladder Cancer Guidelines panel, co-chaired the AUA Microhematuria Guideline panel, and is a leader in the Society of Urologic Oncology Clinical Trials Consortium (SUO-CTC). Welcome, Steve. It's great to have you here.

Stephen A. Boorjian, MD: Thank you, Dr Lee. It's an honor to be here, and I look forward to our discussion together.

Lee: Fantastic. Why don't we jump right in. You've done important work evaluating clinical outcomes in populations with cancers of the prostate, kidney, and bladder. I'm curious to know more about your preclinical research in bladder cancer and how that ultimately steered you toward clinical trials.

Boorjian: I got interested in bladder cancer as a resident under the mentorship of Dr Douglas Scherr at Cornell and had the opportunity during my research time as a resident to study steroid receptors in bladder cancer, answering questions such as, why do men get bladder cancer more frequently than women? It was through studying the preclinical mechanisms of bladder cancer development, thinking about how we might design clinical trials in bladder cancer to prevent disease recurrence, that I began to develop an interest in clinical trial development. I then, as you mentioned, did clinical work in outcomes research in bladder cancer and saw the morbidity that can be associated with surgical resection of bladder cancer — specifically, with a radical cystectomy. That really intensified my interest in helping to look for alternative therapies to radical cystectomy for patients with non–muscle-invasive disease.

Lee: This is an incredible story and journey you've been on, and you've had an amazing impact on the field. We're all grateful that you have the interest you do in the study of bladder cancer. Gene therapies have been tested for other solid tumors for quite some time — for decades. What do you think made this gene therapy successful? Why is it so important right now, in the context of the BCG shortages that we've all experienced, and the race to develop more intravesical agents?

Boorjian: This therapy was the marriage of a preexisting treatment for bladder cancer, which was the protein interferon. This treatment had demonstrated some efficacy when put inside the bladder, but largely due to the limited dwell time and the exposure of the interferon protein to the bladder tumor cells, it ultimately did not pan out as an effective treatment choice. But under the guidance and expertise of Dr Colin Dinney at MD Anderson — who is really the person to be credited with the development of nadofaragene, which has been a passion and a brainchild of his — we looked at changing from developing the protein as the treatment of choice to developing a gene vector. The concept is that the bladder can be turned into an interferon bioreactor. The incremental difference of this gene therapy over others is it's locally delivered — it's easily delivered by putting a catheter into the bladder, putting the medicine inside the bladder, and then allowing the gene to transfuse into the bladder cells. In fact, nadofaragene contains an excipient — Syn3 — which enhances the ability of the adenoviral vector to enter bladder cells and then turn the bladder into a high-interferon, locally interferon-producing organ. As far as why this is important right now, our options for patients after BCG are quite limited. Our guidelines tell us that cystectomy is the gold standard for these patients, but there are many patients who are either unwilling to undergo cystectomy and its attendant morbidity or are unable to undergo cystectomy because of medical comorbidities. So, the approval of a new option in this setting is quite exciting — particularly for our patients going forward.

Lee: Yes, you really touched on some important points. As someone who's been taking care of bladder cancer patients for a couple of decades or more, it is important to note that although we have a definitive therapy for BCG-unresponsive disease, such as cystectomy — which is highly effective but with many quality-of-life concerns for patients, and as you noted, since many patients really are not surgical candidates and others are really just committed to bladder preservation — these novel therapies are critical. We are in a period in which we're seeing a lot of development.

We have this new agent, and I think we all want to credit Colin Dinney for his lifetime of work to create an agent that is making it to patients. So, maybe you could tell us a little bit about how the trial came about, how the SUO-CTC was involved, and some of the critical findings of that trial, which ultimately led to FDA approval.

Boorjian: This drug development represented what many of us hope to be a model partnership between academia and pharma. Specifically, the SUO-CTC was the partner for the FKD Therapies pharma company that helped to develop this agent. At each step, these two moved together. So, in terms of how the agent was tested, it was first tested in a phase 1 study to demonstrate safety and give a preliminary signal of its efficacy. Then, a phase 2, open-label, randomized study of two different doses was conducted. The phase 2 study showed that 35% of patients were high-grade recurrence-free at 12 months after treatment. Those were generally patients who had received considerable amounts of BCG.

That led to the phase 3 study, and this study was done in partnership with the FDA as well as with direct guidance from the FDA in terms of how the trial was designed. It was designed as a single-arm, phase 3 study, which is a little bit unique largely because of the absence of comparator treatments in this disease space. It was a single-arm, phase 3, multicenter study across 33 centers in patients with BCG-unresponsive non–muscle-invasive disease. They had received adequate BCG and were assessed as not being eligible or likely to benefit from additional BCG therapy. Patients were treated with an intravesical one-time dose that could be repeated at 3-month intervals if the patients remained free of high-grade recurrence. The primary outcome of the study was to evaluate the complete response rate among those patients with carcinoma in situ (CIS) — so, BCG-unresponsive CIS. Ultimately, in terms of the primary endpoint and the main take-home findings from this study, it demonstrated that the complete response rate among patients with BCG-unresponsive CIS was 53%, which was exciting to see as an efficacy endpoint for these patients. The study did include a variety of secondary endpoints, but in terms of main take-homes, it was really the response rate in those CIS patients.

Lee: We should put that in context for our audience — 53% recurrence-free survival or high-grade recurrence-free survival at 12 months is unheard of in BCG-unresponsive patients who have been previously treated. The FDA had approved valrubicin many years ago for patients who had BCG-refractory disease. My recollection is that those patients had a recurrence-free survival of something like 8% or 10% at a couple of years. So, quite a bit different, quite a bit lower — just to give our audience the sense of the excitement that the clinical trialists felt when they were able to observe this type of result.

Boorjian: Yes.

Lee: We heard a little bit about the cancer outcome side of it, but for patients and for those delivering the agents, we really need to think about toxicity and adverse events. That's something that I'm sure everyone is always concerned about with a newer agent with which many of us may not have had experience. Can you talk a little bit about some of the toxicity that you observed in the study?

Boorjian: We looked at safety and toxicity from a couple of different angles in reporting the trial results. One of the things we looked at was the rate of disease progression during the time of treatment. We wanted to make sure we weren't allowing patients to progress during treatment. What we found was that the progression rate to muscle-invasive disease was only 5%, which for this high-risk population we felt would not put patients at significantly undue or increased adverse risk. In terms of the specific toxicities, the vast majority of adverse events that were experienced by patients were irritative lower urinary tract symptoms, which I think are likely to be expected from both the catheterization procedure, as well as the instillation of a medication within the bladder. There were only 2% of patients in whom a treatment-emergent adverse event led to discontinuation of the study drug. There were only 2% of patients who had what would be considered a serious drug- or procedure-related adverse event, and there were no deaths due to treatment-related adverse events. In general, we would say this medication had a very favorable safety and toxicity profile. I would also say that when we're thinking about where this fits in this disease space for patients, an intravesical vs an intravenous mechanism of delivery is also quite patient-friendly.

Lee: Yes, I think it's doctor-friendly, too.

Boorjian: Yes.

Lee: It's something that, as a field, we're very comfortable doing — using systemic therapy. Certainly, many groups are delivering systemic therapy to their patients, but it has a different workflow. Having an intravesical agent is ideal. Hopefully that reduces some of the systemic side effects that may be appreciated. Can you talk about the schedule of delivery of the agent? I don't know if we had a chance to touch base on that, because I think that is also something favorable.

Boorjian: I think it's particularly favorable both for clinicians and for patients. The schedule of delivery is once every 3 months. For those patients who remain high-grade recurrence-free, it can be given at 2- to 3-month intervals. I would say that particularly in the era in which we live now — in which we're looking to minimize encounters; minimize the financial toxicity that patients experience with time away from work and repeated office visits; and minimize the impact on their caregivers and other issues, such as when people need to make appointments — this is very favorable. This is a relatively lower-touch kind of interaction that I think is very favorable and puts this agent in a very favorable position in the disease space.

Lee: I couldn't agree more. I think many people are super-excited about this drug and are really interested in using it. I personally have several patients whom I want this drug for now, but it's not readily accessible despite its FDA approval. I don't know if you know anything about that, but I think there are people who have patients with BCG-unresponsive disease who refuse cystectomy and are looking to be treated with this agent immediately. What do you know about the accessibility of the drug?

Boorjian: Yes, I'm getting two to three emails per week about it. I hear you. It's an interesting story. When the trial was completed and published in 2021, it initiated the FDA formal review for this. In that, the next step was developing manufacturing processes. That's really what's been going on from that time. Then, as you mentioned before, in December 2022, the FDA did approve the medication, which was in large part based on the review as well, not only of the safety and efficacy data that you and I just discussed but also the manufacturing process behind that. My understanding now is that Ferring, which has taken over this agent, is targeting this for later this year to be able to be released. I anticipate that in the coming months, we're going to learn quite a bit more about the specifics of the agent and about how we access it. I share your excitement about it and enthusiasm for it. I also have patients who are asking about it as well. Right now, it is my understanding from Ferring that it's 2023 that's being targeted.

Lee: Well, we'll all be anxiously waiting. We have covered a lot of ground. What are a few key takeaways that we want our listeners to consider before we log off?

Boorjian: I want to start by thanking you for having me here. It's been fun and an honor to be part of this podcast. What we have is a new medication, a new class of medication, a medication that has demonstrated very exciting efficacy in terms of successive treatment with a highly favorable safety and toxicity profile for patients. It's a new option in a disease space in which, for decades, we've had relatively limited options to offer patients. As we concluded with discussing, it's also associated with a very favorable timing and dosing schedule. I'm excited to see this move forward over the rest of 2023.

Lee: This has been fantastic talking about our continued journey to curing bladder cancer at some point. For now, we will await yet another agent that will hopefully improve the lives of our patients. I want to thank everyone for listening to our conversation with Dr Steve Boorjian. This is the first episode in the second season of our bladder cancer series. There's much more ahead in the coming episodes. So, be sure to check out the Medscape app and share, save, and subscribe if you've enjoyed this podcast. I'm Cheryl Lee for Medscape InDiscussion.

Listen to additional seasons of this podcast.


Adstiladrin [prescribing information]

Diagnosis and Treatment of Non-muscle Invasive Bladder Cancer: AUA/SUO Guideline (2020)

Enhancement of Intravesical Delivery With Syn3 Potentiates Interferon-alpha2b Gene Therapy for Superficial Bladder Cancer

Radical Cystectomy Is the Treatment of Choice for Invasive Bladder Cancer

Phase I Trial of Intravesical Recombinant Adenovirus Mediated Interferon-α2b Formulated in Syn3 for Bacillus Calmette-Guérin Failures in Nonmuscle Invasive Bladder Cancer

Intravesical rAd–IFNa/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin–Refractory or Relapsed Non–Muscle-Invasive Bladder Cancer: A Phase II Randomized Study

Intravesical Nadofaragene Firadenovec Gene Therapy for BCG-unresponsive Non-muscle-invasive Bladder Cancer: A Single-arm, Open-Label, Repeat-dose Clinical Trial

ADSTILADRIN (=INSTILADRIN) in Patients With High Grade, Bacillus Calmette-Guerin (BCG) Unresponsive Non-muscle Invasive Bladder Cancer (NMIBC)

Use of Intravesical Valrubicin in Clinical Practice for Treatment of Nonmuscle-invasive Bladder Cancer, Including Carcinoma In Situ of the Bladder

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