Apalutamide for Preventing Bladder Cancer Recurrence: A Proof-of-Principle Trial - Edward Messing

June 5, 2024

Sam Chang interviews Edward Messing about his research on using apalutamide for non-muscle invasive bladder cancer. Dr. Messing discusses a trial aiming to explore whether antiandrogens like apalutamide can prevent bladder cancer recurrence, given its higher prevalence in men. This molecular proof-of-principle study, sponsored by the National Cancer Institute, focuses on the role of androgen receptors and the EGF receptor in tumor recurrence. Positive results from this trial could lead to larger chemoprevention studies, potentially offering a new strategy for bladder cancer treatment.

Biographies:

Edward Messing, MD, FACS, Urologist, Professor of Urology and Oncology, University of Rochester Medical Center, Rochester, NY

Sam S. Chang, MD, MBA, Urologist, Patricia and Rodes Hart Professor of Urologic Surgery, Vanderbilt University Medical Center, Chief Surgical Officer, Vanderbilt-Ingram Cancer Center Nashville, TN


Read the Full Video Transcript

Sam Chang: Hello, my name is Sam Chang. I'm a urologist at Vanderbilt University. And we really have a great honor today to have Dr. Ed Messing from the University of Rochester. Dr. Messing is the past Chair there, and the past President of the AUA. And he has always been a real leader in terms of different types of research associated with urothelial carcinoma, going back from evaluation of hematuria and screening to ongoing clinical trials, looking at intravesical therapy. Most recently, he presented at the 2024 AUA, a trial in progress, looking at an agent called apalutamide in non-muscle invasive bladder cancer.

So Dr. Messing, first of all, thank you for spending some time here on UroToday, but also, I look forward to seeing what your inquisitive mind continues to be looking into.

Edward Messing: Well, this is a study, we'll go through it in a minute, but this is a study which is trying to look at the fact that since bladder cancer is a male disease, it's not really only men of course who get it, women get it too, but it's far more prevalent in men than women. And to see if using an antiandrogen could actually be effective in prevention, or secondary prevention of bladder cancer. That's the ultimate goal, having a trial to see if people who take this antiandrogen can have a reduced likelihood of recurrence after a TURBT.

The National Cancer Institute required us to do a preliminary study first, and that's what we're doing. It's a molecular study. So this is a proof of principle trial that is being conducted and sponsored by the Chemoprevention branch of the National Cancer Institute. And it's being run through something called the University of Wisconsin's Chemoprevention Cancer Consortium.

And these are various players on it. The names that you know are urologists who are taking part at these institutions, and then myself at the University of Rochester. Howard Bailey is the head of the Wisconsin's Chemoprevention Task Force, and Howard Parnes is the Chief of the Chemoprevention branch at the NCI.

So the background is that, as you know better than anyone, Sam, bladder cancer is a common disease, and the majority of those tumors initially diagnosed are low-grade non-muscle-invading tumors. And these recur quite frequently, requiring us to cystoscope the patients often, and take people to the operating room and so on. Contributed greatly to bladder cancer being one of the most expensive cancers to treat over the lifetime of patients.

As you also know, men are three or four times more likely to get bladder cancer than women, and this is true around the world. And while some of this may have been that men in the male workplace would have a higher chance of being exposed to carcinogens, with equal carcinogen exposure, smoking, and so on, women have, again, the three to four to one ratio still exists, implying that something more is involved. And one of the things is very likely sex hormones in their receptors. The receptor for testosterone, the androgen receptor is expressed in normal urothelium in most people, but particularly those patients who have low-grade tumors that expressed to the tumors as well. Actually, more than in high-grade tumors.

And there's a lot of evidence that, experimental evidence that androgens in the AR play a role in developing bladder cancer. These include models, carcinogen-induced tumors in rodents, and epidemiological studies of men with prostate cancer on androgen deprivation therapy, or antiandrogens, have lower incidences of getting bladder cancer. The androgen receptor is something called the transcription factor that binds to androgen response elements in the promoting regions of target genes. And that turns off or turns on the expression of those genes that the androgen receptor controls.

Apalutamide is a potent antiandrogen. It binds with the ligand binding portion of the androgen receptor. That's where testosterone binds with great affinity. It's specific for the androgen receptor, as opposed to other antiandrogens. And even with over-expression of the androgen receptor, maintains an antagonistic activity. That's one of the ways that earlier antiandrogens became ineffective in prostate cancer. As a matter of fact, there's something called the Casodex withdrawal effect, because bicalutamide would be withdrawn from patients that suddenly it had turned out to be an agonist rather than an antagonist with up expression of the androgen receptor.

In any case, the androgen target gene we're looking for in this proof of principle study is a receptor for epidermal growth factor. It's also a receptor for other EGF-like molecules transforming growth factor alpha, because EGF is excreted in the urine in very high concentrations in a biologically active form. That's how it was first identified and purified. And Vanderbilt has a connection to that as well, Stanley Cohen.

The phosphorylated form of the EGF receptor is the activated form, but EGF expression, in normal cases it is expressed to the urothelium, but it's expressed only on the basal layer of cells. So the cells don't come in contact with this very potent ligand. In cancers, it becomes expressed on every single cell in the cancer, and every single cell in the urothelium as well, both neighboring and remote to it. And I'm going to show you a... I do this because I took this photomicrograph, so I was proud of it. But this is the ureter, and the EGF receptor is expressed only on the basal layer of cells. This is actually a patient I operated on because he had TB of the ureter. So even in inflammatory of the kidney and even in inflammatory diseases, it's not expressed on the more luminal parts of the cell. In any case, it's also, there's a lot of evidence that higher expression of the EGF receptor is associated with a higher likelihood of tumor recurrences.

Another androgen response gene that we'll be looking at, more or less as a molecular control, is ADAR2, which is an RNA editing protein. Its expression is inhibited by the androgen receptor. So if you turn off the receptor, you should have increased expression of the ADAR2 and serve as molecular control.

So the proposed trial is to take men, biological males. That's, I guess, the appropriate term now. Because apalutamide is not approved in women, it's not been studied actually, with suspected low or lower to intermediate risk urothelial cancer at office cystoscopy. So they could have been people who had prior tumors, or they can be people who were presenting the first time with hematuria or other reasons to cystoscope then. And if you see a tumor in the bladder, they'll be randomized, if they agree to take part, to three to four weeks of either the apalutamide or a placebo, we don't know which one, it's blinded. And of course, that's the time it takes usually to go from cysto in the office to get the case available in the OR.

Both at the office cysto and then at the TUR we'll be collecting urine for a variety of features, including immunocytology. Some immune factors, which Deb Sundi at Ohio State is going to look at, both cytokines and immune cell populations. And we got Pacific Edge to support giving us Cxbladder. So we'll look at the RNAs that are used in this test to identify bladder CaPs to see if any are upregulated or downregulated by the androgen receptor.

And then the patients will go to TURBT. They will get urine and cytology again. The tumor will be resected, but we'll also do biopsies, cold-cup biopsies of the area adjacent to the tumor, both from the tumor, the tumor itself, and then do a variety of studies on those, which are explained here, and then go to the TURBT. And there's a lot of evidence that about 80% of the time you sort of know whether it's low grade or high grade, and you're correct.

The primary hypothesis is that in the apalutamide group, there'll be reduced expression of the EGF receptor in the biopsy from adjacent urothelium. We're doing a variety of things when you do a cold-cup biopsy, you sometimes get contamination by the aminopropyl, which doesn't have the EGF receptor, so we're controlling for that molecularly.

Secondary hypotheses are that the AR suppression in the apalutamide group will correlate with reduced EGFR expression in patients whose tissues express the AR, because not every single person has it in their urothelium. The placebo controls will be used to see if AR expression correlates with EGFR expression in those not receiving apalutamide. And the molecular control, we expect that those on apalutamide should have increased expression of ADAR2.

And from this, we hopefully will find out if it's a successful study, whether we can then get in a larger chemoprevention study. AR-negative subjects could be involved as well. Because the secondary prevention in bladder cancer means that you take the tumor out and then you're doing something to prevent them from getting another tumor. Not the immediate postoperative gemcitabine or intravesical therapy, but something else. And that they take chronically to prevent the new tumor from developing. And so that's the point of that.

The participants will have suspected lower or low to intermediate risk bladder cancer. They need to have sterile urine, which is not a surprise, that's not. And the other criteria are all seen here. The major thing is, they need to have at least a normal testosterone level. The exclusion criteria, the major one to know about, are some medicines that increase the risk of seizures with apalutamide, and it's in the package insert, so I didn't memorize those. But those are the major things. And hopefully, we'll be able to prove for this, that patients will be willing to take it for three or four weeks, and we can find out if it really does what it's supposed to do, so we could do the major chemoprevention study.

Sam Chang: So Ed, first of all, thanks for the shout-out to Dr. Cohen and his work with EGFR. He has a warm place in our hearts in Vanderbilt. It's one of our-

Edward Messing: Absolutely.

Sam Chang: Yeah, one of our Nobel Prize laureates here.

Edward Messing: Absolutely.

Sam Chang: Was a wonderful man. Wonderful man. I was wondering, when you look at this, first of all, incredibly to me, exciting in terms of the possibility of impacting the natural history of non-muscle invasive bladder cancer. Let's say for instance, you don't get a strong signal, a change, either in your expression, or perhaps not affecting the second, the ADAR2. Say there's not as strong a signal. Would you go back and lengthen the time of exposure? Would you switch the patient population that you're looking at that may have more of the original FGFR? If it doesn't show a signal, is that it? Or do you think you go back?

Edward Messing: Well, from the HCI's point of view, that might be it, which is an unfortunate state of affairs. I think that from the point of view of studying this, there are other obvious, we're going to get a lot of RNA. And there are a lot of other, I mean, before we do a second study, there are a lot of other molecules we could look at that are relevant to both bladder cancer and androgen functioning. I cannot imagine that apalutamide won't affect the ADAR2. That is, it's sort of been well worked out that it will do that in a variety of tissues. So I'd be very surprised if it didn't here. I'd also be surprised if it wasn't a positive study for the EGF receptor, but that can be trickier.

But we have a lot of RNA that we'll be getting at, so we could look at other molecules, I think, before starting another study, or having longer duration. I would do that.

And I might add that with apalutamide, there were studies that were done in chemoprevention of prostate cancer, where clearly it has an effect. The androgen receptor has an obvious effect on PSA expression. And within two weeks, the PSA goes to the floor in a normal individual, with a normal male on apalutamide. So I think it should have an effect, if this was a reasonable thing to do.

Sam Chang: And then in terms of the numbers, you've listed the size with great individuals obviously that are going to be actively interested. Are we looking at, I didn't see the targeted number of enrollment. Are we looking for 100? Are we looking for-

Edward Messing: No, no. It is going to be 40 in each arm. Because it is under the presumption that doing this will result in decreased expression for the EGF receptor. And certainly in cell lines, and I've done this in the lab before, stopping the androgen receptor in any way you want will result in reduced expression of the EGF receptor. The statistics for this were based on the assumption that it will likely work. How much exactly is unclear because not every single individual has androgen receptor in their tissue. But it was felt that that would be enough. And this was a big long negotiation with statisticians at Wisconsin and the NCI. So it's a small proof of principle study.

Sam Chang: All right.

Edward Messing: The bigger study will need about 100 people in each arm if it's going to be carried out.

Sam Chang: Okay. So loaded question, don't want to put you on the spot. Millions have been bet and lost on different types of preventive trials, but, say that there's a positive signal in terms of impact on the EGFR as well as on ADAR2, in terms of increased expression, all the things that you expect to see. In your 40 arm trials, and then you perhaps expand it a bit, and you see a positive response. What then next? You would obviously need a large, large trial. What do you envision? I guess it's a loaded question in terms of what do you envision next, but then, what do you envision the primary endpoint being? Disease-free survival. Obviously, it can't be just the change in the markers, it would have to be achieved.

Edward Messing: No, no, no, no, absolutely not. In a larger study, which is a true chemoprevention study, it would be reducing, the people would stay on apalutamide for a year or two years, it depends. Toxicity is an issue with this as well. It's a safe drug in men with advanced metastatic prostate cancer, or already on androgen deprivation therapy, taking an antiandrogen isn't a big deal, but in someone who isn't on that, it can be. So toxicity will be a major thing that we're going to be looking at as well. Although short-term toxicity may not be the same as long term.

But all that said, the purpose would be secondary prevention. The idea would be taking this for at least a year if they had, after resection of a low-grade tumor, and see if it prevented its recurrence? And as I said, the statisticians have gone through this, looking at the likelihood of recurrence and so on, and that study needs 100 to 120 in each arm. If it does what it's supposed to do. It probably won't reduce recurrences to zero, but it would lower them substantially enough that it would be positive.

The question would be, if it was, then would men be willing to take this drug if they had low-grade bladder cancer to prevent a recurrence? And toxicity, and maybe expense, will be the two issues that are separate. I mean, by the time the true secondary chemoprevention trial is over, it may be off patent. I don't know. But I think that that would be the reason. And I think that Janssen is interested in expanding into other markets. So there, they would probably be interested in supporting this.

Sam Chang: Well, Ed, thanks so much for spending some time with us. And more importantly, thank you for years of effort in research and evaluation, diagnosis, screening and therapy for urethral carcinomas and other cancers. We're all indebted to you, and thanks for spending some time with us.

Edward Messing: Well, thank you for having me. I appreciate it, and I'll see you soon.

Sam Chang: Sounds great.