Apalutamide holds potential in NMIBC, expert says

In this interview, Edward M. Messing, MD, discusses the study, “A Randomized Trial of Apalutamide in Non-Muscle Invasive Bladder Cancer (NCI INT 22-09-01)*,” which was highlighted at the 2024 American Urological Association Annual Meeting in San Antonio, Texas. Messing is a urologist at the University of Rochester Medical Center in New York.

Edward M. Messing, MD

Could you describe the background for this study?

Bladder cancer is a common malignancy. It's the second most common urologic malignancy and the first most common urinary tract malignancy. There will be 83,000 new cases this year in the US. The majority of these are low-grade, non-muscle invading tumors. They themselves are not that dangerous, but they could grow and bleed and do all sorts of bad things. If you leave them alone, they'll cause trouble, so you have to treat them. This contributes greatly to bladder cancer being one of the most, if not the most, expensive malignancies to treat over a patient's lifetime.

It's a disease that's primarily a male disease. It's a 3:1 or 4:1 ratio, really all over the world, men to women. Bladder cancer has been thought to be a disease related to exposures to chemicals and things like that. Men used to be much more smokers than women, now it's evened out a little, but even with equal exposures to potential carcinogens, the 3:1 or 4:1 ratio persists, implying that sex hormones or their receptors or both have some role to play in this disease. The receptor for testosterone, the androgen receptor, is found throughout the urothelium, particularly for people with low-grade tumors.

There's a lot of evidence from animal models, carcinogen-induced tumors, rodents, and epidemiological data of men who have prostate cancer who are treated with treatments that lower testosterone or block the androgen receptor [showing that] they get less bladder cancer. So, there's a lot of evidence to point to the androgen receptor being an important player in at least developing this disease. The androgen receptor is what's called a transcription factor. What it means is that when activated, it will bind with androgen response elements in the promoting regions of target genes, and it either turns on or turns off expression of those genes. One of the genes that's an example of it turning on is the expression of PSA. There are some other genes that are not so important in bladder cancer, but that it could turn on and off.

Apalutamide, which is the agent we're going to use, is something called an anti-androgen. It binds with the ligand binding portion of the androgen receptor, where testosterone binds, with great affinity, more than almost any other anti-androgens. Opposed to other anti-androgens, it binds only to the androgen receptor. It won't bind to similar chemicals inside our body like the estrogen receptor, progesterone receptor, or other steroid hormone receptors. And often the anti-androgens, at least the older generation of anti-androgens, will become ineffective, because the androgen receptor as its increased expression, the antagonist activity in the anti-androgens would actually become paradoxically agonists and turn on the androgen receptor. Apalutamide doesn't do that. So, it's a potentially good drug to use to fight the androgen receptor.

Could you expand on the design of this study?

The National Cancer Institute (NCI) said they'd fund a true prevention study, or something called a secondary prevention study, of men with low grade bladder cancer who have been treated and have a very high chance of recovering to see if this anti-androgen would reduce the chances. So, that's the important clinical study. In order to do that, they said you have to do a proof of principle study first.

So, this is a proof of principle. We are looking at apalutamide reducing the expression of another androgen response to target gene, the receptor for something called epidermal growth factor. So, epidermal growth factor is present in all of us. It's excreted in the urine in all human beings in very high concentrations in a biologically active form, having the opportunity to bathe with the urothelium because it sits in our bladder unaltered for hours at a time and then we urinate it out. Then more comes down from the kidneys. The receptor for epidermal growth factor is normally not present on the outer surface of urothelial cells; it's only on the inner surface. That's probably a protective mechanism, because otherwise the cells would divide like crazy all the time. When you get a bladder cancer and the receptor changes its expression, it's expressed on every single cell layer of the urothelium and throughout the tumor. That's true with low-grade tumors and high-grade tumors, and increased expression is associated with a higher risk of bladder cancer recurring. The EGF receptor is an androgen responsive gene.

The purpose of the study is primarily to see if these men who are taking apalutamide–and they'll be randomized, so half will be taking a placebo– can reduce the expression of the EGF receptor in the 3-4 weeks between the time of cystoscope where you see a tumor in the bladder and the time you remove the tumor, which is the TURBT. We're trying to be as quantitative as we can. So, we are looking at the expression of the EGF receptor gene by RT-PCR, reverse transcription-polymerase chain reaction. It's a way to look for messenger RNA. We're going to do that in the patients who are taking apalutamide and the placebo group. The thought is that apalutamide will reduce the expression of the EGF receptor. If it successfully could do that, then hopefully it will prevent bladder cancer and the NCI will let us do a real clinical trial. That's the sum and substance of this study. There are other molecular things we're looking for, but that's the real purpose of it.

Could you expand on the unmet needs in bladder cancer that this study could address?

The biggest unmet need is that this disease is very common. Patients spend a lot of time and money being treated for it. Even if they have full health insurance, they still spent a lot of money because they have to travel to the doctor, they have to travel back and forth, have to take time off from work, or they have to ask their kids to take them. Most of the people with bladder cancer are my age; I'm 77. So, I'm a little above the median age now for it, but close. It's a very inconvenient disease, let alone if it gets much more serious. The idea is that this will reduce the likelihood of the disease recurring. The study I talked about is just the preliminary point to try to do the larger study to see if it really works. It's a preventative study. There's a lot of theoretical reasons why it should.

What efficacy and safety data has been observed with apalutamide to date?

Well, they've not been in bladder; they've all been in prostate. It's a well-known anti-androgen. The primary treatment for metastatic prostate cancer is to stop the production of testosterone. Traditionally that was by removing the testicles, but thankfully that's not done as often anymore. So, it's by giving medicines that stop the production of testosterone. Prostate cancer is an extraordinarily androgen responsive disease; the prostate stands still when that happens even in widely metastatic disease. In numerous circumstances, apalutamide, when combined with castrative therapies, makes those castrative therapies more effective. Patients live longer if they're on apalutamide and medicines that stop testosterone production than if they're on placebos and medicines that stopped testosterone production. There are several huge randomized trials that indicate their efficacy. It also helps extend the life or prevent people from getting metastases in people who've been treated for prostate cancer and their PSA is rising very rapidly. If you give them apalutamide and an LHRH agonist or antagonist that stops the testosterone production, they’ll do much better than if you just give the testosterone stopping therapy. So, it's known in prostate cancer to be very effective in that regard.

Right now, there are some studies testing it somewhat earlier in the disease, but those results are not yet known. It's known to generally be safe. There are certain medications that apalutamide can cause seizures in or facilitate seizures getting worse. So, in this study, patients with seizures will not be able to be part of the study, but that's relatively rare. Otherwise, quite a safe drug, and its side effects are known. The major side effects would be that because testosterone is being removed, the patients, if they are still sexually potent or have a strong desire or have a very reasonable libido, it may be dropped a little bit. It won't be eliminated, but it may be affected. Occasionally it can cause breast tenderness, but that's very rare. So, it's a safe drug.