Plenary Coverage: ASCO Chief Medical Officer Dr. Richard L. Schilsky Discusses LBA2

Welcome to the ASCO Daily News Podcast. I'm Dr. Richard Schilsky, senior vice president and chief medical officer of ASCO. I am pleased to be joined by Dr. Christopher Sweeney, a medical oncologist and professor of medicine at Harvard Medical School and Dana Farber Cancer Institute. He presented abstract LBA2 entitled overall survival results of a phase three randomized trial of standard of care therapy with or without enzalutamide for metastatic hormone sensitive prostate cancer, the ENZAMET trial, an ANZUP led international cooperative group trial. Dr. Sweeney, welcome to the podcast.

Thank you for having me.

So testosterone suppression and androgen receptor blockade, of course, have been the cornerstone of treatment for men with advanced prostate cancer for many, many years. This large trial of men with metastatic hormone sensitive prostate cancer demonstrated an overall survival advantage by substituting enzalutamide for older androgen receptor blockers. Tell us more about how the patients did on this treatment.

Well, the first big line item to report is that men who got the drug enzalutamide, which, as you point out, is the more potent version of the way to block the androgen receptor than our old drugs, lived longer. In terms of relative risk, men had a 33% chance of being alive longer than men who got the older drugs. In terms of absolute numbers, 80% of men who got the early drug were alive at three years versus 72%.

What's buried in all those numbers, though, is that there are different patient populations. Patients who have a higher burden disease, have a faster progression, and, unfortunately, a shorter survival than men who have a lower burden of disease. With our previous iteration of this type of a trial in men starting hormones, we showed that docetaxel benefited patients who had high volume disease very clearly. And we could also see enzalutamide works just as well with docetaxel in that patient group.

On the other hand, men who had a low burden of disease, we didn't really see a benefit with chemotherapy docetaxel. But we did see a big benefit here in this study with using the hormone enzalutamide. So that now comes to the question, well, what about men who are treated with docetaxel? Did enzalutamide help them?

And we actually had a group of patients in this study who we can pull out and analyze separately. And we can see that the enzalutamide delayed the time to progression when it was added to the docetaxel. But at this early analysis, we don't see any meaningful impact in survival.

And that could well be because men who get the hormones and the docetaxel and then have the drugs, like enzalutamide, do just as well as getting all three drugs upfront, testosterone suppression, docetaxel, and the enzalutamide, do just as well as getting docetaxel, testosterone suppression, followed by enzalutamide. So it's a little bit of a parsing out of who the patients were and what treatments they get to work out how they actually fared.
Tell us a little bit more about enzalutamide. This is a drug that's already FDA approved. It's already in use for later lines of therapy. How does it differ from the earlier group of androgen receptor blockers? Do you attribute all of the benefits seen in the enzalutamide group to the drug itself, or were there differences in patient populations perhaps from groups studied with the earlier generation of androgen receptor blockers? It seems like a pretty substantial improvement just by swapping out a newer version of an old drug.

Yes, that's a very interesting observation. So the first notion is that the drug was tailored and designed by chemistry to be a much more potent version of the old drugs. So they're able to see the crystal structure of the androgen receptor and then do chemistry to say, how can we block that and shut that receptor down more efficiently?

What is unique about the trial design, because we ran this as an academic study, is that we incorporated in a control arm, every patient had to have one of the older less potent drugs as a control to really show that the more potent drug did actually have all the benefits and conferred the benefits over the older drug. So it wasn't versus a non-active placebo. So it's very clear as a direct more potent versus less potent drug, we had a survival benefit.
The other thing to note is that we had clues that this may work is because patients who have testosterone suppression and when their cancer progressed, they had an up regulation of the androgen receptor. So the cells say, help me, help me. I need more testosterone or testosterone like hormones to live. And it up regulates that receptor to survive. And it becomes a target that we can use.

Whereas the older drugs would be able to bind to it. But sometimes, they actually became agonists. They turned the receptor on rather than turning it off. Where this drug has complete antagonistic turning the receptor off properties. So it's really quite a clear more potent drug versus less potent drug leading to the survival benefit across both patients with a poor risk, higher volume disease and a lower risk, lower volume disease.

It's really interesting how understanding the structure of the androgen receptor and the chemistry of the drug really seems to have led to a very substantial improvement in patient outcomes. So this is a drug, as I mentioned earlier, that's already FDA approved, although in another line of therapy, but could potentially be substituted into routine clinical care immediately. Do you think the study results justify making that switch?

It's a very important question. So another way to phrase what you just said there, Rich, is we're seeing advances in advanced stage disease. And my mantra is let's go forward by moving backwards into the earliest stage disease where the patients are starting the hormone not when they're progressing on the testosterone suppression. So when they're starting the hormones, we actually see a survival benefit when we give it upfront.

That is a new indication. And so it will be up to the developer of the drug, which is both co-developed by a company called Pfizer and [INAUDIBLE], to present that to the FDA and see if it will get a label extension from the castration setting, resistance setting to the hormone sensitive setting. So that's a work in progress.

Now the important item is to recognize that to be able to access the drug, there's going to have to think through the side effect profile. And there are some side effects with regard to it can cause a little bit more fatigue, a little bit more impairing concentration because of the way it works. And some patients can feel a little bit more frail. So some patients have these side effects, and there have to be dose modifications.

So the risk and benefit profile has to be adjudicated. But by patients living longer and having their cancer controlled for longer, most patients do get a benefit. But the flip side is we also have to work out other alternatives. Docetaxel is an alternative for patients with high volume disease. Abiraterone is another drug that's approved in this setting, which is another different type of a hormone.

And when we write for these drugs, we have to adjudicate how much the patient is going to have to pay. Some patients, they have a copay of $5. Other patients, a copay of about $2,500, because these drugs are very expensive. And if patients have no insurance, the cost is close to $9,000.

So I think it is a very good option that will emerge. I suspect it will get approved. But when patients are counseled by their physicians on the options, they have to review the side effects, the benefits, as well as the financial access issues.

Yeah, very important points to bring up. So it always comes down to risks, benefits, and costs, and how that translates into access. So just to wrap up, obviously, prostate cancer is a very common disease. As our population continues to age, I think we can foresee that it may become even more common in the population.
What's on the horizon for prostate cancer research and treatment? This is a disease where there's been a considerable amount of progress has been made in recent years. But perhaps, there's going to be a growing medical need as the population continues to age.

So where do you see the future in prostate cancer research?

So the first thrust of work that I'm actively involved in and have engaged with collaborations around the globe to do more trials is to go even further back into the disease setting and augment the adjuvant therapy around the time of prostate radiation or prostate surgery to decrease the risk of relapse. So we have less patients who actually develop metastatic disease and die of the disease. So a lot of us are now getting very proactive in that setting.
The other setting is profiling the tumors to work out which patients would be better treated with our current chemotherapy, be it the hormones, be it the combination, as well as develop new drugs that target new targets that are identified. So early identification and more aggressive proactive treatment to prevent relapses. And if patients do relapse, interrogate the tumors more to get more informative data on how best to treat the patient with which new drugs that emerge.

So just along those lines actually, your comment prompted a thought. One of the other abstracts presented in the plenary session was about a PARP inhibitor for maintenance therapy in patients with pancreatic cancer, certainly a difficult disease to treat. There's been some preliminary evidence that PARP inhibitors may have activity in prostate cancer as well. Do you think that's going to be an emerging molecular target in prostate cancer?

I definitely think it will be. And to some degree, it already is a player. What we need to do is being conducted are the proper rigorous trials to work out, which is the genomic profile that of the DNA damage repaired defects in the genes like the BRCA2 gene you're referring to, that actually do portend a potential response. So we see that the DNA damage genes, response genes that may portend a response to a PARP inhibitor are about 20%. But maybe half of those are truly the genes that really are the responders, that define the responders.

And the question now is, of those particular genes that are refined, how many of those actually respond and how long? So we're seeing, I would say, responses of about 50% in that subgroup. So it is very much the notion of precision medicine, because it's the precise group of patients, which inherently is a small subset, but a subset that we can identify and potentially give a meaningful treatment with a reasonable side effect profile. So that data should emerge over the next 12 to 24 months, I think, based on the status of the trials.

Great. Thanks so much for giving us that little glimpse into the future. So again, today, my guest has been Dr. Christopher Sweeney from Harvard Medical School and Dana Farber Cancer Institute. Chris, thanks so much for being on the podcast today.

 
It was my honor.

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