Charles Ryan: Hello from APCCC 2019. I'm joined by Gerhardt Attard from University College of London. Gert, great to talk to you again. You and I both, we've been thinking about abiraterone for a long time now. You presented yesterday a study that I think a lot of us were very interested in seeing, a very practical study on what is the optimal steroid and dose to give with abiraterone. This is probably one of the most commonly asked questions in all of castration-resistant prostate cancer management, I think in terms of the necessity of steroids, the dose, the timing, et cetera. And I think you went a long way towards answering those questions. Tell us what you did and what you found.

Gerhardt Attard: There probably isn't an optimal dose. But I guess, we generated the information to give physicians and patients an understanding of what the pros and cons of either the standard dose of five milligrams pred-BID is, versus lower steroid doses, five milligrams once daily. Which is the dose on label in the MHSBC in the hormone sensitive setting. Or 2.5 BID.

Charles Ryan: And one of the concerns, especially with the five daily dose is, especially in the HSPC setting, is that patients are going to be exposed to potentially a low dose of steroids and some of them may be sub-optimally dosed for a very long period of time. For those who are thinking about prescribing abiraterone in this space, what are the concerns that one might have? For example, if a patient is under dosed on a steroid, I think everybody's so worried about overdosing people on the steroids, but it's really under dosing that could be the problem.

Gerhardt Attard: Correct. The half life of pred is less than 16 hours. What will happen with the dose of once daily in some patients, not all, is that there is incomplete suppression of adrenal corticotrophic hormone and that drives the steroid biosynthesis pathway resulting in higher levels of mineralocorticoids, which increase the risk of a syndrome of mineralocorticoid excess. That, of course, manifests as hypokalemia, hypertension, fluid overload.

Now in our study, we presented the data using violin plots because it's high variability. Clearly not every patient who receives five once daily will have mineralocorticoid excess, but a higher proportion do, than when we use five milligrams BID. Of course, that comes with the benefit of fewer longterm physiological side effects. Primarily in body fat depositions we see much less longterm body fat deposition with five once daily. This is a balance and I am using five milligrams once daily. I think it's important the community understands that there is a risk of more mineralocorticoid excess than the five BID. And many of us have been using five BID for many years now and may have become complacent to some extent. We need to revise our endocrinology ...

Charles Ryan: It's a great point.

Gerhardt Attard: ... books and remember the risk is there.

Charles Ryan: Right. If you're prepared to monitor and adjust dose, five daily is perfectly acceptable. It's on label, but the monitoring needs to take place. And outside of the research context, we really don't measure mineralocorticoid levels. We simply follow for the syndrome as you said, of fluid overload or hyperkalemia and those types of things.

Gerhardt Attard: And blood pressures.

Charles Ryan: And blood pressure of course.

Gerhardt Attard: And potassium.

Charles Ryan: Right. You also did some interesting things with dexamethasone. It's a steroid that has been widely cited as having antitumor activity and we should also say that prednisone, even 10 milligrams of prednisone does have antitumor activity in the CRPC setting. Tell us what you found with dexamethasone and what your thoughts are on that particular agent.

Gerhardt Attard: We use a dose of dexamethasone 0.5 milligrams once daily. We've been interested in this dose for about 20 years and prior to abiraterone, we used to use dexamethasone as a single agent, 0.5 and then a Phase II randomized Phase II study Chris Parker had run, that showed that the 0.5 milligram dex dose, had more activity in terms of PSA declines than pred five (mg) BID. One of the arms in the study we recently reported, randomized patients to dex 0.5 milligrams once daily. In that arm we have excellent control of mineralocorticoid excess so it's effective at controlling the side effects of mineralocorticoid excess. It probably is also associated with more antitumor activity. We were not designed to compare the different doses but we see substantial response rates with dexamethasone. Close to 90% declines in PSA by 50% or greater. A longer time to progression-free survival.

And the correlative studies we performed suggest there is better suppression of androgens and their metabolites with dexamethasone. Probably because it's got a long half-life and there's a very potent glucocorticoid. That comes at a cost of more longterm physiological side effects. Greater rises in serum insulin, greater rises in HOMA-IR, a greater reduction in bone density, more fat deposition. In my practice I use five BID pred in the CRPC setting, five once daily in the HSPC setting. But for the majority of my patients, when PSA starts to rise, I switch the pred steroid dose to dexamethasone 0.5 milligrams once daily.

Charles Ryan: You maintain the abiraterone and switch to the steroid.

Gerhardt Attard: I maintain the abiraterone, correct. And switch the steroid. And we see responses in about 25% of patients. We've reported our retrospective analysis of this. There's a Phase II study run by a Spanish group, [inaudible 00:06:09]'s group, confirming those response rates. Really what we need ultimately is a randomized Phase II, dexa alone versus dex plus abit. But in the absence of that, I continue to perform the steroid switch. It's economical in terms of the change that's happening. Of course the abiraterone's continuing and as I said, I certainly see responses.

Charles Ryan: Right, great. Moving forward, your recommendation, I think you basically just told us how you practice, which is essentially the same thing I do. Five daily in the HSPC setting, five BID in the CRPC setting. I don't routinely use the dexamethasone as a switch, but I certainly do use it in patients with advanced disease. In many cases after exhausting other options. And I've seen anecdotally, very good responses in patients who are essentially refractory to other therapies. I agree that it would be nice for us to get some randomized data on that dexamethasone piece. It's all about a question of our clinical trial bandwidth, I suppose, at this point.

Gerhardt Attard: And priorities. I agree.

Charles Ryan: But anyway, congratulations and thank you for adding this meaningful dialogue to our field because it does, it is a very practical question that I get and I'm sure you get and it is a challenge for many clinicians around the world. Congratulations for helping us with that.

Gerhardt Attard: Thank you.

Charles Ryan: Thank you for joining me.