How Testosterone Levels Inform Intermittent Androgen Deprivation Therapy (ADT)

[Dr. Aditya Bagrodia]
Where do you like to see their testosterone levels level out?

[Dr. Rana McKay]
Undetectable. [laughs] I hope to get it down low and patients always ask me this question,"Well, what about if we get it down to a certain level and whatever?" I'm like, "Everything that we do is to drive the levels even lower." What we measure in the blood is not even what is measured in the tumor.

Studies have actually demonstrated that the intraprostatic and intratumoral androgen levels are even higher than what they are in circulation. Even when the levels are undetectable in circulation, you can still detect potent androgens within the tumor. That's just my rationale to continue to drive the T levels as low as you can get them. When you're on therapy, you're on. When you're off therapy, you're off. Doing this halfway thing is not really constructive.

[Dr. Aditya Bagrodia]
Yes. It used to be less than 50, then less than 20, then it's basically undetectable. I think you hit the nail on the head. There's been just an explosion of medications really trying to eradicate any testosterone from any source beyond just the hypothalamic-pituitary testis axis. It segues into, so maybe for finite favorable risk, of course, there's counseling and it's like, "I’ve just got to get through this and you'll be fine." For the higher risk, it's a longer duration.

Maybe some of the metabolic elements become a little bit more front and center. Then there's you're in the long haul and whether that's going to be intermittent or continuous is very person-specific, disease state-specific, whether they're sensitive or resistant. Just talk a little bit about maybe how you think about continuous versus intermittent ADT when appropriate.

[Dr. Rana McKay]
Yes, very good question. I think certainly in the biochemical recurrent setting, that's where I'm thinking of more intermittent ADT. There's really no data to suggest that continuous ADT is associated with better outcomes, and it probably increases the risk of toxicity. Giving them opportunities where patients can have T recovery is critically key. I think in the metastatic setting, I think in general continuous, but there are caveats to that.

I think a lot of the caveats stem from what PSMA PET imaging has done in the field, what SABR has done in the field with regards to localized treatment for metastatic disease, particularly in individuals with oligometastatic disease.

I think we really challenged the paradigm a little bit in the metastatic setting for those patients that have low volume oligometastatic disease, actually giving more finite treatment and actually thinking about introducing a holiday if the primary has been treated, the metastatic foci have been treated and they've received intensified therapy. I think that's how I like to think about the continuous versus intermittent strategy.

[Dr. Aditya Bagrodia]
Intermittent, so you've got them on your ADT du jour, their castrate, their PSA is undetectable. Then, you decide to give them a little bit of a holiday. Can you talk a little bit about the triggers to get them back on treatment? Are they PSAs? Are they doubling time? Are they patient anxieties or provider anxiety? What does that look like?

[Dr. Rana McKay]
It's all the above and everybody is different. What I will say is you're never going to find in a textbook a number for which, yes, when you hit that number, go ahead and resume because everybody is different. I think it depends on what's their risk, their PSA kinetics, what's their rate of rise? What's their rate of rise in the context of what their testosterone is doing? Are they just rapidly rising because their testosterone is recovering and that's what's driving their doubling time or do they have a stable testosterone and they're rising?

What's the absolute number of the PSA? How did they do with hormone therapy before? Do they want to go back on hormone therapy? What does their PSMA PET scan shows when their PSA gets up to a certain level? I think it's all of these factors that will weigh in when is the right time and the right time is what's right for the patient, quite honestly. In the BCR setting, not to say you're treating a number, but you are. There's no clinical symptoms. They don't have metastases. You're trying to ward off the development of metastases and improve their longevity, but whether you start at three months or at six months or wait a little bit longer, there's no data to say that doing something one way versus another way improves outcomes.

[Dr. Aditya Bagrodia]
Yes, I couldn't agree more. There's people that really get taken for a ride with ADT. There's people that it's not so noticed. There's people that really are upset with PSA levels at various thresholds and there's people that are not. I agree it's individualized and like you said, earlier PSMA PET scanning has flipped everything on its head when it comes to detecting METs. I think this is a topic that can be reviewed enough.

I certainly learn plenty every time and I absolutely think that a lot of people, medical oncologists, radiation oncologists, urologists can safely and effectively prescribe ADT. It behooves us to stay up with it, make sure patients are well-informed and do everything we can at our end as well as the patient to help mitigate side effects.

Maybe as we're wrapping up here, Rana, any parting thoughts for the audience on how you approach ADT or things you're excited about in the future?

[Dr. Rana McKay]
No, very good. I think the way to approach it is to be systematic about it and provide education. I think, actually in communicating with patients about their different experiences when they started ADT, I think one of the biggest take-homes was everybody does it different, every doc does it different. There isn't a system. I think being a little bit more systematic about these are the options that you have and these are the side effects and just-- at our institution, at UCSD, we piloted together like an ADT order set. When you're going to start ADT, these are the things to think of, these are the labs to think of, this is the imaging, here's the teaching. I think that that really takes out a lot of bias from the process.

I think standardization is important and also seeing what the goals are for the patient and aligning with them is really key. I think what's really cool that's coming down the pike is, we continue to bat away at the androgen receptor in prostate cancer and I think the next generation of hormonal agents, we've got CYP11 inhibitors that now, the abiraterone, the CYP17 inhibitor box a little bit lower down in the adrenal hormonal axis.

MK-5684 is a CYP11 inhibitor that blocks even higher up preventing cholesterol from entering into the hormone production pathway and it can be associated with adrenal insufficiency type symptoms, so mineralocorticoid deficiency in addition to glucocorticoid deficiency. That is coming down the pike.

We've seen some pretty promising data. There's also AR degraders, AR protags, there are different kinds of ways to further block the androgen access. I think there's a lot of cool stuff coming down the pike that hopefully will enhance patient survival and not be associated with too much toxicity.