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Alicia Morgans: Hi, I'm so excited to be talking today with Dr. Tanya Dorff, and we're going to be talking about one of the interesting and somewhat controversial presentations and sessions at GU ASCO 2023 where we really learned about testosterone suppression, testosterone recovery, intermittent versus continuous therapy with ADT. Lots to discuss, lots of things we do all the time in practice that sort of seem to come to new light in this particular session. So tell me a little bit about it.

Tanya Dorff: Yes, Dr. Nabid presented a very interesting analysis looking at a large set of patients treated on two different clinical trials of radiation therapy plus different durations of androgen deprivation. So there was six months of androgen deprivation and in the second trial there were 18 months versus 36 months. So what he showed that was really surprising was with six months of ADT, 75% of men recovered normal testosterone levels, but the median time to recovery was 18 months. And then even more surprising perhaps, with 18 months of ADT, only a quarter of men actually recovered to normal levels and the average time was out as far as five years. So I think this is really important for us when we're talking to our patients about side effects of ADT, how long they may last and will they recover their testosterone and if so when?

Alicia Morgans: I agree. And it also I think put some of the radiation ADT trials in a different light in my mind at least, that the expected duration of testosterone suppression and the magnitude of benefit that we imagine with 18 months, with 24 months, it actually might be lifelong castration that's providing some of that benefit, which is a very different decision I think for patients.

Tanya Dorff: It is, and it raises real questions in the setting where we now have these antagonists, LH-RH antagonists like Degarelix and Relugolix where testosterone recovery may be quicker. And we have to think whether six months of ADT with one of these newer drugs is the same as six months of ADT with an LH-RH antagonist or agonist rather.

Alicia Morgans: Absolutely. And also if we might perhaps be better being honest with our patients to say, "Well, we're going to keep going with the drugs for six months, but you're actually not going to have testosterone recovery for a year and a half." So really being much clearer about that, "We're not talking about six months here, we're talking about at least a year, maybe a year and a half," would be more honest.

Tanya Dorff: And then the question was raised, can we help patients who are suffering with ongoing side effects, especially given that we now see some men really don't recover their testosterone? So that question about testosterone replacement was raised, and of course this has been very taboo and yet it's an important question for survivorship. So Shalender Bhasin at Harvard has a study ongoing in prostate cancer survivors who have cleared enough time that we're pretty sure they're cured. Although it's hard in prostate cancer, you have to wait a long time to know whether someone's been cured and randomly assigning them to testosterone replacement or not in patients who are hypogonadal and symptomatic, that's the only reason to do it in my view, is if someone's really having quality of life compromise or health compromise related.

And it's a little bit scary. We know testosterone feeds cancer and yet if there's no cancer then testosterone should be safe if there's nothing to feed. But until we have those data, I'm sure there are physicians out there giving testosterone replacement and they can't really counsel their patients with data until a study like that is actually done.

Alicia Morgans: I would agree. And you know what? I think it's important for us to remember, there are side effects of testosterone suppression that are symptomatic. Of course we all know about hot flashes, fatigue, weight gain, and these kinds of things. Weight gain, not necessarily being a symptom, but something that a patient at least notices. But some of the metabolic changes that happen in a setting of hypogonadism, including insulin insensitivity and cholesterol effects are not things that one would necessarily feel, but are absolutely still affecting the patient in terms of their cardiovascular risk due to their hypogonadism. So I do think certainly we start with a symptomatic population because I completely agree with something that is so controversial. We need to ensure that patients have a patient directed reason to get into a study like that. But if it seems to be safe in those patients, extrapolating that out to a population that is maybe less symptomatic, minimally symptomatic, but still might have the effects from cardiovascular events related to hypogonadism would be, I think, of importance.

Tanya Dorff: Exactly. And then the question arose, as we're treating patients more effectively in the metastatic setting where we are using lifelong castration, how do those other factors, those cardio metabolic risks that you were just talking about and quality of life as well, how do we tell our patients castration lifelong is the only answer without newer updated data about whether treatment holidays, or an intermittent approach could be safe and feasible. I mean, our data are really 93/46, the SWOG study, which used monotherapy, and that was a very different approach. We're now doing treatment to the primary, sometimes metastasis directed therapy, doublets, triplets. We're probably getting our patients into deeper remissions. And so that question of whether a treatment holiday would be possible will be really important to answer, given that they're going to live so much longer and have a longer time to be exposed to these risks of ADT.

Alicia Morgans: Absolutely. There's a really interesting alliance study actually, where if patients are able to achieve very low levels of PSA in the metastatic setting, they're trying to stop androgen deprivation therapy, and I think it's called the I DREAM study, but it will be really interesting to see if we are able to get people into those deep remissions, maybe even to no evidence of disease, perhaps even eradicating disease, who knows with some of the multi modality therapies that we can provide? And maybe this will be an opportunity to and a moment in time when we can accept the opportunity to change from everything, always, all at once forever, to backing off when we might have an opportunity to deescalate.

So really such interesting questions and an interesting time, and I so appreciate you taking the time to raise this session and this conversation for us to consider today. Thank you so much for your time and your expertise.

Tanya Dorff: My pleasure.