Alicia Morgans: Hi, I'm so excited to be here today with Professor Pierre Blanchard, who is joining me from Gustave Roussy in Paris, France, and who also joined me recently at the APCCC 2024 in Lugano, Switzerland. Thank you so much for being here with me today.

Pierre Blanchard: Thank you for the invitation.

Alicia Morgans: Wonderful. So Pierre, you were able to teach all of us about testosterone recovery when we stop our treatments and really help us think more deeply about a topic that has been on top of mind recently, certainly on top of mind for patients forever, but something that we are recently readdressing and acknowledging may take longer than we expect. And that of course, there are complications with low testosterone when we don't want it to be so low. So I wonder if you can share some of the tidbits from your talk.

Pierre Blanchard: Very pleased to do so, and thank you again for the invitation. I'm very happy to be here and to share the talk that I've prepared for the APCCC about testosterone recovery and who is at risk for long-term non-recovery and what are the potential implications of that.

So we'll first discuss the timing of testosterone recovery after LHRH agonists or antagonists and see whether there is an impact of the addition of ARPI or abiraterone. And then see predictive factors of time to testosterone recovery, the impact of a longer time to recovery on patient quality of life and potentially on the tumor, and then briefly discuss testosterone replacement therapy.

So first, the agonists that have been studied in actually multiple studies, so I've just chosen a few of those. The one on the left by Spiegel et al. is a retrospective analysis of two institutions, but it clearly shows that the testosterone recovery here above 2.4 nanograms per mil after the last injection of ADT was roughly a year and a half for short-term ADT and 24 months for long-term ADT. So it's actually a very long time before testosterone is recovered to baseline value.

And on the right slide, you see a secondary analysis of a randomized trial where testosterone recovery was defined either as supra-castrate or full recovery. And you see that there is a delay between those two. But again, it's in the range of a year and a half. And that's from the initiation of ADT. So that's basically a year after the end of the theoretical end of treatment. And that's actually what happens with agonists.

And when we look at antagonists then it's much faster of course, and that's one of the benefits of those medications. So for degarelix, most of the patients, if you see on the left side after two injections of degarelix had recovered testosterone between three and six months after treatment. And on the right side, it's the well-known HERO trial that evaluated the oral relugolix. And you see that compared to leuprolide, patients who had stopped relugolix recovered their testosterone basically two months after the end of treatment. So there's a much faster recovery after antagonists. And it's also related to the formulation. If you take a monthly depot, it's faster than if it's a three-monthly or six-monthly treatment.

Another point that's important to bear in mind, and I would say probably many people don't know that, is that actually radiotherapy in itself can cause a decrease in testosterone, mostly related to low-dose radiation to the testicles. And here you can see that in this study more than 75% of the patients had any decrease in testosterone and 30% of them had a decrease of more than 50% in testosterone. And that was related to radiotherapy alone and no ADT. And that's also related to the field, the treatment field, pelvic nodal radiotherapy or not, and to the type of machines and margins that we use.

If you look at the literature that I have not shown you here is that when you look at the addition of ARPI or abiraterone to hormonal therapy, there is no major impact in terms of testosterone. And when you look at the trials that have used neoadjuvant, for example, dual androgen blockade.

So in conclusion about the first part, when you have testosterone recovery after agonists six to 24 months after the end of theoretical efficacy. For antagonists, it's faster, one to six months after the end of theoretical efficacy. There is no impact of concurrent abiraterone or ARPI. And radiotherapy by itself can lead to a testosterone decrease. Smaller in magnitude, but it can be significant clinically.

So what are the predictive factors of time to testosterone recovery? I've chosen three studies, but most of them are really consistent. The first one is the analysis, the retrospective analysis of two randomized trials from Canada. And what they've shown is the factors associated with a longer testosterone recovery were lower baseline testosterone, the age of a patient, the presence of diabetes, and the duration of ADT. And if you see here on the right side of the slide, the testosterone recovery according to the absence of ADT, that's the blue curve, six months of ADT green curve, and then the pink and red ones for 18 and 36 months. You see that the recovery starts later and that many of the patients who had longer duration of ADT never actually recover their testosterone. So that's very important and potentially very impactful for patients.

The second study is the study that I've already shown you by Spiegel et al. It's a retrospective two-institution study. And again, the factors that are involved here in terms of multivariate analysis for testosterone recovery are patient age, the duration of ADT, baseline testosterone, patient body mass index, and borderline significance for patient race.

The last study that was published this year in European Urology Open Science looked at a large population-based analysis of close to 4,000 patients. Patients that did not recover testosterone were older, had lower testosterone levels at baseline, were more likely to have diabetes, hyperlipidemia, hypertension, and less likely to have sexual dysfunction at baseline.

So what we see here is that those patients who are more frail, older, with longer duration of testosterone, face more difficulties and have a longer time to recovery, if ever they recover their testosterone. And does that have an impact? Yes, it does, because having a lower testosterone or having a longer time to testosterone recovery can lead, as the similar study that I've just quoted earlier showed, to risks of diabetes, depression, sexual dysfunction, and many other situations that can impact the patient’s quality of life.

What we also should bear in mind is that the studies that have shown the benefit of using ADT in combination, for example, with radiotherapy in localized disease, non-metastatic and locally advanced disease, all used LHRH agonists, most of them actually. And so the duration of castration should actually be considered as the real duration of castration and not the duration of prescription of the drug.

It's been studied whether a longer time to testosterone recovery could have an impact on the oncological evolution of the disease. This study by D'Amico et al., looking at a randomized trial and a secondary analysis of a randomized trial, actually showed that patients who had a longer time to testosterone recovery had a better overall survival than the other ones. So that's a bit provocative and it's not been replicated in many other studies, but when we want to shorten the duration of castration and have a faster testosterone recovery, we have to bear in mind that that could have implications on tumor control.

So in summary about the second part, the time to testosterone recovery is associated with patient age, baseline testosterone, ADT duration, and body mass index. A longer time to recovery impacts general health but may also improve DFS in patients without comorbidities.

And last, just one slide on testosterone replacement therapy because I think it's a topic that we do not address very frequently. These tables come from a review that's very clear and that I really encourage all the listeners to read. It's about how to initiate testosterone replacement therapy in patients with a treatment for prostate cancer.

First, all the studies are small cohorts. There's a low level of evidence. There is no indication of an increased risk of recurrence, but that should only be done in men with a proven testosterone deficiency and bothersome symptoms of hypogonadism. Shared decision-making here is paramount due to the theoretical risk of disease recurrence.

So in conclusion and take-home messages: Concomitant and adjuvant ADT improves survival in high-risk, localized prostate cancer. It's important to remember that most of the studies were done with GnRH agonists. Testosterone recovery is long and uncertain with GnRH agonists, but it's faster with antagonists. Time to testosterone recovery is associated with patient age, baseline testosterone, ADT duration, BMI, and comorbidities. The risk-benefit ratio needs to be discussed when planning testosterone replacement therapy, and careful PSA monitoring is required. Thank you for your attention.

Alicia Morgans: Thank you so much. That was fantastic and really quite a deep dive into the whole situation with testosterone recovery, so I appreciate that. I think one of the surprising things, at least from my perspective, was realizing that radiation alone can actually suppress testosterone levels. And I think that's probably something really important for patients to think about as well.

When you're in clinical practice, whether you're using radiation with hormonal suppression or just radiation, how do you use the information that you just presented? Do you change the conversation when you're talking to patients? Do you do testosterone replacement therapy? How does that affect your clinical practice?

Pierre Blanchard: So it does affect my clinical practice. First of all, I never tell a patient that the treatment will be just six months. I always tell them in theory it's six months, but we all know that it's going to be nine to 12 months at minimum. So I present them something that's more realistic than the theoretical duration. That's the first thing.

Then I also try to be clearer about what we call short ADT because six months is not very short, especially if you tell them that it's not going to be six months but closer to 12 months. I tell them it's short in comparison to longer-term ADT, for example, because the words are important. When you tell them short, it's something that they don't necessarily understand.

And then testosterone replacement therapy is something that we do, I would not say frequently, but on a regular basis to a patient who has stopped their ADT for a year, two years, three years, and does not show any sign of recovery and has bothersome symptoms.

So I usually send them to the endocrinologist for a general checkup, and then they do the replacement. It's usually using gels that they put on the skin and not injections. We monitor PSA a bit more frequently, as we also do for patients who just recovered their testosterone. We know that the PSA tends to rise at that time. So we tend to have more stringent monitoring during the beginning of testosterone replacement therapy. And we also check whether the patient has improvement in terms of quality of life. If he does and PSA doesn't move too much, then we keep doing that.

Alicia Morgans: Well, one of the other things that I think is interesting is the relationship between testosterone recovery and comorbidities. And so I wonder, do you advise patients to optimize their comorbidities and maintain weight control to try to support testosterone recovery? Is this a motivating factor perhaps as we counsel our patients on all of their medical conditions?

Pierre Blanchard: Indeed, it is. I think the most frequent advice that we give to the patient is to have physical activity, to exercise, and that has many, many important and positive impacts on their general health status, the comorbidities, and also potentially all the side effects from treatment. So that's something we do say very frequently.

Alicia Morgans: I do think that using that data and evidence to support that kind of an approach is absolutely something that will motivate my patients to get off the couch and start to exercise because everyone wants testosterone recovery when they're through.

And then the final question I'll ask is, do you in clinical practice have the opportunity to make decisions around using an agonist versus an antagonist? I don't know what the approvals necessarily are where you practice, and so maybe you don't, but is this strategy something that we think is helpful in terms of testosterone recovery and probably reasonably similar in terms of disease control? This is something that I remember talking about when some of these approvals first came out in the US several years ago.

Pierre Blanchard: Well, that's a trick question because we have all the agonists and antagonists approved in, I would say, most countries in Europe. And actually it's the case in France. So then the question comes back to what has been used during the trials, and most of those trials have been conducted with agonists. So I think that the use of antagonists is actually quite appealing in patients who would have a short-term ADT as it's really a six-month treatment, it's easier. But the approval is mostly for, as in the HERO trial, longer-term use of ADT, but it would be most beneficial in patients, I would say, with short-term duration of ADT.

And we also discussed the use of those antagonists in patients who have cardiac comorbidities because it may be a lower risk of cardiac events, although that's a little bit controversial. It's not completely obvious to me whether that really causes fewer cardiac events. But that's the two areas where we clearly favor antagonists over agonists.

Alicia Morgans: Yeah, my patients absolutely favor that, especially when, like you said, we have these defined durations and we're trying to get people back on track for the rest of their lives, so that makes sense.

Well, thank you so much for bringing us up to date on testosterone recovery. It is certainly important to all of us. We sincerely appreciate your time and expertise.

Pierre Blanchard: Thank you very much for the invitation.