Jaime Landman: It’s Jaime Landman from the EAU 2019 in beautiful Barcelona. And today I have the great privilege of being with a close friend, colleague and a partner from UCI, Dr. Thomas Ahlering. TA is the Vice Chair, a world-renowned recognized leader in prostate cancer. And I think he shocked me here at the EAU, so, TA, we have been taught or I have always thought that in the setting of prostate cancer, testosterone is a big no-no. I’m going to kill my patient. The testosterone is going to go wild. And then suddenly there are four abstracts here that contradict my thinking. Can you straighten this out for me?

Thomas Ahlering: Well, it’s been an interesting trail, but yes, our findings seem to suggest exactly that. The question is why did we even consider testosterone? And it was about 2007, 2008, 2009, I recognized that there seemed to be like ether in the air, my patients weren’t recovering sexual functions. It had been that way for years. But I couldn’t quite nail it down and I just thought, “Maybe it’s testosterone” so I talked to Dr. Goldstein, who’s in sexual medicine, and he suggested that we do testosterone levels on every patient and he actually implied that I should’ve been doing it for a period of time.

And he really made a strong point that we should do the free testosterone, which is calculated from the sex hormone binding globulin. So starting in 2009 we did. And we mainly did it because in low-risk patients we wanted to see if we could safely administer testosterone to help them in the recovery of sexual function. We finally got our data together and the funding to move along with the study. And the results that we were looking to see, and we were pretty sure we were not going to see increase symptoms. That was the main thing that we wanted to do, that it was safe to apply testosterone to patients in the postoperative period in low-risk patients with a nondetectable PSA.

And we did find that. But more importantly, we found out that they had a decreased incidence of recurrence, so the biochemical recurrence rate was reduced. We wanted to make certain that we were looking at the right groups, so we did a matched analysis working closely with our statistical team. We did lots of different analyses, but we ended up matching for grade and for stage, which are the two most important predictors of biochemical recurrence. We had about 450 men in the control group and we had 152 as I said in the treatment group. And the biochemical recurrence rate was reduced by 53%. The other thing that we found is that in men who are destined to have a recurrence, it delayed the recurrence by about 1.5 years or 18 months.

It’s just counter to what most people would think in some regards. The longer we’ve been with this though, it’s been quite clear in the postoperative period, men are at increased risk of biochemical recurrence with increased weight, obesity, things of that nature. And in fact, we have another protocol looking at diet and exercise, nothing to do with testosterone. And we could demonstrate a slowing or even reduction of PSA just by diet and exercise. The logic in our mind is that in this part of the cancer’s history, in the long lead up period to metastatic disease, testosterone is actually a much more favorable aspect in the disease progression than it is once it becomes metastatic. Of course, once it’s metastatic, we have to eliminate testosterone. But in the lead-up period, which is probably 95% of the disease period, it looks like testosterone is a good thing, not a bad thing.

Jaime Landman: It’s totally shocking so if the initial finding was because you were looking for functional results and indeed you correlated the low testosterone or free testosterone levels I should say, with poor functional results. But in the end, you actually found improved oncologic outcomes.

Thomas Ahlering: Yes.

Jaime Landman: With higher free testosterone levels so that’s a little bit mind-blowing in the setting of years of thinking that that would be the opposite. You said that that was in low-risk patients, your initial findings, have you tried that in higher-risk patients or is that still a taboo?

Thomas Ahlering: Well, as time went along and we had patients get further out, we would move up to four plus three disease, four plus four as long as their PSA was not detectable.

Jaime Landman: And have you found the same improved functional and oncological-

Thomas Ahlering: Well, they’re included in our study to date. Do we know about the higher-risk patients specifically? No, we don’t have enough of those patients. We know that they didn’t explode up, let’s put it that way. But is it a benefit to them? Well, that’ll take more study with much higher numbers.

Jaime Landman: You’ll take a look at that subgroup down the line.

Thomas Ahlering: Yes. Well, and we’re going to move to randomized trials and we’ll stepwise increase the grade as we get more confirmation of the safety. Because testosterone is still contraindicated in the diagnosis of prostate cancer. Now, we’re comfortable. We’ve been okay because these men had their prostate removed, they’ve had their prostate cancer removed so it’s not like we’re dealing with men with prostate cancer. But it’s been used in men with prostate cancer too. Dr. Morgantaler at Harvard has treated men on active surveillance and hypogonadism without any evidence to date of a significant progression as well so there’s a lot of other supporting data that this is very much indeed the case that testosterone and low testosterone is not good in prostate cancer, it’s bad.

Jaime Landman: Really your data is extremely convincing and you did yours under IRB-approved protocol and I know that you have an extraordinary database. I’ve actually never seen anyone who keeps quite the quality of data that you do. Being that you have great quality data at this point, what would you say to the average urologist who’s out there, does a prostatectomy, has a low-risk patient, negative margins now no evidence of disease, would you recommend that they check free testosterone and supplement if the patient has a diminished testosterone level?

Thomas Ahlering: In the face of reduced sexual function, I certainly think it’s something that they should consider. I mean of course, every urologist has to be comfortable with their decision. It was worrisome for me at the beginning, but I gave patients a book to read that really explained the controversy about testosterone and where a lot of the thinking may be inappropriate, so the patients, it’s important to inform the patients, make sure that they’re aware, but hopefully within the next two to three years we’ll be able to see if we can get this as a much more state-of-the-art, maybe into guidelines and things of that nature. But I do think that in other abstracts we have at this meeting, we’ve got a very clear relationship that as the free testosterone levels go down, it’s an inverse relationship with the grade. The grade goes up. And even more importantly, if you look at testosterone over the course of the man’s life, we’d looked at 900 men, we know that the total testosterone doesn’t go down much.

Everyone thinks the testosterone goes down. It doesn’t go down much, maybe 1% but what happens is the SHBG goes up by about a two-fold and the free testosterone goes down about 50%, almost 50% from the 40s to their late 70s. That’s an important factor to know. It should be just like PSA as far as I’m concerned that if we were to say one thing, we should be following testosterone levels as closely as we do the PSA.

Jaime Landman: And again, you mean free testosterone because that’s the key metric there?

Thomas Ahlering: Right. And again, the free testosterone is calculated so you have to draw a total testosterone and SHBG so you get all of them. But yes, the one that you’re really monitoring is that. And then in the patients that are having sexual dysfunction, at the bare minimum, those should be treated and maybe even some of the guys who just have low free testosterone should have it because we’ve never really tested.

If a guy comes in at three months and says, “Well, my sexual function is largely recovered. My functionality is 90% or 85%.” We really didn’t … We’re not going to fix that problem per se, but we may be wrong. Number one, it’s not that it’s a problem, but we could make it better. And it may last quite a bit longer too. That’s what our data is showing as well. Not all men suffer once their free testosterone gets to the bottom 15% from sexual dysfunction, but some do. You have to kind of weigh the whole scene which is low free testosterone and the symptoms. But we’re going to look further into men without the complaints of the sexual function at all actually and just treat the free testosterone because of the biochemical recurrence issue.

Jaime Landman: That was actually my next question because when I asked you if you’d use it, you said for men with erectile dysfunction, yes. And now you’re saying that you might even consider those patients who have a decent sexual function or reasonable sexual function after the operation just for the biochemical recurrence so that’s amazing.

Thomas Ahlering: Well, I think our study is going to include all men with a free testosterone, irrespective of sexual function because of that risk. And we’re going to probably … We’re not sure where we’ll start. We’ll do power analysis and things of that nature. But we’re probably the bottom 20% but you could see with the argument being carried up to the median, it might be important to treat all of the men below the median or even higher. We don’t know. Because again, when we look at the benefit, we also … One of our abstracts at the meeting is that free testosterone does protect the recovery of sexual function. And the other finding is that the higher the free testosterone goes, the lower the grade. The higher the free testosterone goes, the better the sexual function.

It’s not like there’s a bell curve where it gets the free testosterone goes up and it starts getting bad. It doesn’t. It’s just like the higher it goes, the better off you are. The logic would say in the beginning we want to be the most careful, but as time goes along, we want to start exploring throughout the whole spectrum.

Jaime Landman: I think that we’ll end with that, but it is utterly remarkable. A counterintuitive finding that was originally based on you’re looking to improve patients’ function and now not only improve their function, but it turns out you may actually have improved oncologic success with higher free testosterone levels. And of course, as you said several times, prospective randomized trials in the works. And we’re really excited to see that in the future. Thank you so much for participating. I’m very grateful.

Thomas Ahlering: Thank you.

Jaime Landman: Thanks, Tom.