Rethinking Testosterone Therapy in Prostate Cancer Survivors: An Early Look at Positive Clinical Trial Data

[Dr. Jose Silva]
Rodrigo, let's go to the more controversial part of our podcast and it's the work that you have done in testosterone and prostate cancer. You were part of a group then you published the paper on patients that are prostate cancer survivors, low testosterone, very symptomatic, and you started treatment.

[Dr. Rodrigo Valderrábano]
That's right.

[Dr. Jose Silva]
Talk to us about the inclusion criteria, how did it come up?

[Dr. Rodrigo Valderrábano]
Sure. This is work that started before, so I've only been at the Brigham now for about a year and a half, almost two years, and this work was started by my principal investigator and the head of our men's health division, Dr. Bhasin, who's a guru in this space and his papers in the 1990s were the ones that showed us that testosterone was actually anabolic to muscle. Before that everybody was sure that it wasn't, so really transformative work.

Really what we're hitting at here Jose is that there's a lot of data out there that retrospective and/or case reports and case studies showing that people that have had prostate cancer do well with testosterone therapy after complete removal and treatment of the prostate cancer. It's a really important area. About 50% of men that have radical prostatectomy will end up having hypogonadism, even with nerve-sparing surgery. It's not completely clear why this happens, but it must have something to do with the affected vasculature or fibrosis or other things that happen after surgery that affect the testicles.

Essentially, we have to differentiate what you might want to do person by person with somebody in a clinic versus what we're trying to do, which is let's create a trial that we can use to give wide-ranging advice. This is the first trial, a randomized double-blind placebo-controlled trial to give testosterone back to prostate cancer survivors. We're being very careful to pick people that had low-grade and very low disease recurrence, so we're being very careful there. Essentially, we're doing a Gleason score of 3 + 4, no extracapsular invasion or any kind of positive lymph nodes or anything like that. These people could not have had a PSA greater than 20 before surgery. We changed that, initially, we had it in PSA no greater than 10.

[Dr. Jose Silva]
10, okay.

[Dr. Rodrigo Valderrábano]
But actually, everything's been so good that we actually changed it to under 20 and people have still done well. Then, we are treating people that are at least two years out and have had a completely negative PSA for the past two years. These are really the people that had a low grade of recurrence. We've treated with radical prostatectomy and then there's no sign that anything's come back and these were people that were not on Lupron or any other kind of hormonal therapies. Really low risk of recurrence. We've now done close to 70 or 80 people and we haven't seen any kind of safety signal whatsoever in the entire trial.

[Dr. Jose Silva]
What's the regimen? Are you using gel, injections?

[Dr. Rodrigo Valderrábano]
No, we're using injections. It's a really difficult study to recruit for and retain people because they have to drive into Boston every week, but then we're doing it here and we're doing it at Johns Hopkins as well. The PI there is Arthur Burnett, who's a guru in the space as well. The regimen is 100 milligrams of testosterone every week and they come and get their injections and that's for 16 weeks, I believe.

[Dr. Jose Silva]
How often do you do the labs?

[Dr. Rodrigo Valderrábano]
We have PSAs at regular time points, essentially every two to four weeks and it's looking great so far. That's our regimen, how we're doing it. Whether that's really necessary in clinical practice later on, I don't know, but we're just making sure that if we do get a hit and we see biochemical recurrence of prostate cancer, we want to really catch it very early so that's why we're doing it so fast.

[Dr. Jose Silva]
Exactly. In terms of the research that you're doing right now, or your protocol, at some point, you will start doing it, move it every year. Instead of waiting two years after the PSA, you think it is going to move to a year?

[Dr. Rodrigo Valderrábano]
Yes. Certainly, this is not a large trial with thousands of people. I think we're shooting for about 120 people, so it'll be solid, and we'll have power to detect a difference in our outcomes. I think that once this trial comes out, this will be the first randomized clinical trial to show that it's safe and effective, and so, if everything goes to plan, of course, and I think that will spark a conversation where then the conversation will be, "Should we be thinking of doing this even sooner? Should we be doing this in everybody?"

I think it'll be some time before we start changing-- This is the initial step or the next logical step, and then once that conversation is then underway, I think we'll have other studies coming out, people that will be brave and will be trying to do this as well.

[Dr. Jose Silva]
What's the timeline for your research, five years? When will you say it is safe?

[Dr. Rodrigo Valderrábano]
Yes. Like I said, I have to say the endpoint of our trial isn't safety, its effectiveness in sexual function and physical function, but when you treat over 100 people and if nothing happens, then that's more reassuring than not having any data for sure. COVID really threw a wrench into our recruitment. Boston was completely shut down for almost six months to almost a year, and then people were very reluctant to come in. I think the trial will be open for about another year. Johns Hopkins has recently gone underway and they're recruiting people as well at a nice pace. Hopefully, in about a year's time, we'll finish recruitment, which will mean, maybe another six months for the trial results, at least the main results to come out, so give it like two years maybe until we actually publish the data.

[Dr. Jose Silva]
Cool.

[Dr. Rodrigo Valderrábano]
Then after that, I'll be back, and we can talk about how to be even more aggressive.

[Dr. Jose Silva]
Yes, because patients want it. Patients want it, but it gets trickier because right now there's a movement within the urology part of this low-risk cancer doing more active surveillance. What happens in those patients that still have active cancer, but they have symptoms of low testosterone, what are you going to do with it?

[Dr. Rodrigo Valderrábano]
Yes. That's really tough.

[Dr. Jose Silva]
It becomes more tricky, yes.

[Dr. Rodrigo Valderrábano]
The other thing about this, the other part of this is that our thinking has changed. Originally, the idea behind, don't treat anyone with prostate cancer with testosterone, that concept came from data that shows that prostate cancer is very obviously stimulated by testosterone, so that's one piece of data, and then people that are frankly hypogonadal or people that are treated with Lupron and other antiandrogen agents do better after surgery, especially metastatic disease.

Those are the two extremes, and so people thought, "Oh, obviously testosterone is bad." Now, the reality is the level that you need to turn on the androgen receptor, the level of testosterone that you need is very low, so, if you have a testosterone of 200 versus a testosterone of 400 total testosterone, you're not really changing the landscape in terms of whether the testosterone, any androgen will be stimulating prostate cancer cells. If you have 0 versus 400, that's a big difference. Even people that are under active surveillance, if they have a lowish testosterone of let's say 200, 250, and you boosted them up gently, you wouldn't necessarily be compromising them. You wouldn't necessarily be overstimulating it. Hey, listen, if you go up to 1000, and you're not being careful, then obviously that's not the best idea. If you already have testosterone on board, going up a little bit doesn't necessarily mean that you're going to stimulate any kind of dormant cells more.

[Dr. Jose Silva]
Yes, because also those patients that are hypogonadal. You start them on testosterone, PSA starts increasing, then you do the work for elevated PSA, you find cancer and then you have to tell them, "Hey, we need to stop testosterone." Those patients don't like it. They don't like to hear that they have cancer, and they don't like to hear that you're going to stop giving them testosterone, so it becomes trickier.

I always tell them, "Hey, continue the treatment. Let's wait for the biopsy and go from there," because you don't want to stop then just because of the elevated PSA, at least in my opinion. Because if they're feeling good, I don't want them to go back, and that's what the patient doesn't want. They don't want to feel terrible like before.

[Dr. Rodrigo Valderrábano]
It all depends. If it ends up being something very low-grade and obviously if it's something that has where you're seeing lymph nodes and you're seeing metastasis, you could really accelerate it, a critical period where they need to be treated. I don't know, that's where you have to individualize it. We also have to look at why people are on testosterone and if there all are alternative therapies that could help. Testosterone's not necessarily the only answer, and if people aren't feeling well and they have low testosterone because they're obese and they have sleep apnea, then let's treat those and see if they get better.

I don't like to negotiate. You are either deserving of treatment or you're not or you have the criteria, or you don't for testosterone treatment. Sometimes when people are in the gray zone and you're not sure, I say, "Listen, work with me and I'll work with you." At least get on some programs, start losing weight, and start being active and then let's try a low dose and see how it goes, so it really has to be individualized.

[Dr. Jose Silva]
When you say low dose, what do you mean? If it's, let's say with the gel, so are we one pump, for example?

[Dr. Rodrigo Valderrábano]
Yes. You could do like a 1.6% gel, you could do one pump. The important thing is in the initial gel trials, about 10% of people had a terrible response, 10% of people had a ridiculously high response, and then everybody else was in the middle. Just with one pump, you may be getting a pretty good dose effect, and the thing is, somebody that's hypogonadal in the studies that looked at especially sexual function, those studies haven't all been positive. People that have slightly higher levels of total testosterone don't improve symptoms when you give them testosterone, so you may just need to go up the threshold. What the threshold is isn't clear, and it's probably because it's different for everyone, but somewhere around 300 right, just going from 300 to 400 people may feel much, much better, as opposed to going from 300 or 200 to 1000. You don't have to go up that high to see improvement. You use gels or patches that don't have the spikes, certainly. Remember when we do testosterone injections, you're going to have 1000. If you get it two days after, you're going to get 1000, 1,200 of total testosterone. That would not be a great idea when you're treating somebody that's under active surveillance for prostate cancer.

So, when I say low dose, you may want to do something like a gel or a patch, starting at a lower dose. See how it goes. Look at the PSA. If the PSA jumps up, then obviously that person isn't a good candidate for it.

[Dr. Jose Silva]
Great. Rodrigo, you want to add something else? I think it was great.

[Dr. Rodrigo Valderrábano]
Yes. No, I think like everything, medicine, I think everybody should just keep an open mind. We're not saying that testosterone is the cure-all. Certainly, anyone that gets a lot of testosterone is going to feel energized and hyped up, but that doesn't mean it's good for them. I don't want it to come across like we're just trying to sell testosterone no matter what, or give testosterone no matter what. Certainly, there's enough data out there that it's potentially safe.

We're doing this trial, which will come out soon, and that'll be some good baseline data for everybody to base on. We got to give these guys a chance. A lot of these older men after prostate cancer, they feel absolutely terrible. I'm not saying we give testosterone to everybody. I'm actually quite conservative in my own clinic, but we have got to have an open mind and give everybody a chance.