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

Author Olivia Reid covers Rethinking Testosterone Therapy in Prostate Cancer Survivors: An Early Look at Positive Clinical Trial Data on BackTable Urology

Olivia Reid • Updated Dec 21, 2023 • 96 hits

Urologist Dr. Jose Silva and endocrinologist Dr. Rodrigo Valderrábano dive into the groundbreaking research that’s exploring the viability of testosterone treatment in prostate cancer survivors. Dr. Valderrábano is a lead researcher in an ongoing clinical trial that is targeting low testosterone in symptomatic men post-prostate cancer recovery. After rigorously selecting participants with specific criteria, including low-grade disease recurrence post-radical prostatectomy and stringent PSA thresholds, patients in Valderrábano’s trial undergo a 16-week, 100 mg weekly testosterone injection regimen, while being monitored closely for PSA levels and symptom improvement. This study addresses the crucial issue of symptomatic hypogonadism in nearly half of prostate cancer survivors.

The risk-benefit balance becomes evident when considering two distinct patient subgroups. For patients with low recurrence risk and undetectable PSA, testosterone treatment significantly improves quality of life. However, in patients at risk of recurrence, testosterone treatment could fuel cancer growth.

This article features excerpts from the BackTable Urology Podcast. We’ve provided the highlight reel in this article, but you can listen to the full podcast below.

The BackTable Urology Brief

• Dr. Valderrábano’s current clinical trial for patients in recovery from prostate cancer with low testosterone involves administering 100 milligrams of testosterone weekly via injections for 16 weeks, in addition to frequent PSA monitoring.

• This clinical trial has shown encouraging results without encountering safety concerns in approximately 70-80 patients.

• With little to no risk of recurrence, such as in the clinical trial patients, the benefits outweigh the risks with testosterone treatment. In contrast, if a patient undergoing testosterone treatment experiences a cancer relapse, the testosterone will promote the cancer’s growth.

• Dr. Valderrábano advocates for cautious treatment strategies, including the use of smaller testosterone doses to decrease the risk of exacerbating the prostate cancer, yielding a preference for the gel or patch modalities.

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

Table of Contents

(1) Studying the Effects of Testosterone Treatment in Prostate Cancer Survivors

(2) The Pivotal Role of Recurrence Risk in Patient Selection

(3) Rethinking Testosterone Treatment in Prostate Cancer Survivors

Studying the Effects of Testosterone Treatment in Prostate Cancer Survivors

Dr. Valderrábano’s current work, initiated by Dr. Shalender Bhasin at Brigham, has evolved into a clinical trial which tests treatments for low testosterone in symptomatic men in recovery from prostate cancer. To be included in the trial, the patients must be carefully selected with a focus on individuals with low-grade disease recurrence post-radical prostatectomy and the absence of prior hormonal therapies. These patients must have Gleason scores of 3+4 and a stringent PSA threshold to qualify. Once in the trial cohort, 100 milligrams of testosterone is injected weekly over the course of 16 weeks. The patients undergo frequent PSA monitoring, which has thus far shown promising results with limited safety concerns.

[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.

Listen to the Full Podcast

Testosterone Replacement in Prostate Cancer Survivors with Dr. Rodrigo Valderrabano on the BackTable Urology Podcast)
Ep 98 Testosterone Replacement in Prostate Cancer Survivors with Dr. Rodrigo Valderrabano
00:00 / 01:04

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The Pivotal Role of Recurrence Risk in Patient Selection

It has been reported that about half of individuals recovering from prostate cancer experience symptomatic hypogonadism, highlighting the importance of Valderrábano’s current study. The results of the clinical trial have provided great hope for patients, as the testosterone treatments for these patients with a low risk of recurrence and undetectable or very low PSA levels are not only safe and effective but also improve their symptoms dramatically, increasing quality of life. On the other hand, cancer recurrence could be exacerbated by additional testosterone. With little to no risk of recurrence, as in Dr. In Valderrábano's study cohort, the benefits of testosterone treatment likely outweigh the risk. However, if a patient undergoing testosterone treatment experiences a cancer relapse, the testosterone will promote the cancer’s growth, exponentially increasing the problem at hand. This explains the trial’s strict inclusion criteria, emphasizing the need to balance treating aggressively in certain cases with holding off until the body is in a better state of recovery in others.

[Dr. Jose Silva]
Yes, I have a few patients in my practice, in my clinic. I usually follow these patients every six months, just general hypogonadism, but if these patients, the first ones that I started, I was doing every three months, they're all doing good. I haven't had a patient with recurrence. I have a few that are after radiation because definitely-I had a patient that felt that it wasn't worth living, he felt that bad. I felt obligated to do something. I think his testosterone was in the hundreds or low hundreds and he's feeling great.

[Dr. Rodrigo Valderrábano]
Excellent. That's so great to hear.

[Dr. Jose Silva]
Yes, we discussed the outcome. He knew what to expect, we knew that there's no data out there or not that much data and we're doing it because the patients need it.

[Dr. Rodrigo Valderrábano]
I think at the end of this trial, if everything goes as we hypothesized, I think we will be able to say, and for anyone who wants to see it the protocol and of the trial was published in andrology in January, but I think what we will be able to say at the end of this trial if everything goes like it's looking, is that for people with a low risk of recurrence who have undetectable PSA or very low PSA for many years after surgery, we'll be able to offer it. If you're hypogonadal and you're feeling terrible, which about half of people are, then it's safe and effective to give it.

Our outcomes are sexual health and also physical health, so we're looking at VO₂ max, other strength measures, and aerobic capacity measures. Testosterone has worked in every other trial. I don't see why it wouldn't work here or at most, I shouldn't say every other trial, but most other trials looking at people that we now consider hypogonadal, people have had improvements with testosterone replacement therapy. Then someone like your patient, if they're at higher risk, you have to weigh the pros and cons like everything in medicine and if they totally are just feeling terrible and life isn't worth living and you can make them feel better, then that's a great outcome, as long as they're aware of the risks.

[Dr. Jose Silva]
Exactly. The fear will be that that patient has a full-blow recurrence.

[Dr. Rodrigo Valderrábano]
That's right.

[Dr. Jose Silva]
I guess, if it's going to recur, it's going to recur no matter what, it's just depending on when it's going to, and definitely testosterone will push you sooner than later.

[Dr. Rodrigo Valderrábano]
Oh, sure. Let's not beat around the bush. With this low recurrence rate on the low PSA, we're just trying to make sure that the person is "cured." If you're cured, testosterone isn't going to do anything bad. If you know that there are some prosthetic cancer cells hanging around, if a person really hasn't suppressed PSA or if there was extracapsular invasion and there were lymph nodes positive, you know their cells around there, testosterone will promote prostate cancer growth absolutely.

The question is, depending on the person's expected quality of life, the person's expected lifespan, depending on the degree of disease, is it worth it to them to take that risk? That's why when we do this kind of thing, we have to be really careful to monitor people closely to make sure that is someone that's going to recur quickly, we need to catch them quickly, and that's you put the safety net there and you try to help people as much as you can. At the end of the day, that's what we're all trying to do in healthcare.

[Dr. Jose Silva]
For other symptoms like urine incontinence, erectile dysfunction, more people are treating those patients sooner. Before, just like with testosterone, we waited just to make sure that the patient didn't have any recurrence and then we will talk about the inflatable penile implant or a sling or artificial urinary sphincter to correct the incontinence. I think the trend now is doing it sooner. Definitely not three months after, but before the year, six months if that patient has just like you said, low-risk cancer, very low-risk of metastatic disease, then just treat him.

[Dr. Rodrigo Valderrábano]
Again, it's the difference between giving wide-ranging advice from the results of a clinical trial and personalizing medicine to your patient, and their desires and their tolerance for risk. Somebody that you don't wait at least a year to see the PSA suppressed, it would certainly be somebody who is potentially at higher risk, and we just don't know about it, but I could see someone with a recent surgery that has a totally undetectable or extremely low PSA, and they had a very low-risk cancer to begin with. That's somebody, you could be a little bit braver, follow them up closely, and if they're doing fantastic then, and they're aware of the risks, I don't see--We do this stuff all the time in other aspects of health.

When I was at the University of Miami, I really learned a lot from the oncologists. The oncologists when they treat, especially people that are involved in renal cell carcinoma, just really aggressive types of cancer, they are really open to doing other things to help patients. I remember treating somebody for thyroid illness and I told the oncologist, "We're going to give him thyroid medication and then we're going to titrate it every three months, and in about six months to a year, he'll be fine." The oncologist called me back up and said, "Hey man. This guy has a life expectancy of six months. You're telling me you're going to treat him in a year? It's going to be a year 'til he feels good." That opens your eyes, right? Sometimes you have to be a little bit more aggressive and be out of your comfort zone for people that are just feeling terrible, their quality of life is just terrible.

Rethinking Testosterone Treatment in Prostate Cancer Survivors

Dr. Valderrábano adds valuable information in understanding testosterone's role in prostate cancer treatment, challenging the long-held belief that testosterone only exacerbates the disease. The clinical trial, which involves a total of 120 patients, focuses on the enhancement of physical and sexual function in addition to decreasing hypogonadal symptoms. While the timeline was altered due to COVID-related restrictions, Dr. Valderrábano and his team anticipate publishing the trial results within the next two years.

Both the study and general patient responses to testosterone treatment points to the necessity for individualized approaches. This is evident in patients where even the gentle increase from relatively low testosterone levels (around 200-250) to slightly higher levels (around 300-400) is able to enhance well-being without excessively stimulating cancerous cells. In all circumstances though, Dr. Valderrábano advocates for cautious treatment strategies, warning against sharp rises in testosterone levels, which might exacerbate the disease, and leans towards gel or patch applications to mitigate the risks associated with erratic dosing patterns found in injections. Additionally, the endocrinologist underscores the significance of keeping an open mind in the medical community, clarifying that testosterone isn't a universal cure, urging caution, moderation, and stressing that the therapy is not suitable for all prostate cancer patients.

[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.

Podcast Contributors

Dr. Rodrigo Valderrabano discusses Testosterone Replacement in Prostate Cancer Survivors on the BackTable 98 Podcast

Dr. Rodrigo Valderrabano

Dr. Rodrigo Valderrabano is an endocrinologist with Brigham and Women's Hospital in Boston, Massachussetts.

Dr. Jose Silva discusses Testosterone Replacement in Prostate Cancer Survivors on the BackTable 98 Podcast

Dr. Jose Silva

Dr. Jose Silva is a board certified urologist practicing in Central Florida.

Cite This Podcast

BackTable, LLC (Producer). (2023, May 17). Ep. 98 – Testosterone Replacement in Prostate Cancer Survivors [Audio podcast]. Retrieved from https://www.backtable.com

Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.

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