Testosterone therapy and prostate cancer: Risk-benefit and individualized treatment

Mohit Khera, MD, MBA, MPH

In this interview, Mohit Khera, MD, MBA, MPH, shares insights on the use of testosterone replacement therapy in men with prostate cancer, touching on current evidence and also stressing the importance of patient counseling and an individualized approach to treatment. Khera is a professor of urology and holds the F. Brantley Scott Chair in Urology at Baylor College of Medicine in Houston, Texas.

What is your stance on testosterone replacement therapy in patients with a history of prostate cancer, and how do you weigh the risks and benefits in such cases?

I don’t believe that testosterone increases risk of biochemical recurrence or progression in men who have a history of prostate cancer. There are studies [with data] demonstrating that giving men testosterone after radical prostatectomy may decrease biochemical occurrence. In 1 study, Ahlering et al looked at a group of hypogonadal men after a radical prostatectomy who received testosterone supplementation. [Testosterone therapy] delayed biochemical recurrence by 1.5 years and resulted in a 54% reduction in the development of prostate cancer.¹ I am in the camp of believing that testosterone may be protective against biochemical occurrence, but I am the minority. If you look at the AUA [American Urological Association] guidelines, which came out in 2018, those guidelines state that patients with testosterone deficiency and a history of prostate cancer should be informed that there’s inadequate evidence to quantify the risk-benefit ratio of testosterone therapy. The level of evidence was based on expert opinion.

What are your thoughts on patients who are at risk due to family history or an elevated prostate-specific antigen (PSA) level who are receiving testosterone replacement?

I think you have to first decide if you believe that testosterone increases the risk of prostate cancer. I was very happy to see when the AUA in 2018 put out in the testosterone guideline statement that clinicians should inform patients of the absence of evidence linking testosterone therapy to the development of prostate cancer. That was a strong recommendation.

That being said, I do not believe that testosterone causes prostate cancer. The AUA guidelines support that as well. For patients at high risk, I treat them just like I would anyone else, whether I give them testosterone or not, and I follow them just as closely, but I don’t let their history of prostate cancer influence how I treat or follow them.

Can you explain the underlying mechanisms by which testosterone can influence prostate cancer progression. How does this affect your clinical decision-making when considering testosterone replacement therapy for patients?

I want you to think of the indications for testosterone therapy in 2 different ways. One is the conventional indication for testosterone replacement therapy, which we’re all familiar with—giving men testosterone who are symptomatic and are deficient in serum testosterone levels. And the other one is a new concept that was introduced roughly 10 years ago called BAT—bipolar androgen therapy. Testosterone therapy, if you look at the package insert, is contraindicated in men with metastatic prostate cancer. In BAT, which is giving high doses of testosterone, the indication is metastatic prostate cancer, so [they’re] completely opposite.

Now, there are several theories regarding how testosterone influences prostate cancer. One mechanism is that testosterone binds androgen receptors within [the] prostate and stimulates prostate cancer cell growth. However, when you give testosterone in high doses, as we see with BAT, this can actually down-regulate androgen receptors in prostate cancer cells, and this down regulation can inhibit prostate cancer cell growth. Another potential mechanism for BAT is that high doses of testosterone can induce apoptosis within prostate cancer cells. And finally, it is hypothesized that elevated androgen levels through BAT can actually disrupt the cell cycle and thus inhibit [the] proliferation of prostate cancer cells.

I think our understanding of testosterone and its effect on prostate cancer is continuously evolving.

How do you assess the potential for recurrence or metastasis when considering testosterone replacement therapy in prostate cancer survivors, and what surveillance strategies do you use during therapy? For example, when somebody has been treated for high-risk prostate cancer and is now without evidence of disease, is there a time when it is safe to resume testosterone replacement?

I think you have to look at this on a case-by-case basis; particularly, what type of treatment…they received. For example, I monitor a patient [who received radiation] differently [from how] I treat a [patient who underwent] radical prostatectomy. The key here is I don’t believe that testosterone increases the risk of prostate cancer progression or biochemical recurrence. If a patient has a history of a radical prostatectomy, I typically wait at least 3 months and make sure they have an undetectable PSA [level].

Counseling is also very important. I let patients know what the AUA guidelines say. AUA guidelines state that the risk-benefit ratio is still unknown, and so you make sure to appropriately counsel patients. You don’t want to mislead them. They have to know that this is an evolving field, and more studies need to be done. If the patient has a history of radiation and they were moderate to high risk typically, they would have received androgen deprivation therapy anywhere from 6 to 18 months. The issue is that when you start these patients on testosterone supplementation, if their starting testosterone level is low, you expect their PSA to go up, and this can cause anxiety for not only the patient but also sometimes for the medical oncologist. So typically, for high-risk patients, I will wait 18 months before I start them on testosterone therapy. If they were low to moderate risk, I can start them earlier. If the starting testosterone level is low, particularly below 250 ng/dL, they need to be aware that their PSA [level] will probably rise and plateau, typically after the third month.

In cases of hypogonadism in patients with prostate cancer who have undergone treatments such as prostatectomy or radiation, how do you determine whether testosterone replacement is safe or appropriate?

I think it’s all about counseling. It is important to discuss the AUA guidelines , particularly that the risk-benefit ratio is still unknown and we need more studies. But I [explain to] them that the current available data do not show any increased risk. It’s very important to counsel patients appropriately prior to starting them on TRT [testosterone replacement therapy] after prostate cancer. It is also important to note that the EAU [European Association of Urology] guidelines state that it is appropriate to give testosterone to certain patients after radical prostatectomy if they’re appropriately selected, monitored, and counseled.

Which latest research findings or clinical guidelines inform your approach to managing testosterone replacement therapy in patients with prostate cancer, particularly regarding the risk of cancer recurrence or progression?

Unfortunately, most of the guidelines have not been updated in quite some time. The AUA testosterone guidelines were last published in 2018. But there have been some very interesting [data from] trials that have been more recently published….

[Findings from] the TRANSFORMER trial (NCT02286921) came out in 2021, [a trial that] essentially looked at patients with metastatic prostate cancer. They were either given BAT or enzalutamide [Xtandi], which is [the] standard of care. [In] all…these patients, abiraterone [Zytiga] had failed, so then they were eligible for enzalutamide. The authors found that whether a patient took BAT or enzalutamide, there was no difference in overall survival. [That is] pretty astonishing. But if you took BAT that became resistant, and then switched to enzalutamide, those patients actually had the best overall survival. To me, that is really eye opening, because you would have never thought to give patients with metastatic prostate cancer high doses of testosterone, nor would you expect it to be equivalent to the standard of care, which is enzalutamide, for overall survival.²

The second paper [concerns data from a recent study by Flores et al]. This is a large series looking at almost 5200 [patients] who underwent radical prostatectomy [RP] and had groups grade 1 to 3 on RP pathology, of which 198 patients received testosterone therapy. These authors found was that there was no difference in biochemical recurrence in men receiving testosterone vs those men not receiving testosterone after radical prostatectomy. They also noticed that the men who received testosterone had a much lower risk of biochemical recurrence, although it was not statistically significant.³

How does past use of androgen deprivation therapy influence the decision to initiate testosterone in a patient with prostate cancer?

I think the more complex [cases of hypogonadal patients with] prostate cancer are those [patients] who have a history of radiation therapy and ADT [androgen deprivation therapy]. ADT typically drops the patient below the prostate saturation point, and thus these patients will experience a rise in PSA once I start TRT. I believe the saturation point is roughly 250 ng/dL. So if your starting testosterone is less than 250 ng/dL—say it’s 150 ng/dL—and you start this patient on testosterone supplementation, I expect the PSA to go up. In order to understand how to counsel these patients, one must understand the prostate saturation model.

Is there anything you would like to add?

I think that testosterone replacement therapy for [patients with] prostate cancer has to be individualized. It has to be based on numerous factors such as comorbid conditions, life expectancy, Gleason score, pathology, and severity of symptoms. It is important that everyone understands the potential risks and benefits prior to starting [patients] on therapy. Each case should be tailored individually.

REFERENCES

1. Ahlering TE, Huynh LM, Towe M, et al. Testosterone replacement therapy reduces biochemical recurrence after radical prostatectomy. BJU Int. 2020;126(1):91-96. doi:10.1111/bju.15042

2. Denmeade SR, Wang H, Agarwal N, et al. TRANSFORMER: a randomized phase II study comparing bipolar androgen therapy versus enzalutamide in asymptomatic men with castration-resistant metastatic prostate cancer. J Clin Oncol. 2021;39(12):1371-1382. doi:10.1200/JCO.20.02759

3. Flores JM, Vertosick EA, Salter CA, et al. Testosterone therapy in men after radical prostatectomy for low-intermediate organ-confined prostate cancer. J Urol. 2025;213(1):27-33. doi:10.1097/JU.0000000000004267