SUO 2022: Use of Exogenous Testosterone in The Setting Of Screening, Active Surveillance, and After Treatment of Localized Disease

( At the 2022 Prostate Cancer Session of the Annual Meeting of the Society of Urologic Oncology, Dr. Mohit Khera presented on the use of testosterone replacement therapy among patients with prostate cancer, including in the setting of screening, active surveillance, and after treatment for localized prostate cancer.

Beginning, Dr. Khera noted that there has been a paradigm shift with respect to the association between testosterone and prostate cancer over time. Initially, exogenous testosterone was considered dangerous in the context prostate cancer. Since that time, perspectives have progressed to consider it safe, and then potentially protective, and finally (though beyond the scope of his talk) therapeutic. While this is a topic of considerable interest and importance to patients and physicians, there is a relatively limited evidentiary base – there are 15 studies assessing the role of testosterone replacement in patients following radical prostatectomy, 6 among those treated with active surveillance, and 9 among those receiving radiotherapy. Patient numbers and duration of follow-up are limited among these studies. 

Dr. Khera highlighted one study among men treated with testosterone therapy following radiotherapy. Among 98 hypogonadal men followed for approximately 40 months, testosterone replacement was associated with increased serum testosterone (from 209 ng/dl to 420 ng/dl) though PSA marginally changed (from 0.08 ng/mL to 0.09 ng/mL). This increase was somewhat large among patients with high-risk disease (from 0.10 ng/ml to 0.36 ng/ml). However, only 6 men (6.1%) met the criteria for biochemical recurrence.

Dr. Khera transitioned from this clinical data into a discussion of the saturation model for physiologic testosterone replacement. He noted that there is an underlying molecular basis for this saturation model in which the androgen receptor becomes maximally bound to androgen (i.e. saturated) at concentrations of approximately 250 ng/dl (~8 nmol/L).

Taking this principle to the clinical application, he noted work among 450 hypogonadal men started on testosterone replacement therapy for 12 months, stratified by starting testosterone of less than or greater than 250 ng/dl. Among those with testosterone greater than 250 ng/dl, there were minimal PSA effects. However, in those with testosterone less than 250 ng/dl, there was evidence of a significant increase in PSA levels after 12 months of testosterone therapy.

Among 103 men who had previously undergone radical prostatectomy and then we treated with testosterone therapy, compared to 49 eugonadal men who had also previously undergone prostatectomy, biochemical recurrence was restricted to patients with high risk disease, regardless of testosterone replacement. In fact, among the 12 patients with high-risk disease who experienced biochemical recurrence, 4 were in the testosterone therapy group (15.3%) while 8 were in the control group (53%). Dr. Khera noted that these data, while certainly not conclusive in any way, suggest a potential benefit in terms of prostate cancer outcomes with the use of testosterone supplementation.

He then cited some basic science data to corroborate this. He and colleagues treated prostate cancer LNCaP cell with various testosterone levels and then assessed their growth kinetics. Moving from these in vitro data to animal models, a similar principle was assessed in murine xenograft models. These mice were treated with either orchiectomy, orchiectomy with low dose testosterone replacement, orchiectomy with high dose testosterone replacement, and then normal controls. Interestingly, as highlighted in the figure below, there was an “inverted U” demonstrated with suppression of tumor growth in patients with very low testosterone (orchiectomy) and those with high levels of testosterone treatment (5mg supplementation).

Dr. Khera then noted that Dr. Loeb and colleagues assessed the association between testosterone replacement therapy and the risk of prostate cancer, using administrative data from Sweden. Notably, there was no association identified between testosterone replacement therapy and overall prostate cancer. However, patients receiving testosterone replacement therapy had a lower risk of aggressive prostate (odds ratio 0.50, 95% CI 0.37 to 0.67). While not prospectively assessed, he noted that testosterone replacement therapy may slow recurrence in low-risk prostate cancer. Among 859 patients undergoing robotic assisted radical prostatectomy, the authors identified 152 with low-risk disease who had no evidence of disease following surgery and received testosterone replacement therapy. After a median follow-up of 3.5 years, cancer recurrence rates were lower in patients treated with testosterone (7.2%) than those who did not receive testosterone (12.6%). Further in men “destined to recur”, Dr. Khera noted that patients receiving therapy had a delayed time to recurrence by approximately 1.5 years.

Dr. Khera then noted that the 2018 American Urological Association guidelines have two key recommendations that are relevant: first, clinicians should inform patients that there is an absence of evidence linking testosterone therapy to the development of prostate cancer; second, patients with testosterone deficiency and a history of prostate cancer should be informed that there is inadequate evidence to quantify the risk-benefit ratio of testosterone therapy. Addressing the question of who may receive testosterone therapy, the FDA noted that those who have undergone radical prostatectomy and have two undetectable PSA levels subsequently, in the absence of adverse pathologic findings including positive surgical margins, evidence of residual disease, Gleason grade group of 3 or greater, or evidence of advanced or metastatic prostate cancer.

In a small cohort of 13 men treated with active surveillance who subsequently received at least 6 months of testosterone replacement therapy, there was no evidence of cancer progression and more than half (54%) had no evidence of cancer on follow-up biopsy. In a second study among 338 patients who would be eligible for active surveillance but treated with radical prostatectomy, those who had low serum testosterone prior to surgery were more likely to have upgrading, upstaging, unfavorable disease, and positive surgical margins. Thus, these authors suggested that low serum testosterone should be a criterion for the selection of patients for active surveillance with this treatment strategy discouraged among those with a low serum testosterone (<300 ng/dl).

Moving forward, Dr. Khera emphasized that there will forthcoming prospective data. The recent TRAVERSE trial will provide randomized controlled data. This study has randomized 6000 men to receive testosterone replacement therapy or placebo with the primary endpoint of major adverse cardiac events. However, one of the key secondary endpoints is the incidence of high-grade prostate cancer.

In conclusion, Dr. Khera noted that there is no current evidence that testosterone replacement therapy promotes the initiation of prostate cancer in hypogonadal men. Further, early data does not demonstrate an increased risk of prostate cancer progression for men on active surveillance, though low testosterone may be an independent poor prognostic factor for these men.

Presented by: Mohit Khera, MD, MBA, MPH, Baylor College of Medicine, Houston, TX