madman
Super Moderator
Abstract
IMPORTANCE
The effect of testosterone replacement therapy (TRT) on the risk of prostate cancer and other adverse prostate events is unknown.
OBJECTIVE
To compare the effect of TRT vs placebo on the incidences of high-grade prostate cancers (Gleason score 4 + 3), any prostate cancer, acute urinary retention, invasive prostate procedures, and pharmacologic treatment for lower urinary tract symptoms in men with hypogonadism.
DESIGN, SETTING, AND PARTICIPANTS
This placebo-controlled, double-blind randomized clinical trial enrolled 5246 men (aged 45-80 years) from 316 US trial sites who had 2 testosterone concentrations less than 300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk. Men with prostate-specific antigen (PSA) concentrations greater than 3.0 ng/mL and International Prostate Symptom Score (IPSS) greater than 19 were excluded. Enrollment took place between May 23, 2018, and February 1, 2022, and end-of-study visits were conducted between May 31, 2022, and January 19, 2023.
INTERVENTION
Participants were randomized, with stratification for prior CVD, to topical 1.62%testosterone gel or placebo.
MAIN OUTCOMES AND MEASURES
The primary prostate safety endpoint was the incidence of adjudicated high-grade prostate cancer. Secondary endpoints included incidence of any adjudicated prostate cancer, acute urinary retention, invasive prostate surgical procedure, prostate biopsy, and new pharmacologic treatment. The intervention effect was analyzed using a discrete-time proportional hazards model.
RESULTS
A total of 5204 men (mean [SD] age, 63.3 [7.9] years) were analyzed. At baseline, the mean (SD) PSA concentration was 0.92 (0.67) ng/mL, and the mean (SD) IPSS was 7.1 (5.6). The mean(SD) treatment duration was 21.8 (14.2) months in the TRT group and 21.6 (14.0) months in the placebo group. During 14 304 person-years of follow-up, the incidence of high-grade prostate cancer (5 of 2596 [0.19%] in the TRT group vs 3 of 2602 [0.12%] in the placebo group; hazard ratio, 1.62; 95% CI, 0.39-6.77; P = .51) did not differ significantly between groups; the incidences of any prostate cancer, acute urinary retention, invasive surgical procedures, prostate biopsy, and new pharmacologic treatment also did not differ significantly. Change in IPSS did not differ between groups. The PSA concentrations increased more in testosterone-treated than placebo-treated men.
CONCLUSIONS AND RELEVANCE
In a population of middle-aged and older men with hypogonadism, carefully evaluated to exclude those at high risk of prostate cancer, the incidences of high-grade or any prostate cancer and other prostate events were low and did not differ significantly between testosterone- and placebo-treated men. The study’s findings may facilitate a more informed appraisal of the potential risks of TRT.
Introduction
The relationship between testosterone replacement therapy (TRT) and the risk of prostate cancer remains incompletely studied.1-3 Epidemiologic studies have not found a consistent association between prostate cancer risk and testosterone levels or polymorphisms in genes involved in androgen action.4-13 Prostate events were not adjudicated in any testosterone trial, and none have reported the incidence of high-grade prostate cancer or other prostate events, such as acute urinary retention, invasive prostate procedures, or the initiation of new pharmacologic therapy for benign prostatic hyperplasia (BPH).1,14 Because of uncertainty about the risk of prostate events during TRT, most professional society guidelines recommend against TRT in men with a history or increased risk of prostate cancer.1,2,15
In 2015, the US Food and Drug Administration required testosterone manufacturers to conduct a randomized clinical trial to determine the effect of TRT on major adverse cardiovascular events( MACEs).16 The Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) study was designed to meet this regulatory requirement.17 Because of its large size and longer duration, the TRAVERSE study offered a unique opportunity to evaluate the effects of TRT on prostate safety events.17 The study compared the effects of TRT and placebo on the incidences of high-grade prostate cancer, any prostate cancer, acute urinary retention, invasive prostate surgical procedures for BPH, and initiation of pharmacologic therapy for BPH. Prostate events were recorded using a structured protocol and adjudicated. To minimize ascertainment bias due to the greater likelihood of urologic referral for prostate biopsy because of testosterone-induced elevation in prostate-specific antigen (PSA) concentrations, the TRAVERSE study protocol prespecified procedures for managing PSA elevations and urologic referrals.
Hormone Levels
The mean (SD) total testosterone was 220 (48) ng/dL at baseline.18 As reported, testosterone and estradiol levels,18 as well as dihydrotestosterone levels (eTable 2 in Supplement 3), increased significantly in testosterone-treated men but did not change in placebo-treated men.
Discussion
The TRAVERSE study is, to our knowledge, the largest randomized trial of TRT conducted to date, with prospectively recorded and adjudicated prostate safety outcomes. Among middle-aged and older men with hypogonadism who had or were at increased risk of CVD, the incidence of high-grade or any prostate cancer in TRT-treated men with a baseline PSA concentration less than 3.0 ng/ml was low and not significantly different from that in placebo-treated men. This group of men whose PSA concentration is less than 3.0 ng/mL represents most of the aging US population.26 Similarly, incidences of acute urinary retention, invasive surgical procedures for BPH, or new pharmacologic treatment for LUTSs did not differ between the treatment groups. The invasive prostate surgical procedures were more common in the TRT group compared with the placebo group, although the difference was not significant. Consistent with meta-analyses of smaller testosterone trials, TRT did not increase IPSSs.14,27 Although PSA concentrations increased more among the TRT group than the placebo group, the mean increase was small, and the between-group difference did not widen after 12 months. Thus, in a population of men with hypogonadism and PSA concentrations less than 3 ng/ml who were evaluated carefully to exclude those at increased prostate cancer risk, TRT was associated with a low risk of adverse prostate events, including cancer.
Prostate cancer is highly prevalent among older men, but only a small fraction have high-grade tumors.19 Androgen receptor signaling plays a central role in prostate cancer biology, and testosterone treatment promotes the growth of metastatic prostate cancer.28 A Mendelian randomization analysis found an increased incidence of prostate cancer in men with higher genetically determined testosterone levels29; conversely, men with Klinefelter syndrome have a lower risk of prostate cancer.30 These data have led to concerns that TRT could promote the progression of subclinical low-grade prostate cancer. 1 Because TRT increases PSA in men with hypogonadism, PSA elevations in older men receiving TRT could lead to prostate biopsy and detection of a subclinical low-grade prostate cancer.1To minimize the risk of unnecessary prostate biopsies and mitigate ascertainment bias while enabling detection of prostate cancers for which clinical management may reduce long-term disease-related morbidity and mortality, the study protocol specified PSA elevation thresholds for referral to a urologist.21,31 Elevations in PSA concentrations above these thresholds were verified, and participants with confirmed PSA elevation were asked to watch a video on the significance of PSA elevation and the benefits and risks of prostate biopsy to facilitate a shared decision on prostate biopsy. This approach was effective in reducing the number of prostate biopsies in both treatment groups; the small number of biopsies and high percentage of positive biopsy results in the trial support its usefulness in facilitating shared decision-making before prostate biopsy in men receiving TRT.
Limitations
The trial has some limitations. These findings should not be applied to patients with known prostate cancer, those with higher PSA values, or men who do not have confirmed hypogonadism. Although the TRAVERSE study was longer than most other randomized clinical trials of TRT, carcinogens may require many years to induce malignant neoplasms. The trial’s structured evaluation of men after PSA testing did not include prostate imaging or other biomarker tests that may influence the decision to perform a biopsy. It is possible that shared decision-making played a role in lower rates of prostate biopsy; results could be different in a setting in which shared decision-making is not made available. Although the trial’s sample size is the largest of any randomized testosterone trials to date, the numbers and incidences of any prostate cancer and high-grade prostate cancer were low. Because of the small number of prostate cancer events, these findings should not be interpreted to imply that the risk of prostate cancer in the testosterone and placebo groups was similar. The trial's findings indicate that in men with hypogonadism who were screened and monitored carefully using a structured protocol, the risk of high-grade or any prostate cancer and other prostate events is low. The trial’s findings do not apply to men at high risk of prostate cancer, who were excluded. Rates of study medication discontinuation and loss to follow-up were high, although not dissimilar from those in randomized trials in other symptomatic conditions 32,33 or in hypogonadal men prescribed TRT. 34 The trial was conducted during the COVID-19 pandemic, which affected retention. However, nonretention rates were similar in the 2 groups. Among participants who discontinued trial participation, nearly half did so after end-of-study visits had started, and findings were similar in sensitivity analyses limited to follow-up durations of 1 month or 1 year after the last administered dose. The study population met the Endocrine Society’s criteria for hypogonadism1 but had high rates of diabetes, obesity, and other comorbid conditions, not dissimilar from men with hypogonadism35 receiving TRT in the US.36
Conclusions
In this randomized clinical trial of men with hypogonadism who were carefully evaluated to exclude those at high risk for prostate cancer and followed using a standardized monitoring plan, TRT was associated with low and similar incidences of high-grade or any prostate cancer, acute urinary retention, and invasive surgical procedures for BPH compared with a placebo. Testosterone replacement therapy did not worsen LUTSs. The concern about prostate risk heavily influences decision-making by clinicians and patients who are considering TRT for hypogonadism. The study findings will facilitate a more informed appraisal of the potential risks of TRT.
IMPORTANCE
The effect of testosterone replacement therapy (TRT) on the risk of prostate cancer and other adverse prostate events is unknown.
OBJECTIVE
To compare the effect of TRT vs placebo on the incidences of high-grade prostate cancers (Gleason score 4 + 3), any prostate cancer, acute urinary retention, invasive prostate procedures, and pharmacologic treatment for lower urinary tract symptoms in men with hypogonadism.
DESIGN, SETTING, AND PARTICIPANTS
This placebo-controlled, double-blind randomized clinical trial enrolled 5246 men (aged 45-80 years) from 316 US trial sites who had 2 testosterone concentrations less than 300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk. Men with prostate-specific antigen (PSA) concentrations greater than 3.0 ng/mL and International Prostate Symptom Score (IPSS) greater than 19 were excluded. Enrollment took place between May 23, 2018, and February 1, 2022, and end-of-study visits were conducted between May 31, 2022, and January 19, 2023.
INTERVENTION
Participants were randomized, with stratification for prior CVD, to topical 1.62%testosterone gel or placebo.
MAIN OUTCOMES AND MEASURES
The primary prostate safety endpoint was the incidence of adjudicated high-grade prostate cancer. Secondary endpoints included incidence of any adjudicated prostate cancer, acute urinary retention, invasive prostate surgical procedure, prostate biopsy, and new pharmacologic treatment. The intervention effect was analyzed using a discrete-time proportional hazards model.
RESULTS
A total of 5204 men (mean [SD] age, 63.3 [7.9] years) were analyzed. At baseline, the mean (SD) PSA concentration was 0.92 (0.67) ng/mL, and the mean (SD) IPSS was 7.1 (5.6). The mean(SD) treatment duration was 21.8 (14.2) months in the TRT group and 21.6 (14.0) months in the placebo group. During 14 304 person-years of follow-up, the incidence of high-grade prostate cancer (5 of 2596 [0.19%] in the TRT group vs 3 of 2602 [0.12%] in the placebo group; hazard ratio, 1.62; 95% CI, 0.39-6.77; P = .51) did not differ significantly between groups; the incidences of any prostate cancer, acute urinary retention, invasive surgical procedures, prostate biopsy, and new pharmacologic treatment also did not differ significantly. Change in IPSS did not differ between groups. The PSA concentrations increased more in testosterone-treated than placebo-treated men.
CONCLUSIONS AND RELEVANCE
In a population of middle-aged and older men with hypogonadism, carefully evaluated to exclude those at high risk of prostate cancer, the incidences of high-grade or any prostate cancer and other prostate events were low and did not differ significantly between testosterone- and placebo-treated men. The study’s findings may facilitate a more informed appraisal of the potential risks of TRT.
Introduction
The relationship between testosterone replacement therapy (TRT) and the risk of prostate cancer remains incompletely studied.1-3 Epidemiologic studies have not found a consistent association between prostate cancer risk and testosterone levels or polymorphisms in genes involved in androgen action.4-13 Prostate events were not adjudicated in any testosterone trial, and none have reported the incidence of high-grade prostate cancer or other prostate events, such as acute urinary retention, invasive prostate procedures, or the initiation of new pharmacologic therapy for benign prostatic hyperplasia (BPH).1,14 Because of uncertainty about the risk of prostate events during TRT, most professional society guidelines recommend against TRT in men with a history or increased risk of prostate cancer.1,2,15
In 2015, the US Food and Drug Administration required testosterone manufacturers to conduct a randomized clinical trial to determine the effect of TRT on major adverse cardiovascular events( MACEs).16 The Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) study was designed to meet this regulatory requirement.17 Because of its large size and longer duration, the TRAVERSE study offered a unique opportunity to evaluate the effects of TRT on prostate safety events.17 The study compared the effects of TRT and placebo on the incidences of high-grade prostate cancer, any prostate cancer, acute urinary retention, invasive prostate surgical procedures for BPH, and initiation of pharmacologic therapy for BPH. Prostate events were recorded using a structured protocol and adjudicated. To minimize ascertainment bias due to the greater likelihood of urologic referral for prostate biopsy because of testosterone-induced elevation in prostate-specific antigen (PSA) concentrations, the TRAVERSE study protocol prespecified procedures for managing PSA elevations and urologic referrals.
Hormone Levels
The mean (SD) total testosterone was 220 (48) ng/dL at baseline.18 As reported, testosterone and estradiol levels,18 as well as dihydrotestosterone levels (eTable 2 in Supplement 3), increased significantly in testosterone-treated men but did not change in placebo-treated men.
Discussion
The TRAVERSE study is, to our knowledge, the largest randomized trial of TRT conducted to date, with prospectively recorded and adjudicated prostate safety outcomes. Among middle-aged and older men with hypogonadism who had or were at increased risk of CVD, the incidence of high-grade or any prostate cancer in TRT-treated men with a baseline PSA concentration less than 3.0 ng/ml was low and not significantly different from that in placebo-treated men. This group of men whose PSA concentration is less than 3.0 ng/mL represents most of the aging US population.26 Similarly, incidences of acute urinary retention, invasive surgical procedures for BPH, or new pharmacologic treatment for LUTSs did not differ between the treatment groups. The invasive prostate surgical procedures were more common in the TRT group compared with the placebo group, although the difference was not significant. Consistent with meta-analyses of smaller testosterone trials, TRT did not increase IPSSs.14,27 Although PSA concentrations increased more among the TRT group than the placebo group, the mean increase was small, and the between-group difference did not widen after 12 months. Thus, in a population of men with hypogonadism and PSA concentrations less than 3 ng/ml who were evaluated carefully to exclude those at increased prostate cancer risk, TRT was associated with a low risk of adverse prostate events, including cancer.
Prostate cancer is highly prevalent among older men, but only a small fraction have high-grade tumors.19 Androgen receptor signaling plays a central role in prostate cancer biology, and testosterone treatment promotes the growth of metastatic prostate cancer.28 A Mendelian randomization analysis found an increased incidence of prostate cancer in men with higher genetically determined testosterone levels29; conversely, men with Klinefelter syndrome have a lower risk of prostate cancer.30 These data have led to concerns that TRT could promote the progression of subclinical low-grade prostate cancer. 1 Because TRT increases PSA in men with hypogonadism, PSA elevations in older men receiving TRT could lead to prostate biopsy and detection of a subclinical low-grade prostate cancer.1To minimize the risk of unnecessary prostate biopsies and mitigate ascertainment bias while enabling detection of prostate cancers for which clinical management may reduce long-term disease-related morbidity and mortality, the study protocol specified PSA elevation thresholds for referral to a urologist.21,31 Elevations in PSA concentrations above these thresholds were verified, and participants with confirmed PSA elevation were asked to watch a video on the significance of PSA elevation and the benefits and risks of prostate biopsy to facilitate a shared decision on prostate biopsy. This approach was effective in reducing the number of prostate biopsies in both treatment groups; the small number of biopsies and high percentage of positive biopsy results in the trial support its usefulness in facilitating shared decision-making before prostate biopsy in men receiving TRT.
Limitations
The trial has some limitations. These findings should not be applied to patients with known prostate cancer, those with higher PSA values, or men who do not have confirmed hypogonadism. Although the TRAVERSE study was longer than most other randomized clinical trials of TRT, carcinogens may require many years to induce malignant neoplasms. The trial’s structured evaluation of men after PSA testing did not include prostate imaging or other biomarker tests that may influence the decision to perform a biopsy. It is possible that shared decision-making played a role in lower rates of prostate biopsy; results could be different in a setting in which shared decision-making is not made available. Although the trial’s sample size is the largest of any randomized testosterone trials to date, the numbers and incidences of any prostate cancer and high-grade prostate cancer were low. Because of the small number of prostate cancer events, these findings should not be interpreted to imply that the risk of prostate cancer in the testosterone and placebo groups was similar. The trial's findings indicate that in men with hypogonadism who were screened and monitored carefully using a structured protocol, the risk of high-grade or any prostate cancer and other prostate events is low. The trial’s findings do not apply to men at high risk of prostate cancer, who were excluded. Rates of study medication discontinuation and loss to follow-up were high, although not dissimilar from those in randomized trials in other symptomatic conditions 32,33 or in hypogonadal men prescribed TRT. 34 The trial was conducted during the COVID-19 pandemic, which affected retention. However, nonretention rates were similar in the 2 groups. Among participants who discontinued trial participation, nearly half did so after end-of-study visits had started, and findings were similar in sensitivity analyses limited to follow-up durations of 1 month or 1 year after the last administered dose. The study population met the Endocrine Society’s criteria for hypogonadism1 but had high rates of diabetes, obesity, and other comorbid conditions, not dissimilar from men with hypogonadism35 receiving TRT in the US.36
Conclusions
In this randomized clinical trial of men with hypogonadism who were carefully evaluated to exclude those at high risk for prostate cancer and followed using a standardized monitoring plan, TRT was associated with low and similar incidences of high-grade or any prostate cancer, acute urinary retention, and invasive surgical procedures for BPH compared with a placebo. Testosterone replacement therapy did not worsen LUTSs. The concern about prostate risk heavily influences decision-making by clinicians and patients who are considering TRT for hypogonadism. The study findings will facilitate a more informed appraisal of the potential risks of TRT.
