A majority of men with prostate cancer have low-grade cancer and an excellent prognosis after radical prostatectomy. Hypogonadism and associated symptoms impair quality of life in prostate cancer survivors. Many guidelines, citing a lack of randomized clinical trials showing safety and efficacy of testosterone replacement therapy (TRT), consider a history of prostate cancer a contraindication for TRT.
To evaluate the short-term safety and efficacy of TRT in prostate cancer survivors with symptomatic hypogonadism.
This randomized, placebo-controlled, double-blind, parallel-group, phase 2 trial was conducted at 2 academic medical centers in men 40 years and older with organ-confined, low-grade prostate cancer (Gleason score of 6 [3 + 3] or 7 [3 + 4]). Participants had undetectable prostate-specific antigen (PSA) for at least 2 years after radical prostatectomy, a mean of 2 testosterone levels less than 275 ng/dL, and low libido, erectile dysfunction, or fatigue. Patients were allocated using concealed, block randomization, with stratification for age (40-60 years or >60 years) and phosphodiesterase-5 inhibitor (PDE5I) use. The first participant was randomized on May 13, 2019, and the last study visit was completed on May 16, 2025.
Testosterone cypionate, 100 mg, or placebo intramuscularly weekly for 12 weeks.
The primary efficacy outcome was sexual activity. Secondary outcomes included sexual desire, erectile function, well-being, body composition, aerobic capacity, and physical function. The safety outcome was biochemical recurrence (PSA ≥ 0.2 ng/mL).
A total of 136 men were randomized, 68 to receive testosterone cypionate, 100 mg, and 68 to receive placebo, and 125 men completed the study. Groups were similar at baseline (mean [SD] age, 68.6 [6.5] years; 52 [38%] had a Gleason score of 6; and 84 [62%] had a Gleason score of 7). No participant in either group experienced biochemical recurrence. TRT significantly increased sexual activity more than placebo, adjusted for PDE5I use and age (between-group difference, 0.91 daily events [95% CI, 0.56-1.26]; P < .001). TRT increased sexual desire and prostate cancer quality-of-life sexual domain score, and decreased negative affect more than placebo. Erectile function did not change. TRT significantly improved body composition, loaded stair-climbing power, and peak aerobic performance (VO2 peak) compared with placebo.
In this randomized clinical trial, TRT for 12 weeks in men treated with radical prostatectomy for low-grade prostate cancer significantly improved sexual activity, sexual desire, well-being, body composition, physical function, and aerobic performance compared to placebo without biochemical recurrence. The trial was neither long enough nor large enough to evaluate clinical recurrence or long-term safety; this proof-of-concept trial was essential for rationalizing a larger, long-term study. These findings do not apply to men with high-grade prostate cancer or those treated with androgen deprivation therapy or radiation therapy.
ClinicalTrials.gov Identifier: NCT03716739
Testosterone replacement therapy after radical prostatectomy: Are we finally entering the evidence-based era?
For decades, testosterone replacement therapy (TRT) was considered contraindicated in men with prostate cancer (PCa) because of the historical belief that testosterone directly stimulates PCa growth. This paradigm originated from the landmark work of Huggins and Hodges in 1941, who demonstrated that androgen deprivation induced clinical improvement in metastatic prostate cancer and that exogenous testosterone appeared to increase disease activity in a small number of patients. These observations on PCa androgen dependency led to Huggins winning the Nobel Prize in 1966 and to the bases of androgen deprivation therapy. However, these findings also led to the longstanding assumption that higher testosterone levels invariably promote PCa progression. However, the original data were limited, involved advanced metastatic disease, and predated modern concepts of physiological testosterone replacement. Over the last two decades, the “saturation model”, largely promoted by Morgentaler and colleagues, challenged this dogma by suggesting that androgen receptors become saturated at relatively low testosterone levels, beyond which additional testosterone may not further stimulate tumor growth. Subsequent observational studies in carefully selected men treated for localised PCa have reported low recurrence rates after TRT, progressively shifting the field toward a more individualised and evidence-based approach focused not only on oncologic safety but also on survivorship and quality of life.
Despite increasing observational evidence suggesting oncologic safety in carefully selected patients, most international guidelines still consider previous PCa only in selected men whilst others still consider it a relative contraindication to TRT because of the lack of prospective randomised evidence.
In this context, the recently published phase II randomised clinical trial by Bhasin et al. represents an important milestone in the field. Not because of the level of evidence but rather as it testifies the willingness of an evidence-based paradigm shift.
The investigators randomised 136 hypogonadal men previously treated with radical prostatectomy for organ-confined low-intermediate risk PCa (Gleason 3+3 or 3+4) to receive either testosterone cypionate or placebo for 12 weeks with a subsequent three months follow up. Importantly, all patients had undetectable (<0.2ng/mL) PSA for at least 2 years before enrollment.
The study demonstrated significant improvements in:
In favor of TRT, without biochemical recurrence during treatment or during the short post-treatment follow-up period.
These findings are of interest. Yet, many clinicians remain reluctant to prescribe TRT because of persistent oncologic concerns.
This study provides the first prospective randomised data to date supporting the short-term functional benefits of TRT in carefully selected PCa patients.
Of note, several important limitations must temper enthusiasm.
First, this was a relatively small phase II trial and was clearly underpowered to evaluate oncologic safety endpoints.
Second, follow-up duration was short, making it impossible to draw conclusions regarding long-term biochemical recurrence, metastatic progression, or cancer-specific survival.
Third, results only apply to a highly selected population with favourable pathology after radical prostatectomy and cannot be generalised to:
· high-risk disease, would ideally represent the setting of interest, as the vast majority of men included in the trial would not be actively treated but rather undergo active surveillance or gland preserving strategies in the modern era
· men treated with radiotherapy
· patients receiving androgen deprivation therapy or men with detectable PSA
Another important point is that the absence of biochemical recurrence over a short follow up in low to intermediate risk disease should not be interpreted as definitive evidence of oncologic safety.
Nevertheless, this trial may represent a paradigm shift. Rather than asking whether TRT should categorically be avoided after PCa, the field may progressively move toward identifying which patients can safely benefit from carefully monitored testosterone restoration.
Ultimately, the study by Bhasin et al. reinforces an increasingly important concept in uro-oncology: quality of life matters, and evidence-based supportive care strategies should not be overlooked in men cured from low-risk PCa. Their work paves the way for Phase III trials and Phase II trials in patients at higher PCa risk who would benefit from TRT.