Testosterone Treatment in Prostate Cancer Survivors With Hypogonadism

Importance: 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. Objective: To evaluate the short-term safety and efficacy of TRT in prostate cancer survivors with symptomatic hypogonadism. Design, Setting, and Participants: 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. Intervention: Testosterone cypionate, 100 mg, or placebo intramuscularly weekly for 12 weeks. Main Outcomes and Measures: 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). Results: 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. Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT03716739.