Prostate Safety Events During Testosterone Replacement Therapy in Men With Hypogonadism: A Randomized Clinical Trial.

The incidence of high-grade prostate cancer (Gleason score ≥4+3) did not differ significantly between TRT and placebo groups.

• 5 of 2596 (0.19%) in the TRT group vs 3 of 2602 (0.12%) in the placebo group developed high-grade prostate cancer.
• Hazard ratio was 1.62 (95% CI, 0.39–6.77; P = .51).
• This was the primary prostate safety end point of the trial.
• Follow-up totaled 14,304 person-years across both groups.

The incidences of any prostate cancer, acute urinary retention, invasive surgical procedures, prostate biopsy, and new pharmacologic treatment for lower urinary tract symptoms did not differ significantly between TRT and placebo groups.

• All secondary prostate safety end points were analyzed using a discrete-time proportional hazards model.
• No statistically significant differences were found for any of these secondary end points.
• Men with PSA >3.0 ng/mL or IPSS >19 were excluded at baseline, limiting the study to a lower-risk population.

PSA concentrations increased more in testosterone-treated men than in placebo-treated men.

• This was observed over a mean treatment duration of 21.8 (SD 14.2) months in the TRT group and 21.6 (SD 14.0) months in the placebo group.
• Despite the PSA increase, this did not translate into a statistically significant difference in prostate cancer incidence.
• Baseline mean PSA concentration was 0.92 (SD 0.67) ng/mL across the study population.

Change in International Prostate Symptom Score (IPSS) did not differ between TRT and placebo groups.

• Baseline mean IPSS was 7.1 (SD 5.6), indicating mildly symptomatic men on average.
• Men with IPSS >19 were excluded at enrollment.
• No statistically significant between-group difference in IPSS change was observed over the follow-up period.

The trial enrolled 5246 men with hypogonadism and cardiovascular disease or increased cardiovascular risk, with 5204 analyzed.

• Participants were aged 45–80 years (mean [SD] age, 63.3 [7.9] years) from 316 US trial sites.
• Eligibility required 2 testosterone concentrations <300 ng/dL and hypogonadal symptoms.
• Men were randomized to topical 1.62% testosterone gel or placebo, stratified for prior cardiovascular disease.
• Enrollment occurred between May 23, 2018, and February 1, 2022; end-of-study visits between May 31, 2022, and January 19, 2023.

Men at high risk of prostate cancer were excluded from the trial by pre-specified PSA and IPSS thresholds.

• Exclusion criteria included PSA >3.0 ng/mL and IPSS >19 at baseline.
• The authors note these findings apply to 'a population of middle-aged and older men with hypogonadism, carefully evaluated to exclude those at high risk of prostate cancer.'
• Overall incidences of prostate events were described as 'low' in both groups.