Clinical Trial Protocol: Impact of Testosterone Replacement Therapy on Functional and Oncological Outcomes Following Radical Prostatectomy (ENFORCE Study).

Abstract

Background and objective: Testosterone deficiency (TD) affects 18-38% of men undergoing radical prostatectomy (RP) for localised prostate cancer and may impair postoperative sexual rehabilitation. Testosterone replacement therapy (TRT) may improve sexual function and is assumed to be oncologically safe following RP, though evidence is based on nonrandomised, retrospective studies. The ENFORCE study evaluates the effects of TRT on sexual function recovery and on biochemical recurrence (BCR) following RP in men with TD.

Clinical trial design and time frame: The ENFORCE study is a phase 3, multicentre, randomised, single-blind, placebo-controlled trial being conducted at ten Dutch centres. Eligible patients with TD (total testosterone <8 nmol/l, or total testosterone 8-12 nmol/l with free testosterone <225 pmol/l) and minimal preserved erectile function (Expanded Prostate Cancer Index Composite 26 [EPIC-26] sexual domain ≥40) undergoing RP are randomised to receive TRT or placebo from 6-12 wk after RP until 1 yr after RP.

Endpoints: The primary endpoint is sexual function at 12 mo (EPIC-26 sexual domain). The secondary endpoints include sexual function at 6 and 24 mo, and quality of life, and hormonal and urinary function at 12 and 24 mo, assessed by the EPIC-26 and Aging Males' Symptoms questionnaires. BCR is evaluated at 12, 24, and 60 mo.

Data sources and statistical analysis: Outcomes include patient-reported outcomes and laboratory results. Linear regression will assess the effect of TRT on sexual function, adjusting for baseline variability.

Strengths and limitations: Strengths include the randomised design and long-term follow-up. Limitations include potential recruitment challenges due to specific inclusion criteria, limited to men with TD and minimal preserved sexual function.

Funding: This work was supported by KWF Dutch Cancer Society, Besins Healthcare, and Canisius Wilhelmina Hospital Research Fund.

Ethics and trial registration: This trial was approved by the Medical Research Ethics Committee Oost-Nederland (ClinicalTrials.gov, NCT04833426).

Patient summary: For men with low testosterone undergoing surgery for prostate cancer (radical prostatectomy), testosterone replacement therapy (TRT) may improve recovery of sexual function and general well-being. The ENFORCE trial investigates whether TRT indeed improves sexual recovery after prostate cancer surgery and whether it can be administered safely. Although TRT is generally believed to be safe, this is based on small or potentially biased studies, and has never been investigated in a large clinical trial. Some concerns remain that TRT increases the risk of prostate cancer recurrence. The results of this trial may provide answers about the benefits and safety of TRT after prostate cancer surgery.