Impact of Peri-operative tEstosterone Levels on oNcological and Functional Outcomes in RadiCal prostatEctomy (ENFORCE)

Impact of Peri-operative tEstosterone Levels on oNcological and Functional Outcomes in RadiCal prostatEctomy

Impact of Peri-operative tEstosterone Levels on oNcological and Functional Outcomes in RadiCal prostatEctomy

Sexual dysfunction is a common side effect of radical prostatectomy (RP) and has a significant negative impact on quality of life. With age the testosterone level in men declines; around 30% of men over 70 years of age meet the criteria of testosterone deficiency (TD). The negative impact of both TD and RP on sexual performance are likely to add up. The aim of this study is to assess the efficacy and safety of testosterone replacement therapy (TRT) on functional and oncological outcomes in testosterone deficient men following RP for prostate cancer (PCa).

Rationale: Radical prostatectomy (RP) is currently the most common treatment for non-metastatic prostate cancer (PCa). Two frequent side effects of this procedure are urinary incontinence and erectile dysfunction, both having a significant negative impact on quality of life. Additionally, it is known that with age the testosterone level in men declines. This does not lead to symptoms in all men (asymptomatic testosterone deficiency). Both testosterone deficiency (TD) and radical prostatectomy are well-established to have a significant negative impact on sexual performance and are likely to add up in patients with a low testosterone following RP. Objective: The aim of this study is to assess the effect of testosterone replacement therapy (TRT) on functional and oncological outcomes in testosterone deficient men following RP for PCa. Study design: This study is a phase 3 prospective, randomized, placebo-controlled, single-blind clinical trial. Study population: All men over 18 years old diagnosed with non-metastatic prostate cancer who are scheduled for RP within three months as primary treatment, can be prescreened for inclusion. Prior to the RP, serum testosterone will be determined. Subsequently, within six weeks after the RP, serum testosterone will be determined again and patients will be screened for inclusion. If necessary, a third measurement of testosterone will be done. Eligible patients meet the criteria for TD and other inclusion criteria. Intervention: Patients will be randomized for testosterone replacement therapy (TRT) or placebo as a daily administered topical gel starting within 8 weeks after RP. Patients will receive TRT or placebo for one year following RP and will be monitored for another year for functional outcomes and for four more years to establish 5-year biochemical recurrence (BCR) free survival. Main study parameters/endpoints: The primary study endpoint is a clinically relevant (12 points or more) difference in the EPIC-26 domain for sexual functioning 12 months after RP in favor of testosterone deficient men receiving TRT compared with testosterone deficient men receiving placebo. Secondary endpoints include: urinary incontinence score, hormonal functioning score and BCR-free survival. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The number of visits and blood drawings are equal to standard of care follow-up after RP, with the exception of two or three extra blood samples at the first prescreening visit and within six weeks following RP. We ask patients to remain with their hospital for 24 months after RP for follow-up and to complete online questionnaires for the given visits. The five-year biochemical recurrence (BCR) free survival will be obtained through patient's medical records and if insufficient, through the Dutch Cancer Registry (NKR). Patients who receive TRT or placebo can experience local side-effects such as itching, rash and/or irritation at the site of application. In addition, patients who receive TRT can experience systemic sideeffects are gain of weight, hot flashes, acne and an increase in red blood count level. Furthermore, TRT might improve sexual functioning, urinary continence, hormonal functioning and BCR-free survival, but this is not certain and is subject of research in this study.

Daily application of two pump auctions of 16.2mg/ml testosterone gel. Dosage may be altered depending on clinical response

Clinically relevant (≥12 points) difference in the EPIC-26 sexual functioning domain score, 12 months after radical prostatectomy between groups.

Functional recovery after radical prostatectomy will be assessed by EPIC-26 questionnaire, a Patient Reported Outcome Measure (PROM). Patients will be asked to complete this questionnaire online.

Clinically relevant (≥12 points) difference in the EPIC-26 sexual functioning domain score 3 months after radical prostatectomy between groups.

Clinically relevant (≥12 points) difference in the EPIC-26 sexual functioning domain score 24 months after radical prostatectomy between groups.

Clinically relevant (≥9 points) difference in the EPIC-26 urinary incontinence domain score, 12 months after radical prostatectomy between groups.

Clinically relevant (≥9 points) difference in the EPIC-26 urinary incontinence domain score, 24 months after radical prostatectomy between groups.

Clinically relevant (≥6 points) difference in the EPIC-26 for hormonal functioning domain score, 12 months after radical prostatectomy between groups.

Clinically relevant (≥6 points) difference in the EPIC-26 for hormonal functioning domain score, 24 months after radical prostatectomy between groups.

Biochemical recurrence (BCR) is defined as the occurrence of measurable (>0.1 ng/ml) prostate specific antigen (PSA), during routinely follow-up up to five years after surgery, determined at two different occasions with at least one week between them.The BCR-rate between the placebo and control group will be compared to determine the influence of testosterone therapy on BCR.

Inclusion Criteria: Unmeasurable PSA after RP pT2-pT3a after RP ISUP 1-3 regardless of surgical margins ISUP 4-5 with negative surgical margins At least one-sided nerve-sparing procedure Baseline score sexual functioning domain of ≥ 40 points (EPIC-26) Exclusion Criteria: Metastatic disease (cN1/M1) pT3b or pT4 after RP Prior treatment for PCa Prior TRT Medical history of male breast- or liver carcinoma Uncontrolled hypertension General contra-indication for TRT Allergy for components in TRT Use of vitamin K-antagonists BMI > 30