A Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Utility of Tacrolimus (FK506) for the Prevention of Erectile Dysfunction Following Bilateral Nerve-Sparing Radical Prostatectomy.
INTRODUCTION
Radical prostatectomy (RP) is associated with erectile dysfunction, largely mediated through cavernous nerve injury. There are robust pre-clinical data supporting a potential role for neuromodulatory agents in this patient population. This study assessed tacrolimus in improving erectile function recovery rates after RP (ClinicalTrials.gov number, NCT00106392).


AIM
To define the utility of oral tacrolimus in improving erectile function recovery after nerve sparing radical prostatectomy.


METHODS
A randomized, double-blind trial compared tacrolimus 2-3 mg daily and placebo in men undergoing RP. Patients had localized prostate cancer and excellent baseline erectile function, underwent bilateral nerve-sparing RP, and were followed up for at least 18 months after RP. Patients received study drug for 27 weeks and completed the International Index of Erectile Function erectile function domain (EFD) questionnaire at baseline and serially after surgery.


MAIN OUTCOME MEASURES
International Index of Erectile Function erectile function domain score.


RESULTS
Data were available for 124 patients (59 tacrolimus, 65 placebo); mean age was 54.6 ± 6.2 years. No patient experienced permanent creatinine or potassium elevation. At baseline, mean EFD scores were 28.6 ± 2.1 (tacrolimus group) and 29 ± 1.5 (placebo group). By week 5, mean EFD scores had dropped to 8 ± 9.4 (tacrolimus) and 9 ± 10.7 (placebo). At 18 months, mean EFD scores were 16.0 ± 11.3 (tacrolimus) and 20.2 ± 9.0 (placebo) (P = .09). Tacrolimus failed to meet significance (hazard ratio = 0.83; P = .50), with no difference in: (i) percentage of patients achieving normal spontaneous erectile function (EFD score ≥24), (ii) time to normalization of EFD score (≥24), (iii) percentage of patients capable of intercourse in response to phosphieserase type 5 inhibitor (PDE5i), and (iv) time to achieve response to PDE5i.


CLINICAL IMPLICATIONS
Despite positive animal data, oral tacrolimus as used in this trial failed to improve erectile function after nerve sparing radical prostatectomy.


STRENGTHS & LIMITATIONS
The study is limited by a high attrition rate. The strengths include a randomized, placebo controlled design, extensive patient monitoring, use of medication diaries and a validated instrument as the primary outcome measure.


CONCLUSION
Despite supportive animal data, tacrolimus used in this fashion in the RP population failed to demonstrate any superiority over placebo. Mulhall JP, Klein EA, Slawin K, et al. A Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Utility of Tacrolimus (FK506) for the Prevention of Erectile Dysfunction Following Bilateral Nerve-Sparing Radical Prostatectomy. J Sex Med 2018;15:1293-1299.
['Mulhall|John P|JP|', 'Klein|Eric A|EA|', 'Slawin|Kevin|K|', 'Henning|Alice K|AK|', 'Scardino|Peter T|PT|']
D000368:Aged D004311:Double-Blind Method D007172:Erectile Dysfunction D006801:Humans D008297:Male D008875:Middle Aged D018377:Neurotransmitter Agents D010410:Penile Erection D011183:Postoperative Complications D011468:Prostatectomy D011471:Prostatic Neoplasms D020127:Recovery of Function D011795:Surveys and Questionnaires D016559:Tacrolimus D016896:Treatment Outcome D014481:United States
Tacrolimus Radical Prostatectomy Erectile Function Recovery Prostate Cancer Immunophilin Ligands Neuromodulation