Multicenter phase 3 trial of transdermal estradiol patches in locally advanced prostate cancer

Transdermal estradiol (tE2) is an alternative to luteinizing hormone-releasing hormone (LHRH) agonists as androgen deprivation therapy for prostate cancer. With tE2, testosterone is suppressed, and the side effects of estrogen depletion due to LHRH agonists and the thromboembolic side effects of oral estrogen are mitigated. In a phase 3 trial at 75 UK centers. Men with locally advanced (M0 and N0 or N+) prostate cancer were randomized to receive tE2 patches (100 μg of estradiol every 24 hours) or LHRH agonists. The primary outcome was 3-years metastasis-free survival (MFS) rate, with a noninferiority margin of 4 percentage points. Among 1360 randomized patients (median age 72 years; IQR 68-77; 85% T3 tumor stage; 65% N0 nodal stage), the observed 3-year MFS rate was 87.1% with tE2 and 85.9% with LHRH agonists (HR 0.96; upper limit of the one-sided 95% CI 1.1; which met the criterion for noninferiority). Among patients continuing the assigned treatment, castrate levels of testosterone (<1.7 nmol per liter) were sustained during the first year after randomization in 85% in each group. Observed 5-year overall survival rate was 81.1% with tE2 and 79.2% with LHRH agonists (HR 0.90; 95% CI 0.75-1.07). During treatment, hot flashes occurred in 44% of patients who received tE2 and 89% of those who received LHRH agonists (grade≥2, 8% and 37%, respectively) and gynecomastia in 85% and 42% (grade ≥2: 37% and 9%). The authors conclude that in patients with locally advanced prostate cancer, tE2 was noninferior to LHRH agonists for 3-year MFS, with a lower incidence of hot flashes but a higher incidence of gynecomastia.