Transdermal Estradiol Noninferior to LHRH Agonists in Locally Advanced Prostate Cancer

Key Clinical Summary: 

• Design/Population: This phase 3 randomized noninferiority trial enrolled 1360 patients with locally advanced prostate cancer to receive transdermal estradiol or LHRH agonists. 
• Key Outcomes: Transdermal estradiol demonstrated noninferior metastasis-free survival and similar overall survival compared with LHRH agonists. Testosterone suppression rates were comparable between treatment groups.
• Clinical Relevance: Transdermal estradiol offers an alternative androgen-deprivation therapy with fewer vasomotor symptoms but increased gynecomastia. This approach may be considered for selected patients based on toxicity preferences.

Results from a phase 3 study demonstrated that transdermal estradiol was noninferior to luteinizing hormone-releasing hormone (LHRH) agonists for survival outcomes in patients with locally advanced prostate cancer.

“Transdermal estradiol is an alternative to LHRH agonists as androgen-deprivation therapy in patients with prostate cancer,” stated Ruth Langley, FRCP, PhD, University College, London, England, and coauthors. “With [transdermal estradiol], 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 this study, 1360 patients were randomized to receive either 100 μg every 24 hours of transdermal estradiol patches or LHRH agonists. The primary end point was 3-year metastasis-free survival, with a prespecified noninferiority margin corresponding to a hazard ratio of 1.31. The key secondary end points included testosterone suppression, overall survival (OS), and safety.

At analysis, the 3-year metastasis-free survival rate was 87.1% in the transdermal estradiol arm and 85.9% in the LHRH agonist arm (hazard ratio [HR], 0.96). Castrate testosterone levels were maintained in 85% of patients in both groups during the first year. The 5-year OS rate was 81.1% in the transdermal estradiol arm and 79.2% with LHRH agonist arm (HR, 0.90).

The safety profile differed between treatment arms. Hot flashes occurred in 44% of patients in the transdermal estradiol arm and 89% of patients in the LHRH agonist arm, with grade ≥ 2 events occurring in 8% and 37% of patients, respectively. Gynecomastia occurred in 85% of patients in the transdermal estradiol arm and 42% of patients in the LHRH agonist arm, with grade ≥ 2 events occurring in 37% and 9% of patients, respectively.

As Dr Langley et al. concluded, “in patients with locally advanced prostate cancer, [transdermal estradiol] was noninferior to LHRH agonists for 3-year metastasis-free survival, with a lower incidence of hot flashes but a higher incidence of gynecomastia.” 

Source: 

Langley RE, Gilbert DC, Mangar S, et al. Transdermal estradiol patches in locally advanced prostate cancer. N Engl J Med. Published online: March 25, 2026. doi:10.1056/NEJMoa2511781