Transdermal estradiol Matches LHRH Agonists in Survival With Different Side Effect Profile in prostate cancer: NEJM

A recent study published in The New England Journal of Medicine found that transdermal estradiol (tE2) therapy was noninferior to luteinizing hormone–releasing hormone (LHRH) agonists in terms of 3-year metastasis-free survival in patients with locally advanced prostate cancer. It was associated with fewer hot flashes but a higher incidence of gynecomastia.

Androgen-deprivation therapy reduces testosterone levels, which fuel prostate cancer growth. While LHRH agonists are widely used, they are known to cause significant side effects linked to estrogen depletion and bone-related complications. Oral estrogen has previously been explored as an alternative but carries a higher risk of thromboembolic events. Transdermal estradiol aims to bypass these risks while maintaining hormonal suppression.

This phase 3 randomized trial enrolled 1,360 men across 75 centers in the UK between 2007 and 2022. The participants had locally advanced prostate cancer without distant metastases and were randomly assigned to receive either estradiol patches or conventional LHRH agonists.

The primary endpoint of this study was metastasis-free survival at 3 years. The results showed that 87.1% of patients using estradiol patches remained free of metastasis, when compared to 85.9% of those receiving LHRH agonists. The hazard ratio of 0.96 confirmed that the patch was not inferior to standard therapy, meeting the predefined criteria of the trial.

Both treatment groups achieved and maintained castrate levels of testosterone in 85% of patients during the first year. Overall survival rates at 5 years were also similar, at 81.1% for the estradiol group and 79.2% for the LHRH group.

The patients using estradiol patches reported substantially fewer hot flashes around 44% when compared to 89% in the LHRH group. Severe hot flashes were also less common. On the other hand, gynecomastia was more frequent with estradiol, by affecting 85% of patients when compared to 42% in the standard therapy group.

Overall, the findings of this study suggest that transdermal estradiol represents a credible alternative to LHRH agonists for men with locally advanced prostate cancer. Further research is imperative to explore long-term safety outcomes and to refine patient selection for this therapy.

Source:

Langley, R. E., Gilbert, D. C., Mangar, S., Rosen, S., Bourmaki, E., Rush, H. L., Kananga Sundaram, S., Alhasso, A., Kockelbergh, R., Abdel-Aty, H., Amos, C. L., Brown, L., Brown, S., Carvalho, C., Chan, K., Collins, G., Cross, W., Deighan, J., Dixit, S., … Nankivell, M. (2026). Transdermal estradiol patches in locally advanced prostate cancer. The New England Journal of Medicine, NEJMoa2511781. https://doi.org/10.1056/nejmoa2511781