Transdermal estradiol patches positioned as ADT alternative for prostate cancer

A large phase 3 randomized trial has demonstrated that transdermal estradiol (tE2) patches are noninferior to injectable luteinizing hormone–releasing hormone (LHRH) agonists for 3-year metastasis-free survival (MFS) in men with locally advanced prostate cancer.¹

The findings, published in the New England Journal of Medicine, represent the culmination of nearly 2 decades of work through the PATCH (NCT00303784) and STAMPEDE-1 (NCT00268476) trial programs. Previous data from the phase 2 randomized trials showed that tE2 patches had an improved metabolic profile, preservation of bone mineral density, improved quality-of-life scores, and no evidence of higher cardiovascular risk compared with LHRH agonists.

The trial enrolled 1360 patients across 75 centers in the United Kingdom between 2007 and 2022. Patients were randomly assigned to receive tE2 patches delivering 100 μg of estradiol per 24 hours or to standard LHRH agonists administered by subcutaneous injection. The median age of participants was 72 years (IQR, 68 to 77). Across the study population, 85% of patients had T3 tumors, and 65% had N0 nodal stage disease.

The primary outcome was 3-year MFS, with a noninferiority margin of 4 percentage points corresponding to a target HR of 1.31 derived from observed outcomes in the LHRH agonist group. Secondary outcomes included castrate levels of testosterone (less than 1.7 nmol/L), overall survival (OS), and safety.

Three-year MFS was 87.1% with tE2 vs 85.9% with LHRH agonists, yielding an HR of 0.96 for confirmed metastasis or death (upper limit of the one-sided 95% confidence interval, 1.11), which met the criterion for noninferiority. Five-year OS was 81.1% with tE2 and 79.2% with LHRH agonists (HR, 0.90; 95% CI, 0.75 to 1.07). Castrate levels of testosterone (less than 1.7 nmol/L) were sustained during the first year after randomization in 85% of patients in each group among those continuing assigned treatment.

The safety profile for tE2 differed from standard LHRH injections. Hot flashes occurred in 44% of the tE2 group compared with 89% of the LHRH agonist group. Grade 2 or higher hot flashes were reported in 8% vs 37% of patients, respectively. Conversely, gynecomastia was more common in the tE2 group, occurring in 85% of patients in the tE2 cohort vs 42% of patients in the standard LHRH cohort. Grade 2 or higher gynecomastia events occurred in 37% vs 9% of patients, respectively. Further, 2.8% of patients in the tE2 arm vs 5.8% of patients in the LHRH arm experienced at least 1 bone fracture at 5 years after entering the trial.

According to the authors, these results demonstrate that transdermal estradiol can be considered a clinically viable choice for testosterone suppression.

“We believe our findings should lead to men with locally advanced prostate cancer being able to choose which hormone therapy suits them best,” said lead author Ruth E. Langley, FRCP, PhD, of the MRC Clinical Trials Unit at the University College, London (UCL), in a news release on the findings.² “For some men, for instance, hot flushes can be very debilitating, and so the patches could greatly increase their quality of life.”

The tE2 patches used in the trial are the same formulation currently licensed for menopausal hormone replacement therapy in women. These patches are not currently indicated to treat prostate cancer, meaning that, for now, tE2 remains available only through off-label prescribing.

Langley added, “We hope these patches can be made more easily available to treat prostate cancer so that men have the benefit of a choice of treatment.”

UCL Business Ltd, the university's commercialization arm, is working with Langley and her team to engage with potential manufacturers and license holders to pursue regulatory approval of the patches for prostate cancer.

"Seeing these positive results published is a testament to all of the patients that took part in the trial and the hard work undertaken by research teams at UK hospitals over many years,” said Duncan C. Gilbert, FRCP, PhD, a consultant clinical oncologist based at the MRC Clinical Trials Unit at UCL, who recruited many patients for the trial. “The ease of administration and improved [adverse] effect profile offers real choice for patients, and I look forward to this option for testosterone suppression being available to the wider population of patients needing treatment for prostate cancer."

REFERENCES

1. Langley RE, Gilbert DC, Mangar S, et al; STAMPEDE-1 and PATCH Investigators. Transdermal estradiol patches in locally advanced prostate cancer. N Engl J Med. 2026;394(16):1595-1607. doi:10.1056/NEJMoa2511781

2. Hormone patches effective for locally advanced prostate cancer. News release. University College London. March 26, 2026. Accessed March 31, 2026. https://www.ucl.ac.uk/news/2026/mar/hormone-patches-effective-locally-advanced-prostate-cancer