Estradiol Patch Matches Standard Hormone Therapy in Phase 3 Trial

A transdermal estradiol patch used as androgen-deprivation therapy proved noninferior to luteinizing hormone-releasing hormone (LHRH) agonists for metastasis-free survival in men with locally advanced prostate cancer, according to a large phase 3 randomized trial published in the New England Journal of Medicine.¹ The findings position transdermal estradiol (tE2) as an alternative to standard injectable hormonal therapy, with a meaningfully different adverse events profile that may influence treatment decision-making.

“Following studies testing the relative cardiovascular safety of transdermal estradiol, this publication represents a large open-label study demonstrating similar efficacy outcomes using a strong intermediate end point and may represent an additional treatment option where available,” Scott T. Tagawa, MD, MS, FACP, FASCO, said. Dr Tagawa was not involved in the study.

“Importantly this will give an additional treatment option with shared decision making. Differences in route of administration are important to some patients, with some adverse events [AEs] related to this aspect in addition to patient preferences. There are trade offs in AE profiles with this type of estrogen versus LHRH agonist, some of which will be important to individual patients,” Tagawa, professor of medicine and urology at Weill Cornell Medicine, New York, New York, continued.

The trial showed a 3-year metastasis-free survival of 87.1% in the tE2 group compared with 85.9% in the LHRH agonist group (difference, 1.2 percentage points; 95% CI, -2.5 to 4.9). The hazard ratio for confirmed metastasis or death was 0.96, with the upper limit of the one-sided 95% CI at 1.11, well below the prespecified noninferiority threshold of 1.31. Five-year overall survival also trended in favor of tE2 at 81.1% compared with 79.2% with LHRH agonists (HR, 0.90; 95% CI, 0.75-1.07), though that difference did not reach statistical significance.

Trial Design and Patient Population

The study was conducted through 2 academic networks, PATCH (NCT00303784) and STAMPEDE-1 (NCT00268476), using a seamless phase 2 to 3 adaptive design that enrolled 1360 patients across 75 UK centers from 2007 through 2022. Patients were randomly assigned without blinding to tE2 patches releasing 100 micrograms of estradiol per 24 hours or to standard LHRH agonists administered by subcutaneous injection. The trial incorporated evolving standards of care over its long recruitment window, including the addition of prostate radiotherapy in 2014 and concomitant docetaxel in 2015.

The population was representative of high-risk nonmetastatic disease. The median age was 72 years, 85% of patients had T3 tumors, 23% had node-positive disease, and 60% had a Gleason score of 8, 9, or 10. Baseline characteristics were well balanced between treatment arms.

Efficacy and Testosterone Suppression

The noninferiority criterion was clearly met, with the upper bound of the one-sided 95% CI for the hazard ratio equivalent to excluding a between-group difference of just 2 percentage points in metastasis-free survival. Among evaluable PATCH patients, estosterone levels below 1.7 nmol/L were sustained during the first year of treatment in 85% of patients in each group who continued their assigned therapy. The tE2 group achieved faster initial testosterone suppression at 1 month (83% compared with 60% for LHRH agonists), with rates converging thereafter.

Safety and Tolerability

The 2 regimens produced distinctly different adverse event profiles. Grade 3 or higher adverse events occurred in 16% of tE2 patients compared with 19% of those receiving LHRH agonists, indicating broadly comparable overall toxicity.

Hot flashes were less common with tE2, occurring in 44% of patients compared with 89% of those receiving LHRH agonists, with grade 2 or higher events reported in 8% compared with 37%, respectively. Gynecomastia represented the principal drawback of tE2, occurring in 85% of patients in that group compared with 42% of those receiving LHRH agonists, with grade 2 or higher events in 37% compared with 9%. Prophylactic breast irradiation, used in only 8% of tE2 patients, did not appear to meaningfully reduce gynecomastia rates.

Fracture data favored tE2 substantially. At least 1 fracture had occurred in 2.8% of patients in the tE2 arm by year 5 and 5.1% by year 10, compared with 5.8% and 10.5%, respectively, in the LHRH agonist group, consistent with prior evidence that tE2 preserves bone mineral density. Rates of erectile dysfunction and decreased libido were similar across both arms at approximately 65% and 60%, respectively.

Caveats and Clinical Implications

The authors acknowledged that the long recruitment window introduced heterogeneity in background therapy, that quality-of-life data have not yet been analyzed, and that median treatment duration was shorter in the tE2 arm at 3.25 years compared with 4.27 years for LHRH agonists, largely due to patients switching because of toxicity or disease progression.

The PATCH/STAMPEDE-1 data provide a robust evidence base to incorporate tE2 patches into treatment discussions as a genuine alternative to injectable hormonal therapy, particularly for patients seeking to avoid injections, minimize vasomotor symptoms, or reduce long-term skeletal complications.

REFERENCE

Langley RE, Gilbert DC, Mangar S, et al. Transdermal estradiol patches in locally advanced prostate cancer. N Engl J Med. 2026; published March 25, 2026. Accessed March 27, 2026. https://tinyurl.com/4mb8t82f