Estradiol Patch Matches LHRH Agonists for Locally Advanced Prostate Cancer

Transdermal estradiol for locally advanced prostate cancer matched luteinizing hormone-releasing hormone (LHRH) agonists as androgen deprivation therapy (ADT) for reducing distant metastasis, and with fewer vasomotor symptoms, a large randomized trial showed.

Men treated with the transdermal patches had a 3-year metastasis-free survival (MFS) of 87.1% versus 85.9% with LHRH agonists, a difference that met prespecified statistical criteria for noninferiority. Overall survival (OS) at 5 years also did not differ between groups. The two interventions maintained castrate levels of testosterone in an identical proportion of patients.

Hot flashes occurred less frequently with estradiol but gynecomastia occurred more often, reported Ruth E. Langley, PhD, of University College London, and colleagues in the New England Journal of Medicine.

“Given these findings, tE2 [transdermal estradiol] patches can be considered an alternative choice for testosterone suppression in men with metastasis stage M0 and nodal stage N0 or N+ prostate cancer,” the authors concluded. “The patches appear to be as effective as standard LHRH agonists against prostate cancer and are associated with a lower incidence of the short-term and long-term deleterious adverse events related to estrogen depletion during treatment with LHRH agonists.”

For more than 80 years, shortly after Huggins and Hodges reported prostate cancer regression after marked reductions in testosterone, ADT has been a mainstay of treatment for the cancer. Most often, LHRH agonists have been used to reduce serum testosterone to <50 ng/dL (castrate levels).

However, LHRH agonists have several toxic effects, Langley and colleagues noted. Notable adverse effects include erectile dysfunction, loss of muscle mass and bone mineral density, adverse cardiometabolic changes, and hot flashes.

Exogenous estrogen offers an alternative approach to lowering testosterone, effected by means of a negative feedback loop involving the hypothalamus and pituitary gland. The approach also mitigates adverse effects of estrogen depletion, the authors continued.

Studies of oral estrogen confirmed the suppressive effect on testosterone but was associated with an increased incidence of thromboembolic events, attributed to first-pass hepatic metabolism and increased levels of liver-derived plasma proteins and coagulation factors. Langley and colleagues previously showed that estrogen administration by transdermal patch avoids first-pass hepatic metabolism, conferring a lower risk of thromboembolic complications.

The accumulation of evidence provided the rationale for a phase II-III adaptive trial to assess the safety and efficacy of transdermal estradiol patches in patients with locally advanced prostate cancer. The phase II component of the study examined cardiovascular morbidity and mortality in 200 patients and showed a better metabolic profile and no early evidence of increased cardiovascular risk.

During phase III, investigators randomized patients with locally advanced prostate cancer to receive daily estradiol patches or standard LHRH agonist therapy. The primary outcome was 3-year MFS. The trial had a noninferiority margin of four percentage points, corresponding to a hazard ratio of 1.31.

Data analysis included 1,360 patients, enrolled at 75 centers in Great Britain. The patients had a median age of 72, 85% had stage T3 tumors, and 65% had N0 nodal status.

The primary analysis showing slightly better 3-year MFS with transdermal estradiol translated into an HR of 0.96 and an upper limit of confidence intervals of 1.11, satisfying criteria for noninferiority. Among men who continued assigned treatment, castrate testosterone levels were maintained in 85% of patients in each treatment arm. The 5-year OS also slightly favored transdermal estradiol (81.1% vs 79.2%, HR 0.90, 95% CI 0.75-1.07).

The two testosterone-suppressing treatments involved toxicity tradeoffs. Hot flashes occurred twice as often with LHRH agonists (89% vs 44%), whereas transdermal estradiol was associated with a twofold increase in gynecomastia (85% vs 42%).

The results initially were reported at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium by Nicholas James, MD, of Royal Marsden Hospital in London. During a discussion that followed the presentation, James said investigators did not offer radiation therapy for gynecomastia because the treatment could cause tissue damage and usually does not relieve pain associated with the condition, which most patients find more bothersome.

An unidentified member of the audience pointed out the side effects observed in the study were similar to those from the ENZAMET trial of enzalutamide (Xtandi) plus ADT and that progression-free survival were similar between enzalutamide paired with an LHRH agonist or estrogen. She wondered whether the results were driven primarily by the androgen receptor pathway inhibitor.

“Do we really need to give the ADT? Can we drop the testosterone suppression completely?” James replied. “That’s a very interesting question that we can’t really answer from these data, but it’s something we should pursue much more.”