Patients may have another option for long-term testosterone suppression with a markedly different side-effect profile.
Transdermal estradiol patches may offer men with locally advanced prostate cancer an effective alternative to standard androgen deprivation therapy (ADT), with patients experiencing similar cancer outcomes but fewer hot flushes, according to results from a large phase 3 trial.
Researchers found that the patches were non-inferior to luteinising hormone-releasing hormone (LHRH) agonists for preventing metastasis or death over three years, while substantially reducing one of ADT’s most troublesome side effects.
The trial enrolled 1360 UK men with histologically confirmed locally advanced, non-metastatic prostate cancer who were commencing long-term ADT between 2007 and 2022. They were randomised to receive estradiol patches (n=721) or standard LHRH agonists (n=639).
The median participant age was 72 years, with 85% having T3 disease and 65% having node-negative disease at enrolment. Most participants (60%) had Gleason scores of 8 to 10, reflecting a predominantly high-risk population. Participants continued to receive evolving standard-of-care treatment throughout the study, including prostate radiotherapy and, later, concomitant docetaxel for selected patients.
Three-year metastasis-free survival was 87.1% among patients treated with patches, compared with 85.9% in the LHRH agonist group. The hazard ratio for confirmed metastasis or death was 0.96, meeting the study’s predefined criteria for non-inferiority.
Overall survival was also comparable; at five years, 81.1% of patch patients were alive compared with 79.2% of those receiving LHRH agonists, with no statistically significant difference between groups (HR 0.90; 95% CI 0.75-1.07).
The investigators also found that both approaches were equally effective at suppressing testosterone. Among patients who remained on their allocated treatment, 85% in each group maintained castrate testosterone levels throughout the first year.
LHRH agonists have long been the cornerstone of ADT but suppress both testosterone and estradiol, contributing to hot flushes, bone loss, metabolic changes, and other adverse effects. Transdermal estradiol suppresses testosterone while maintaining circulating estrogen levels, potentially avoiding some complications of estrogen depletion. Unlike oral estrogen, transdermal delivery bypasses first-pass liver metabolism and is associated with a lower thromboembolic risk.
The side-effect profile differed substantially between treatments. Hot flushes occurred in 44% of men using estradiol patches compared with 89% of those receiving LHRH agonists. Moderate-to-severe hot flushes (grade 2 or higher) were reported by just 8% of patients treated with estradiol, compared with 37% of those receiving standard therapy.
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However, estradiol treatment was associated with considerably higher rates of gynecomastia. Breast enlargement occurred in 85% of patients receiving patches compared with 42% of those treated with LHRH agonists, while moderate-to-severe cases occurred in 37% and 9%, respectively.
Rates of erectile dysfunction and reduced libido were similar between treatment groups, affecting approximately two-thirds of patients regardless of treatment.
Serious adverse events were uncommon and comparable between the groups. Grade 3 or higher adverse events occurred in 16% of patients receiving estradiol and 19% receiving LHRH agonists.
“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,” authors concluded.
“Given these findings, tE2 patches can be considered an alternative choice for testosterone suppression in men with metastasis stage M0 and nodal stage N0 or N+ prostate cancer.”
Although gynecomastia remains an important limitation of estradiol therapy, the researchers said the reduction in hot flushes and other estrogen-depletion effects may make transdermal estradiol an attractive option for some men.
They added that the differing side-effect profiles and routes of administration should form part of shared decision-making when selecting androgen deprivation therapy.
