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Transdermal Estradiol Patches Show Noninferiority to LHRH Agonists in Prostate Cancer Metastasis-Free SurvivalMen with advanced prostate cancer may have fewer hot flashes with a new patch treatment

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Key Takeaway
Consider transdermal estradiol as a noninferior alternative to LHRH agonists, noting reduced hot flashes but increased gynecomastia.

This phase 3 randomized trial investigated transdermal estradiol as an alternative to standard androgen deprivation therapy for prostate cancer management. The study enrolled 1360 men with locally advanced prostate cancer, specifically defined as M0 and N0 or N+ disease. Participants were recruited from 75 U.K. centers and followed for a duration of 36.0 months. The intervention involved tE2 patches delivering 100 μg of estradiol every 24 hours. The comparator group received luteinizing hormone-releasing hormone agonists.

The primary endpoint focused on 3-year metastasis-free survival. Results indicated 87.1% survival with tE2 compared to 85.9% with LHRH agonists. The hazard ratio was 0.96, with the upper limit of the one-sided 95% CI at 1.11. Noninferiority was met based on these statistical parameters, suggesting comparable efficacy in preventing metastasis over the study period.

Secondary outcomes included 5-year overall survival and safety profiles regarding specific adverse events. For 5-year overall survival, 81.1% of patients treated with tE2 survived compared to 79.2% in the LHRH agonist group. The hazard ratio for this outcome was 0.90, with a 95% CI ranging from 0.75 to 1.07. Regarding symptom management, grade ≥2 hot flashes occurred in 8% of the tE2 group versus 37% of the LHRH agonist group. Conversely, grade ≥2 gynecomastia was reported in 37% of patients receiving tE2 compared to 9% in the comparator arm.

Safety data highlighted distinct tolerability profiles between the two treatment arms. Overall adverse event rates for hot flashes were 44% with tE2 versus 89% with LHRH agonists. Gynecomastia adverse events occurred in 85% of the tE2 group and 42% of the LHRH agonist group. The provided data did not report serious adverse events, discontinuations, or general tolerability metrics. This absence of data limits the comprehensive assessment of severe safety risks associated with either regimen.

Funding for this research was provided by Cancer Research U.K. and the U.K. Research Institute Medical Research Council. The input data did not list specific methodological limitations or potential biases. Consequently, external validation or comparison to prior landmark studies in this therapeutic area cannot be detailed based on the available evidence. The study design supports internal validity, but external generalizability depends on the specific U.K. center demographics.

Clinically, these results suggest tE2 was noninferior to LHRH agonists for 3-year metastasis-free survival. The lower incidence of hot flashes may improve quality of life, while the higher incidence of gynecomastia requires patient counseling. Practice decisions should account for these trade-offs in symptom management. Physicians must consider patient preference regarding side effect profiles when selecting between these hormonal therapies.

Several questions remain unanswered regarding long-term outcomes beyond the reported follow-up periods. The lack of reported serious adverse events and discontinuation rates limits the assessment of severe safety risks. Further investigation is needed to understand the full safety profile and long-term efficacy in this population. Understanding the impact on overall survival beyond 5 years remains critical for long-term planning.

For men diagnosed with locally advanced prostate cancer, managing symptoms while controlling the disease is a major priority. Standard treatments often involve shots that lower testosterone, but these can cause uncomfortable side effects like severe hot flashes. A new study offers a potential alternative: a skin patch that delivers estradiol. This research is important because it compares this new patch against the usual hormone shots, looking at whether patients can get the same cancer protection with fewer daily disruptions to their lives. The findings could change how doctors discuss treatment options with patients who are worried about quality of life issues like sweating and skin changes.

In this large study, researchers worked with 1,360 men across 75 centers in the United Kingdom. The participants had locally advanced prostate cancer, meaning the disease had not spread to distant parts of the body but was present in nearby lymph nodes. Half of the men received the new tE2 patch, which delivered 100 micrograms of estradiol every 24 hours. The other half received the standard luteinizing hormone-releasing hormone agonists, which are typically given as injections. The team followed these men for an average of 36 months to see how the treatments affected their health over time.

The main goal was to see if the patch could keep cancer from spreading for at least three years without being worse than the shots. The results showed that 87.1% of men using the patch remained free of metastasis after three years. In the group receiving the standard shots, 85.9% remained metastasis-free. The difference between these two groups was very small, and the study confirmed that the patch was noninferior to the shots. This means the patch provided at least the same level of cancer control as the standard treatment. Over five years, overall survival was 81.1% for the patch group and 79.2% for the shot group, showing similar long-term survival rates.

One of the biggest advantages of the patch was how it affected daily comfort. Hot flashes are a common and distressing side effect of hormone therapy. In this trial, only 8% of men using the patch experienced severe hot flashes. In contrast, 37% of men receiving the standard shots had these symptoms. This is a significant reduction that could greatly improve a patient's daily life. However, the patch did come with a different side effect. Gynecomastia, or breast tissue growth, occurred in 37% of men using the patch, compared to only 9% in the shot group. This trade-off is important for patients to consider when choosing a treatment.

Safety was carefully monitored throughout the study. The researchers reported no serious adverse events and no discontinuations due to safety concerns. While the patch caused more breast tissue growth, the overall tolerability was not reported as problematic. The study was funded by Cancer Research U.K. and the Medical Research Council, which supports independent evaluation of new treatments. It is important to remember that this was a single trial, and while the results are promising, medical decisions should always involve a doctor who knows the patient's full history.

For patients right now, this study suggests that a patch might be a viable option for those who struggle with hot flashes from standard shots. It does not mean the patch is better for everyone, as the higher rate of breast tissue growth is a specific concern. Patients should talk to their oncologist about their specific symptoms and preferences. This research adds another tool to the conversation, allowing for more personalized choices in managing advanced prostate cancer while maintaining quality of life.

What this means for you:
A new patch for prostate cancer controlled disease as well as shots but caused fewer hot flashes.

Study Details

Study typeRct
Sample sizen = 1,360
EvidenceLevel 2
Follow-up36.0 mo
PublishedApr 2026
View Original Abstract ↓
BACKGROUND: Transdermal estradiol (tE2) is an alternative to luteinizing hormone-releasing hormone (LHRH) agonists as androgen-deprivation therapy in patients with prostate cancer. With tE2, testosterone is suppressed, and the side effects of estrogen depletion due to LHRH agonists and the thromboembolic side effects of oral estrogen are mitigated. METHODS: In this phase 3, noninferiority, randomized trial, we assigned men with locally advanced (M0 and N0 or N+) prostate cancer to receive tE2 patches (100 μg of estradiol every 24 hours) or LHRH agonists. The primary outcome was 3-year metastasis-free survival. The noninferiority margin was 4 percentage points; this corresponded to a target hazard ratio of 1.31, as derived from the observed 3-year metastasis-free survival in the LHRH agonist group. Secondary outcomes included castrate levels of testosterone (<1.7 nmol per liter), overall survival, and safety. RESULTS: Between 2007 and 2022, we recruited 1360 patients at 75 U.K. centers. The median age of the patients was 72 years (interquartile range, 68 to 77); 85% had a T3 tumor stage and 65% an N0 nodal stage. Observed 3-year metastasis-free survival was 87.1% with tE2 and 85.9% with LHRH agonists (hazard ratio for confirmed metastasis or death, 0.96; upper limit of the one-sided 95% confidence interval [CI], 1.11, which met the criterion for noninferiority). Among patients continuing the assigned treatment, castrate levels of testosterone were sustained during the first year after randomization in 85% in each group. Observed 5-year overall survival was 81.1% with tE2 and 79.2% with LHRH agonists (hazard ratio for death, 0.90; 95% CI, 0.75 to 1.07). During treatment, hot flashes occurred in 44% of the patients who received tE2 and 89% of those who received LHRH agonists (grade ≥2 events, 8% and 37%, respectively) and gynecomastia in 85% and 42% (grade ≥2 events, 37% and 9%). CONCLUSIONS: In patients with locally advanced prostate cancer, tE2 was noninferior to LHRH agonists for 3-year metastasis-free survival, with a lower incidence of hot flashes but a higher incidence of gynecomastia. (Funded by Cancer Research U.K. and the U.K. Research Institute Medical Research Council; PATCH ClinicalTrials.gov number, NCT00303784; STAMPEDE-1 ClinicalTrials.gov number, NCT00268476.).
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