For Doctors in a Hurry
- Clinicians require effective androgen deprivation therapies for prostate cancer that minimize the adverse effects of estrogen depletion.
- The study randomized 1360 men with locally advanced prostate cancer to receive either transdermal estradiol or luteinizing hormone-releasing hormone agonists.
- Three-year metastasis-free survival was 87.1% for transdermal estradiol and 85.9% for agonists, confirming noninferiority with a hazard ratio of 0.96.
- The researchers concluded that transdermal estradiol provides equivalent oncologic control to standard hormone therapy for locally advanced prostate cancer.
- Physicians may consider transdermal estradiol to reduce hot flashes, though they must monitor patients for increased risks of gynecomastia.
Mitigating the Morbidity of Estrogen Depletion in Prostate Cancer
Standard androgen deprivation therapy for prostate cancer focuses on suppressing testosterone, but the resulting depletion of estradiol often leads to debilitating side effects that impair patient quality of life [1, 2]. While luteinizing hormone-releasing hormone agonists effectively achieve castrate levels, patients frequently experience vasomotor symptoms (hot flashes) and progressive bone mineral density loss [3, 1, 4]. Historical attempts to use oral estrogens were hampered by significant thromboembolic and cardiovascular risks, leading to a shift toward transdermal delivery methods to bypass hepatic first-pass metabolism, which is the process where the liver metabolizes a drug and increases the production of clotting factors before the medication reaches systemic circulation [5, 2]. Current clinical guidelines emphasize the need for better integration of patient-reported outcomes, which are standardized reports from patients regarding their own health status, and side-effect management in long-term hormonal therapy [6, 7]. A new study now offers evidence regarding the comparative efficacy and safety of transdermal estradiol as a primary androgen deprivation strategy.
Trial Design and Patient Characteristics
The researchers conducted a phase 3, noninferiority, randomized trial to evaluate the efficacy of transdermal estradiol (tE2) compared to standard luteinizing hormone-releasing hormone (LHRH) agonists. Between 2007 and 2022, the study recruited 1360 patients across 75 U.K. centers, focusing on men with locally advanced prostate cancer. This population was defined as having M0 disease (no distant metastasis) and either N0 (no regional lymph node involvement) or N+ (positive regional lymph nodes) status. The cohort had a median age of 72 years (interquartile range, 68 to 77). Pathological characteristics were consistent with high-risk localized disease, as 85% of patients presented with a T3 tumor stage, indicating a tumor that has extended through the prostatic capsule, and 65% had an N0 nodal stage. The trial received funding from Cancer Research U.K. and the U.K. Research Institute Medical Research Council. Participants were assigned to receive either 100 μg of estradiol every 24 hours via transdermal patches or conventional LHRH agonists. The primary outcome was 3-year metastasis-free survival, a composite endpoint measuring the time until the first evidence of distant metastasis or death from any cause. To establish noninferiority, a statistical determination that a new treatment is not unacceptably worse than the standard of care, the researchers set a margin of 4 percentage points. This margin corresponded to a target hazard ratio of 1.31, a measure of the relative risk of an event occurring in the treatment group versus the control group, derived from the observed 3-year metastasis-free survival in the LHRH agonist group. Secondary outcomes included the maintenance of castrate levels of testosterone, defined as less than 1.7 nmol per liter, as well as overall survival and safety profiles.
Oncological Equivalence and Testosterone Suppression
The primary analysis of the trial demonstrated that transdermal estradiol is an effective alternative to LHRH agonists for androgen-deprivation therapy. The researchers found that the observed 3-year metastasis-free survival was 87.1% in the tE2 group compared to 85.9% in the LHRH agonist group. This resulted in a hazard ratio for confirmed metastasis or death of 0.96, with an upper limit of the one-sided 95% confidence interval (CI) of 1.11. Because this upper limit remained well below the predefined target hazard ratio of 1.31, the findings met the rigorous statistical criterion for noninferiority, confirming that the estradiol patch does not compromise oncological control in the medium term. Beyond metastasis-free survival, the study reported favorable long-term survival outcomes. The observed 5-year overall survival was 81.1% for patients receiving tE2 and 79.2% for those receiving LHRH agonists. The hazard ratio for death was calculated at 0.90 (95% CI, 0.75 to 1.07), further supporting the therapeutic equivalence of the two approaches. These survival metrics indicate that the use of transdermal estrogen does not introduce an increased risk of mortality compared to standard-of-care androgen deprivation in this patient population. A critical component of the study was the ability of transdermal patches to achieve and maintain the physiological goals of androgen-deprivation therapy. The researchers monitored the suppression of testosterone to castrate levels, which was defined as a concentration of less than 1.7 nmol per liter. Among patients who continued their assigned treatment, castrate levels of testosterone were sustained during the first year after randomization in 85% of patients in both the tE2 and LHRH agonist groups. This parity in biochemical suppression suggests that the 100 μg daily dose of estradiol is as reliable as injectable agonists in maintaining the hormonal environment necessary to manage locally advanced prostate cancer.
Divergent Side Effect Profiles
The clinical utility of transdermal estradiol lies in its ability to suppress testosterone while mitigating the side effects of estrogen depletion, such as vasomotor symptoms, and avoiding the thromboembolic risks, or the formation of blood clots, typically associated with oral estrogen formulations. By delivering estradiol through the skin, the therapy bypasses the first-pass hepatic metabolism that increases clotting factors in the liver. In this trial, the researchers observed a substantial reduction in vasomotor instability among those using the patch. Hot flashes occurred in 44% of patients receiving tE2 compared to 89% of those receiving LHRH agonists. The difference in symptom severity was also pronounced, as grade 2 or higher hot flashes occurred in only 8% of the tE2 group compared to 37% of the LHRH agonist group. This reduction in the frequency and intensity of hot flashes represents a significant shift in the tolerability profile for patients undergoing androgen deprivation. While the estradiol patch reduced vasomotor symptoms, it was associated with a higher incidence of estrogen-related breast changes. Gynecomastia, the enlargement of male breast tissue, occurred in 85% of patients receiving tE2 compared to 42% of those receiving LHRH agonists. The severity of these changes also differed between the cohorts, with grade 2 or higher gynecomastia occurring in 37% of the tE2 group and 9% of the LHRH agonist group. Clinicians must therefore weigh the trade-off between a lower burden of hot flashes and a higher likelihood of breast enlargement and tenderness. These divergent side effect profiles suggest that transdermal estradiol offers a distinct symptomatic trajectory, allowing for more personalized treatment selection based on individual patient priorities regarding vasomotor relief versus physical changes in breast tissue.
References
1. Bennink HJTC, Krijgh J, Egberts JFM, et al. Maintaining bone health by estrogen therapy in patients with advanced prostate cancer: a narrative review.. Endocrine connections. 2022. doi:10.1530/EC-22-0182
2. Bennink HJTC, Prowse A, Egberts JFM, Debruyne FMJ, Huhtaniemi IT, Tombal B. The Loss of Estradiol by Androgen Deprivation in Prostate Cancer Patients Shows the Importance of Estrogens in Males.. Journal of the Endocrine Society. 2024. doi:10.1210/jendso/bvae107
3. Lin KL, Talmor B, Crumbaker M, Joshua AM. A Review of Hot Flash Management in Patients With Prostate Cancer.. The Journal of clinical endocrinology and metabolism. 2025. doi:10.1210/clinem/dgaf302
4. Barreira JV, Barreira P, Falcão G, et al. Cognitive Impairment in Prostate Cancer Patients Receiving Androgen Deprivation Therapy: A Scoping Review. Cancers. 2025. doi:10.3390/cancers17152501
5. Borst SE, Shuster JJ, Zou B, et al. Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta-analysis. BMC Medicine. 2014. doi:10.1186/s12916-014-0211-5
6. Hemelrijck MV, Sparano F, Moris L, et al. Harnessing the patient voice in prostate cancer research: Systematic review on the use of patient‐reported outcomes in randomized controlled trials to support clinical decision‐making. Cancer Medicine. 2020. doi:10.1002/cam4.3018
7. Mohler JL, Antonarakis ES, Armstrong AJ, et al. Prostate Cancer, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network. 2019. doi:10.6004/jnccn.2019.0023
