Androgen deprivation therapy (ADT) remains the cornerstone treatment for patients with metastatic prostate cancer. However, it is frequently associated with adverse effects such as vasomotor symptoms, including hot flashes, fatigue, and bone density loss, which significantly impact patients' quality of life. The rapid advancements in therapeutic strategies for advanced prostate cancer have led to investigations into alternative approaches. A study presented at the 2025 ASCO GU Annual Meeting introduced transdermal estrogen as a potential ADT alternative, offering a new option for metastatic prostate cancer patients.Findings from the Phase II Study on Transdermal Estrogen
A phase II study suggests that estradiol patches could serve as an effective ADT alternative for metastatic prostate cancer patients undergoing treatment with androgen receptor pathway inhibitors. Traditionally, luteinizing hormone-releasing hormone analogs (LHRHa) have been the standard ADT approach. However, their mechanism suppresses both testosterone and estrogen, leading to complications such as hot flashes, fatigue, and a decline in bone density. The findings from earlier clinical trials indicate that estradiol patches may provide a comparable therapeutic effect while mitigating these adverse reactions.
STAMPEDE Trial Results and Clinical Implications
The study presented at the 2025 ASCO GU Annual Meeting evaluated the potential of estradiol patches in metastatic prostate cancer patients receiving androgen receptor pathway inhibitors. Results from the phase II component of the STAMPEDE trial demonstrated that transdermal estrogen produced a prostate-specific antigen (PSA) response comparable to that of LHRHa while reducing the severity of associated side effects. Professor Nicholas James, a leading investigator from The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London, emphasized that hot flashes and fatigue remain among the most distressing symptoms for patients undergoing ADT. Additionally, the decline in bone density poses a significant risk for fragility fractures, particularly as more metastatic prostate cancer patients experience extended survival.
The Advantages of Transdermal Estrogen as an ADT Alternative
Professor James highlighted that transdermal estrogen, specifically estradiol used in menopausal hormone therapy, presents several advantages as an ADT alternative. Unlike LHRHa, it suppresses testosterone without depleting estrogen, which helps maintain bone density. Moreover, transdermal estrogen is a cost-effective treatment option that circumvents the thrombotic risks associated with oral estrogen therapy.
Evidence from Previous Studies and Its Impact on Oncological Outcomes
Earlier studies, including data from the STAMPEDE and PATCH trials, demonstrated that estradiol patches achieve similar androgen suppression rates to LHRHa while improving metabolic health, quality of life, and bone density in patients with locally advanced or metastatic prostate cancer. Data presented at the 2024 ESMO Congress further suggested that transdermal estrogen is non-inferior to LHRHa in terms of metastasis-free survival in men with locally advanced disease.
New Study Evaluating the Efficacy and Safety of Transdermal Estrogen in Metastatic Prostate Cancer
At the 2025 ASCO GU Annual Meeting, a study assessed the efficacy and safety of transdermal estrogen in combination with androgen receptor pathway inhibitors for patients with metastatic (M1) prostate cancer. The study enrolled 79 patients with a median age of 69 years who were scheduled to receive androgen receptor pathway inhibitors, such as abiraterone, enzalutamide, or apalutamide. Participants were randomized to receive either LHRHa or transdermal estradiol therapy, administered at a dose of 100 µg per 24 hours. Once testosterone levels dropped to 1.7 ng/mL or below, patients using estradiol patches replaced three patches every two weeks.
The results showed that after six months, 61% of patients in both groups achieved PSA levels of 0.2 ng/mL or lower. Notably, patients using estradiol patches experienced a lower incidence of hot flashes compared to those receiving LHRHa, with grade 2 hot flashes occurring in 5% of the estradiol group versus 24% in the LHRHa group. Additionally, the rate of any-grade hypertension was lower in the estradiol group, at 5% compared to 17% in the LHRHa group. However, gynecomastia was more frequent among patients using estradiol patches, with grade 1 and 2 gynecomastia occurring in 35% and 8% of patients, respectively, compared to 10% and 0% in the LHRHa group.
Professor James stated that no unexpected toxicities were observed during the study. Ongoing analyses are assessing whether transdermal estrogen provides non-inferior metastasis-free survival compared to other ADT therapies, with results expected later this year.
Potential Role of Transdermal Estrogen in Clinical Practice
Professor James emphasized that estradiol patches may be particularly beneficial for patients experiencing severe side effects from LHRHa, such as hot flashes and fatigue. From an economic perspective, estradiol patches present a cost-effective alternative, especially in healthcare systems with limited resources and for patients in regions like the United States who are uninsured or underinsured. He noted that the repurposing of an older, low-cost drug can significantly enhance patient outcomes without the need for new drug development.
Nicholas James, MD, PhD
The Institute of Cancer Research, London & The Royal Marsden NHS Foundation Trust
Professor Nicholas James is a Consultant in Clinical Oncology at Queen Elizabeth Hospital, Birmingham, and an Honorary Professor of Clinical Oncology at the University of Birmingham’s Cancer and Genomic Sciences Department.
Renowned internationally for his work in genitourinary cancers, Professor James pioneered the STAMPEDE trial, which has enrolled over 10,000 men with advanced prostate cancer to evaluate ten different therapeutic strategies. STAMPEDE’s findings—particularly regarding first-line docetaxel chemotherapy and abiraterone—have transformed global clinical practice by demonstrating the substantial survival benefits of existing treatments in newly diagnosed patients.
In bladder cancer research, Professor James has led multiple chemo-radiotherapy trials, culminating in the largest randomized trial in the field, published in The New England Journal of Medicine. A commentary described the study as a “milestone” and “practice-changing”, demonstrating that low-dose synchronous chemotherapy reduces the recurrence rate of invasive bladder cancer by 43%.
Additionally, Professor James served as a member of the European Association of Urology (EAU) Bladder Cancer Guidelines Panel from 2013 to 2016.
