In the 1,360-patient PATCH/STAMPEDE-1 trial, transdermal oestradiol patches were non-inferior to LHRH agonists for 3-year metastasis-free survival in locally advanced prostate cancer; hot flushes fell markedly while gynaecomastia increased (NEJM, 2026).
The result of an academic research programme spanning almost twenty years, published in the NEJM: the transdermal oestradiol patch used in menopausal hormone therapy is becoming a genuine option for androgen suppression
5 August 2026 | Source: New England Journal of Medicine, ASCO Post, Urology Times, University College London | Topic: Locally Advanced Prostate Cancer / Hormone Therapy
KEY FINDINGS
- Trial: A multicentre, open-label, seamless phase 2 to phase 3 adaptive non-inferiority trial conducted within the PATCH (NCT00303784) and STAMPEDE-1 (NCT00268476) programmes.
- Population: 1,360 patients with locally advanced prostate cancer; 75 centres in the United Kingdom, randomized between 2007 and 2022. Median age 72 (IQR 68-77); 85% T3 tumours, 65% N0.
- Primary outcome: Three-year metastasis-free survival 87.1% (tE2) versus 85.9% (LHRH); HR 0.96 (upper bound of the one-sided 95% CI 1.11) - the non-inferiority criterion was met.
- Overall survival (5 years): 81.1% versus 79.2%; HR 0.90 (95% CI 0.75-1.07).
- Castrate testosterone level (<1.7 nmol/L): 85% in both arms throughout the first year.
- Hot flushes: 44% (tE2) versus 89% (LHRH); grade ≥2: 8% versus 37%. Gynaecomastia: 85% versus 42%; grade ≥2: 37% versus 9%.
- Fracture (at least one at 5 years): 2.8% (tE2) versus 5.8% (LHRH). Grade ≥3 adverse events: 16% versus 19%.
Background: The Cost of Androgen Deprivation Therapy
Androgen deprivation therapy (ADT) is the cornerstone of the management of locally advanced and metastatic prostate cancer, and LHRH agonists have been the standard in this field for decades. However, the systemic suppression of oestrogen alongside testosterone creates a significant metabolic and skeletal burden over the long term: loss of bone mineral density and fracture risk, insulin resistance and metabolic syndrome, sarcopenia, increased cardiovascular risk and vasomotor symptoms that seriously impair quality of life. Hot flushes occur in approximately 80-90% of patients, disrupt sleep and directly affect adherence to treatment.
Why oestrogen? Parenteral oestrogen is the historical forerunner of ADT in prostate cancer. However, the high rates of thromboembolic and cardiovascular complications observed with oral diethylstilbestrol (DES) led to the withdrawal of this approach from clinical practice. The critical point is this: this toxicity is thought to be largely attributable to first-pass hepatic metabolism, that is, to the oral route itself.
Transdermal administration bypasses the first-pass effect and raises oestrogen levels without stimulating the synthesis of prothrombotic factors in the liver. In addition, transdermal oestradiol lowers testosterone to castrate levels while preserving systemic oestrogen levels; this theoretically means the prevention of some of the bone loss, hot flushes and metabolic side effects.
Study Design
| Parameter | Detail |
|---|---|
| Design | Multicentre, open-label, randomized, non-inferiority; adaptive phase 2 to 3 |
| Number of centres | 75 centres (United Kingdom) |
| Randomization period | 2007-2022 |
| Number of patients | 1,360 (tE2 n=721; LHRH agonist n=639) |
| Experimental arm | Transdermal oestradiol patch, 100 µg/24 hours; starting dose 4 patches twice weekly |
| Control arm | LHRH agonist, subcutaneous injection every 4 or 12 weeks |
| Permitted additional therapy | Bicalutamide or flutamide, for up to 8 weeks |
| Primary endpoint | Three-year metastasis-free survival (MFS); non-inferiority margin 4 points (target HR 1.31) |
| Secondary endpoints | Castrate testosterone level (<1.7 nmol/L), overall survival, safety |
Key Results
| Endpoint | Transdermal oestradiol | LHRH agonist | Effect size |
|---|---|---|---|
| Three-year metastasis-free survival | 87.1% | 85.9% | HR 0.96 (upper bound of the one-sided 95% CI 1.11) |
| Five-year overall survival | 81.1% | 79.2% | HR 0.90 (95% CI 0.75-1.07) |
| Castrate testosterone at year 1 (<1.7 nmol/L) | 85% | 85% | No difference |
No significant difference was found between the two strategies for the primary endpoint, and the non-inferiority criterion was clearly met. The overall survival data point in the same direction, with a numerical trend favouring tE2; but because the confidence interval crosses 1, no claim of superiority can be made. That the efficacy of testosterone suppression was identical in the two arms (85%) is mechanistically important: transdermal oestradiol suppresses the hypothalamic-pituitary-gonadal axis with the same strength as LHRH agonists.
Safety and tolerability
| Adverse event | Transdermal oestradiol | LHRH agonist |
|---|---|---|
| Grade ≥3 adverse event (any) | 16% | 19% |
| Hot flushes - any grade | 44% | 89% |
| Hot flushes - grade ≥2 | 8% | 37% |
| Gynaecomastia - any grade | 85% | 42% |
| Gynaecomastia - grade ≥2 | 37% | 9% |
| At least one fracture at 5 years | 2.8% | 5.8% |
The side effect profile shows that the two strategies are not interchangeable but qualitatively different options. The frequency of hot flushes was halved, and clinically meaningful (grade ≥2) hot flushes fell to approximately one fifth. Against this, gynaecomastia was markedly more frequent and more severe in the tE2 arm. The difference in the five-year fracture rate is consistent with the protective effect of oestrogen on bone.
Lead author Professor Ruth E. Langley (MRC Clinical Trials Unit, UCL) emphasises that the findings should open the way for men with locally advanced prostate cancer to choose the hormone therapy most suitable for them, and that for some men the patches could greatly improve quality of life in terms of hot flushes, which can be extremely debilitating.
Implications for Clinical Practice
1. A genuine "choice" has emerged in androgen suppression
The demonstration of oncological equivalence means treatment choice can now be made not on efficacy alone but on side effect profile and patient preference. Transdermal oestradiol can be discussed as the preferred option in patients whose vasomotor symptoms seriously impair quality of life; an LHRH agonist in patients who find gynaecomastia unacceptable or who have marked concerns about body image.
2. A mechanistic advantage for patients with concerns about bone health
In patients planned for long-term ADT, with osteopenia/osteoporosis or a history of fracture, the difference in the five-year fracture rate is a meaningful input to the clinical decision; in this group tE2 carries the potential to reduce the need for additional bone-protective therapy.
3. Management of gynaecomastia is an inseparable part of the treatment
A grade ≥2 gynaecomastia rate of 37% cannot be ignored. If this strategy is to be adopted, prophylactic breast irradiation or tamoxifen prophylaxis should be discussed at the start of the treatment plan and the patient informed clearly.
4. Ease of administration and the cost dimension
The transdermal patch can be applied by the patient at home; it removes the need for regular hospital/injection appointments. The formulation used is the product already licensed for menopausal hormone replacement therapy in women and carries a clear advantage in cost compared with LHRH agonists.
5. Licensing status: an important constraint
Transdermal oestradiol patches are not licensed in the prostate cancer indication; they can currently be prescribed only off-label. Their entry into guidelines and routine use depends on the course of the ongoing licensing process.
6. Limitations of the data
The trial is open-label and toxicity reporting may have been affected by this design. The population is limited to locally advanced disease; data on use in metastatic disease and together with modern ARPI combinations are limited. In addition, the accrual period spanned 15 years; over this time, imaging (particularly PSMA PET), radiotherapy techniques and systemic treatment standards changed considerably.
Conclusion
PATCH/STAMPEDE-1 is an exemplary demonstration of how powerful the results of drug repurposing and long-term academic research can be. A low-cost, widely accessible formulation developed for menopausal hormone therapy is positioned as an oncologically equivalent alternative to LHRH agonists for androgen suppression in locally advanced prostate cancer.
The real contribution of this trial is not that it defines a new peak of efficacy but that it offers the patient a choice. Being able to make an informed choice between hot flushes and gynaecomastia; being able to choose a patch applied at home rather than an injection; being able to protect bone health better - these are clinically meaningful gains that strengthen the patient's agency in the treatment process. The question for the period ahead is the place of transdermal oestradiol in metastatic hormone-sensitive disease and within ARPI-based combinations.
References
- Langley RE, Gilbert DC, Mangar S, et al; STAMPEDE-1 and PATCH Investigators. Transdermal Estradiol Patches in Locally Advanced Prostate Cancer. N Engl J Med. 2026;394(16):1595-1607. doi:10.1056/NEJMoa2511781 (PMID: 41880608)
- The ASCO Post. Transdermal Estradiol Patches vs LHRH Agonists in Locally Advanced Prostate Cancer. 31 March 2026.
- Urology Times. Transdermal estradiol patches positioned as ADT alternative for prostate cancer.
- University College London. Hormone patches effective for locally advanced prostate cancer. Press release, 26 March 2026.
- Targeted Oncology. Estradiol Patch Matches Standard Hormone Therapy in Locally Advanced Prostate Cancer, Phase 3 Trial Finds.
- Langley RE, et al. A Repurposing Programme Evaluating Transdermal Oestradiol Patches Within the PATCH and STAMPEDE Trials. Clin Oncol. (PMID: 37973477)
Important Note: The data reported in this article are for scientific information. The patch treatment in question does not currently have a licensed indication for prostate cancer. The choice of hormone therapy is made by assessing the stage of disease, accompanying conditions, bone health, cardiovascular risk profile and personal priorities together. Always consult your physician regarding treatment decisions.
Dr. Murat Binbay - Urology, Uro-Oncology and Robotic Surgery
