Suggested Guidelines and Considerations for Prescribing Transdermal Estradiol (tE2) as an Alternative to LHRH agonists for Androgen Deprivation Therapy (ADT)
Langley at al. reported at ESMO’s 2024 annual meeting 14-yr survival data for M0 advanced prostate cancer (PCa) patients who commenced ADT with transdermal estradiol (tE2) patches versus LHRH agonists. The data were from the original PATCH study that was rolled into an arm of the STAMPEDE platform trial [1, 2]. There were essentially no differences in metastasis-free and overall survival for the patients on either LHRH ADT or tE2 ADT.
Furthermore James et al. extended those results and showed that the PSA responses were similar in M0 and M1 patients treated with tE2+ARPI or LHRHa+ARPI [ARPI = androgen receptor pathway inhibitor; 3]. This additionally supports tE2 as an option for ADT in the treatment of PCa.
Compared to patients on LHRH agonists, those on tE2 patches for ADT had significantly improved bone mineral density and better cholesterol and glucose profiles [4]. The patients also reported significantly fewer hot flashes and overall better QoL, possibly secondary to reduced nocturnal hot flashes leading to better sleep quality and less daytime fatigue. No increased risks of cardiovascular events were observed with tE2 therapy [5, 6]. As such, some patients, who are candidates for ADT, are now requesting that they try tE2 rather than an LHRH agonist for ADT.
The use of tE2 for ADT, however, has not been formally approved as a SOC. So, it is an off-label use.
In discussing the tE2 option with patients, the following points should be mentioned:
- As an off-label use, the patients will likely have to pay for the tE2 products out of their own pocket. Costs can range from $20 to $100 (USD) per month for tE2 products.
- Likely side effects of tE2 patches for ADT include gynecomastia, breast soreness, and nipple sensitivity (mastalgia). Prophylactic breast irradiation may help minimize these side effects.
- A less likely side effect is dermatitis from adhesives used in E2 patches, though avoidable by using topical gel/cream tE2 products rather than patches.
- The half-life of E2 in the blood is short; i.e., less than a day. Because of this, patients need to have their E2 blood draws done at a consistent time after application of tE2 products, if one wants to accurately track changes in E2 serum concentrations.
- The PATCH study team has not reported elevated incidence of breast cancer in men using high dose tE2 for ADT. However, if there is a family history of breast cancer, we recommend getting genetic testing before starting tE2.
The official PATCH protocol [7, 8] is summarized here:
- Apply 4 simultaneous E2 patches (strength per patch releasing 100 μg per 24 hr).
- Change all patches twice a week.
- Measure serum PSA, testosterone (T), and E2 once a month initially; and then every 3 months for the first 2 years; and finally every 6 months after that.
- Reduce number of patches to 3 patches twice weekly when T < 50 ng/dl (castrate level). • The duration/indication of patch use would be the same as standard ADT (LHRHa) use and is dependent upon the clinical situation.
- For the “M0” high risk locally advanced cohort duration is nowadays usually around 2 years, in combination with other standard approaches, such as RT to the prostate.
- For M1 metastatic patients, the duration of ADT may be life-long.
The PATCH study, the aim was to keep the serum E2 level between 250 -2000 pmol/L (70 – 580 pg/ml). Medium E2 serum level observed was 790 pmol/L (230 pg/ml).
Some additional considerations for patients include:
- Following the official PATCH protocol, tE2 patches should be applied to the patient’s upper buttocks, hips, or abdomen.
- Serum E2 levels depend linearly on the dose of tE2 applied to the skin.
- A serum E2 level >120 pg/ml has been shown to eliminate hot flashes in post-menopausal women.
- An individual’s serum E2 levels may vary widely (as much as 10 X) compared to the PATCH study’s average serum level of 230 pg/ml (for 700+ men).
- An individual patient’s serum E2 levels may also vary by as much a factor of 2 X from measurement to measurement.
- Blood draws should be consistently done at the same time after applying E2.
- Due to differences in patch materials and design, serum E2 levels can vary by a factor of 3 X between different patch products that are supposedly of the same strength (i.e., 0.1 mg E2 per patch). Thus, changing patch products will likely require re-titration of the number of patches used simultaneously.
- Overall PCa survival probabilities improves when T < 20 ng/ml and a serum E2 > 250 pg/ml can suppress T to that level. [9-12]
- The reduction in T serum level is not proportional to the increase in E2 serum levels. For example, doubling the dose of tE2 will not necessarily cut serum T by 50%, even in castrate sensitive prostate cancer. For that reason, the dose of tE2 needs to be monitored and adjusted for each patient until desired target levels of T and PSA are achieved.
- Additional T suppression with tE2 is not strongly dependent on serum E2 levels when E2 > 250 pg/ml. Thus, patients should not expect vastly improved PCa control with serum E2 > 250 pg/ml.
- It takes about 3-4 weeks of continuous E2 patch use to reach an approximately steady-state serum E2 response.
- Daily use E2 gel or cream may be effectively substituted for E2 patches. Estradiol gel can be ordered in North America through Estrogel.com or Divigel.com. Estradiol gel/cream can also be obtained via compounding pharmacies with a doctor’s prescription. E2 can be adjusted from 0.06% to 1 % concentration in topical products, at a cost of approximately $20 US/month for high concentration (i.e., 1 %) gel or cream.
- tE2 gel or cream should be applied to as small an area as possible in order to maximize total absorption. Additionally, absorption is fastest when tE2 is applied to areas of skin that have little underlying fat (e.g., the jaw line or scrotum).
- tE2 patches and gels/creams are considerably cheaper than LHRH agonists and antagonists, by as much as a factor of 1000 X.
- Because ADT with tE2 can be at least 10-100 times cheaper than ADT with LHRH agonists or antagonists, insurance companies will often cover the cost with an appropriate letter from the prescribing physician.
On a personal note, Richard has been using tE2 products almost continuously for over 20 years with good PSA control. Bob has been using tE2 for 1 year. Paul began using tE2 patches in 2008, when there were few options for managing his nmCRPC. He participated in a clinical trial in 2012 that required discontinuing estrogen and resumed ADT with an LHRH agonist. His QoL deteriorated. Once the trial concluded, he returned to tE2 for ADT and his QoL recovered.
Bob and Richard now use topical tE2 gel rather than patch products. They have also experimented with: 1) applying the gel to body surfaces with less fat than the thighs, abdomen or hips, and 2) using compounded tE2 gel with a much higher concentration than in the commercially-available gel products.
We are happy to discuss our experiences with tE2 products with physicians interested in offering the tE2 option to their patients who are candidates for ADT.
R. Watson, PhD R. Wassersug, PhD Paul Schellhammer, MD
janebob99@lobo.net richard.wassersug@ubc.ca pschellham@aol.com
References
[3] James N., et al., “Transdermal oestradiol (tE2) patches as androgen deprivation therapy (ADT): Efficacy and safety of combining with androgen receptor pathway inhibitors (ARPIs) in metastatic (M1) prostate cancer—Randomised comparison from the STAMPEDE trial platform”, J Clin Oncol 43, 2025 (suppl 5; abstr 21); 2025 ASCO Genitourinary Cancers Symposium.
[4] Langley, Ruth E. et al., (2016) A Randomised Comparison Evaluating Changes in Bone Mineral Density in Advanced Prostate Cancer: Luteinising Hormone-releasing Hormone Agonists Versus Transdermal Oestradiol, European Urology, Volume 69, Issue 6, 2016, Pages 1016-1025, https://www.sciencedirect.com/science/article/pii/S0302283815012014.
[5] Langley, Ruth E. et al., (2013) Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09). The Lancet Oncology, Volume 14, Issue 4, 306 – 316; https://www.sciencedirect.com/science/article/pii/S1470204513700251.
[6] Langley, Ruth E. et al., (2021) Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme, The Lancet, Volume 397, Issue 10274, 581 – 591; https://www.sciencedirect.com/science/article/abs/pii/S0140673621001008.
[7] Gilbert, D. C .et al. (2024) A Repurposing Programme Evaluating Transdermal Oestradiol Patches for the Treatment of Prostate Cancer Within the PATCH and STAMPEDE Trials: Current Results and Adapting Trial Design, Clinical Oncology, Volume 36, Issue 1, e11 – e19.
[8] Langley RE, Godsland IF, Kynaston H, Clarke NW, Rosen SD, Morgan RC, Pollock P, Kockelbergh R, Lalani el-N, Dearnaley D, Parmar M, Abel PD. “Early hormonal data from a multicentre phase II trial using transdermal oestrogen patches as first-line hormonal therapy in patients with locally advanced or metastatic prostate cancer.” BJU Int. 2008 Aug;102(4):442-5.
[9] de Liano, .G.,et al., https://www.nature.com/articles/bjc2014189.pdf (2014).
[10] Klotz, et al., https://pubmed.ncbi.nlm.nih.gov/25732157 (2015).
[11] Ozyigit, G., et al., https://pubmed.ncbi.nlm.nih.gov/31528544 (2019).
[12] Atkins, K., et al., https://pubmed.ncbi.nlm.nih.gov/29266181 (2018).