Transdermal estradiol (tE2) as an alternative androgen deprivation therapy (ADT) in locally advanced prostate cancer

Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonists or gonadotropin-releasing hormone (GnRH) agonists have been the standard approach for locally advanced and node-positive prostate cancer for decades, with varying optimal duration (1). While effective at achieving castrate testosterone levels, LHRH agonists deplete both testosterone and estradiol, which results in an unpleasant side-effect profile that includes bone mineral density loss, fractures, hot flashes, metabolic dysfunction, and muscle wasting. Oral estrogen (diethylstilbestrol) was historically used for ADT and effectively lowered testosterone levels (2), but was largely abandoned due to thromboembolic cardiovascular toxicity attributed to first-pass hepatic metabolism, economic disinterest (3), and safer alternative options. Unlike oral estrogen, transdermal estradiol (tE2) bypasses the liver (4), potentially offering testosterone suppression while still maintaining estrogen levels and avoiding cardiovascular toxicity. In this article, Langley et al. (5) report results from a large adaptive phase II to III randomized trial in men with advanced prostate cancer, demonstrating that tE2 patches provide noninferior cancer control compared with LHRH, while offering a distinct toxicity profile with fewer estrogen-depletion effects but substantially more gynecomastia and patch-related issues. The two cohorts were derived from prostate adenocarcinoma transcutaneous hormones (PATCH) and STAMPEDE-1 Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy.

The trial enrolled 1,360 men with locally advanced nonmetastatic prostate cancer (T3–T4 or N+, M0) from 2007 to 2022. Patients were randomized to tE2 patches (four 100 µg patches twice weekly, reduced to three if castrate levels of testosterone is achieved at 4 weeks) versus standard LHRH agonists. The primary endpoint was metastasis-free survival (MFS) (confirmed metastasis or death from any cause), designed as a noninferiority comparison. The study population had a median age of 72 years, with 60% having high-risk disease of Gleason 8–10 disease. Prostate radiotherapy was planned for 928 of 1,360 patients (68% of patients) and its use differed by recruitment period and trial network, and docetaxel was planned for 80 patients (6%). Overall, 721 patients were assigned to tE2 and 639 to LHRH agonists.

The study met the primary endpoint of noninferiority of tE2 to LHRH agonists in terms of MFS. Specifically, the 3-year MFS for tE2 was 87.1% compared to the LHRH agonist arm at 85.9% with a hazard ratio for confirmed metastasis or death at 0.96 [upper one-sided 95% confidence interval (CI) ≈1.11], establishing noninferiority of tE2 (noninferiority margin 1.31). The noninferiority margin was clinically meaningful and prespecified as 4 percentage points, corresponding to a target hazard ratio of 1.31, hence why the hazard ratio upper confidence boundary of 1.11 satisfied the trial criterion. Other secondary endpoints included safety, testosterone kinetics, and overall survival. Five-year overall survival was 81.1% in the tE2 group versus 79.2% in the LHRH agonist group (hazard ratio for death 0.90; 95% CI: 0.75–1.07). Castrate testosterone levels were achieved more rapidly with tE2 due to the absence of a testosterone surge, with similar castration rates between the two groups by 3 months. However, it should be noted that the castration analysis was based mainly on the PATCH trial patient population with available testosterone data, because the STAMPEDE-1 patients were not included in the testosterone analysis.

The side effect differences between treatment arms were clinically significant as well (see Table 1). Hot flashes occurred in 44% of tE2 patients versus 89% of LHRH agonist patients; grade ≥2 hot flashes occurred in 8% versus 37%, respectively. Fracture rates at 5 years were 2.8% with tE2 versus 5.8% with LHRH agonists, although this was only among the PATCH patients and not the entire cohort. The primary toxicity of tE2 was gynecomastia, occurring in 85% of patients compared with 42% in the LHRH agonist group. Importantly, there was no excess cardiovascular toxicity observed with tE2 (hazard ratio for first cardiovascular event 1.11; 95% CI: 0.80–1.53), partially addressing historical concerns regarding estrogen therapy and thromboembolic risk. On the other hand, these findings, together with prior PATCH cardiovascular analyses, reduce but do not eliminate concern about excess cardiovascular toxicity in appropriately selected patients

The authors concluded that tE2 patches represent an effective, noninferior alternative to LHRH agonists for androgen deprivation in locally advanced prostate cancer, with advantages including preserved bone health, better metabolic profile, fewer hot flashes, lack of testosterone flare, and patient self-administration, albeit with higher rates of gynecomastia. While these are undoubted strengths of the paper, including a non-inferiority comparison, especially since LHRH-agonists have long been used in the treatment of advanced prostate cancer, there are weaknesses as well, particularly in the vague reporting of quality of life (QoL) and patient-reported outcomes (PROs) which are somewhat incompletely reported. Although some QoL signals (e.g., hot flashes, physical function in prior analyses) are mentioned, a full presentation of QoL data and PROs in this report would strengthen conclusions about tolerability and daily living impact. In particular, the gynecomastia rate would be considered significant and not mitigated by prophylactic radiation which occurred in only 8% of patients (only in the PATCH-tE2 cohort patients). The potential use of prophylactic breast irradiation may add an intervention that may not be acceptable or feasible in all settings. The long-term cosmetic or psychosocial impact warrants further study (especially regarding reversibility for most men long after cessation of the patch). In addition, this particular publication did not address the increasing use of additional androgen receptor pathway inhibitors (ARPIs) in metastatic prostate cancer, although safety and feasibility of the combination with tE2 was reported in a different but small subgroup beyond this article (6). Furthermore, contemporary treatment intensification with ARPIs may affect generalizability and requires prospective or adequately powered subgroup evidence beyond that which was discussed in this article. It is important to evaluate QoL and patient perceptions, particularly in relation to gynecomastia. The incidence was 85% with tE2 versus 42% with LHRH agonists, and grade ≥2 gynecomastia occurred in 37% versus 9%, respectively. For men receiving curative-intent therapy, cosmetic impact, breast pain, sexual self-image, reversibility, and acceptability may determine real-world adoption as much as MFS. Mastodynia, which may impact men with prostate cancer, was not addressed and reported as well. In addition, while the question of adherence is inferred to be better for the patch, there seems to be a higher cross-over rate and switch to LHRH-agonists. While self-administration is attractive and rather convenient, patches require strict adherence, skin tolerance, correct placement, ongoing estradiol/testosterone monitoring, and dose adjustment to ensure adequate drug delivery. The median treatment duration differed between arms (tE2: ~3.25 years vs. LHRH: ~4.27 years), and some patients switched from tE2 to LHRH. This could complicate attribution of long-term outcomes to the initial randomization and may reflect tolerability issues or disease progression influencing exposure. While this does not invalidate the intention-to-treat analysis, it complicates attribution of long-term adverse-event differences to sustained exposure. The duration of ADT amongst the 2 patient populations and degree of recovery beyond a year were also not addressed. Nonetheless, while efforts are currently underway to formally license transdermal patches for prostate cancer treatment, it is not yet approved and licensed for use in advanced prostate cancer.

The use of tE2 in a wide population of patients from these 2 big trials show that tE2 can be a good alternative to the use of LHRH agonists as ADT for men with locally advanced M0 or node-positive prostate cancer, since this particular report focused specifically on men with M0 disease, including N0, NX, or N+ locally advanced prostate cancer, but not metastatic disease. It is important to note that the potential low cost, availability, and self-administration of tE2 patches makes it an attractive option in an area where resources might be limited. However, QoL data remains to be limited and needs to be further analyzed, to see how acceptable gynecomastia might be in men who are undergoing curative-intent treatment and with low mitigating effects of radiation, or perhaps the need for prophylactic radiation to mitigate its side-effects, despite all of the above improvement in other parameters like hypertension, fracture rates and hot flashes. Further subgroup and sensitivity analyses with regard to age, comorbidity burden, baseline bone health to identify populations with the strongest benefit-risk profiles for the use of transdermal patch should be undertaken. In addition, it is important to note that these results do not automatically generalize to men with major cardiovascular comorbidity, metastatic disease, or modern intensified systemic therapy pathways, particularly given the non-inferiority study design of these trials. Ultimately, the path to regulatory approval rather than “off-label” use might render easier access and acceptance, from patients’ perspectives as well.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1001/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1001/coif). J.B.A.C. serves as an unpaid editorial board member of Translational Cancer Research from August 2025 to June 2027. She also reports consulting fees from Bayer, Novartis, Astra Zeneca, EMD Serono/Merck KgA, Merck MSD, Pfizer, and Astellas, none related to this manuscript. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Zaorsky NG, Sun Y, Nabid A, et al. Optimal Duration of Androgen Deprivation Therapy With Definitive Radiotherapy for Localized Prostate Cancer: A Meta-Analysis. JAMA Oncol 2026;12:58-65. [Crossref] [PubMed]
2. Malkowicz SB. The role of diethylstilbestrol in the treatment of prostate cancer. Urology 2001;58:108-13. [Crossref] [PubMed]
3. Bird D, Ravindra NM. Transdermal drug delivery and patches—An overview. Med Devices Sens 2020;3:e10069.
4. Balfour JA, Heel RC. Transdermal estradiol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of menopausal complaints. Drugs 1990;40:561-82.
5. Langley RE, Gilbert DC, Mangar S, et al. Transdermal Estradiol Patches in Locally Advanced Prostate Cancer. N Engl J Med 2026;394:1595-607. [Crossref] [PubMed]
6. James ND, Rush H, Nankivell MG. DT): 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 2025;43:21.