tE2 for ADT

[PCaWarrior]

Maybe beating this horse to death...

Estrogen Therapy (e.g., Transdermal Estradiol)

o Previously used but abandoned due to heart-related side effects with oral estrogen.

o Transdermal estradiol (PATCH trial) is being reconsidered as a safer option with potential benefits for bone and metabolic health.

o Patches achieve non inferior PSA and testosterone control. They also reverse bone loss in many cases. Lupron and other ADT options result in osteoporosis risk. Lupron has an inferior cardiac risk profile. Men using estrogen patches report superior libido and sexual function than men on Lupron. The downside to estrogen patches is a marked increase in the number of cases of gynecomastia.

o Gels might be a cheaper option. They also have a short half-life which can be good or bad. They aren’t backed by high level data like patches are.

o Trial support

1. Both the PATCH and STAMPEDE trials demonstrated non-inferiority of transdermal estradiol (tE2) patches compared to luteinizing hormone-releasing hormone agonists (LHRHa) for androgen suppression in prostate cancer, with additional quality-of-life benefits.

2. PATCH Trial:

1. Design: Phase 2/3 randomized trial (n=1,694) comparing tE2 patches (100 µg/24h) vs. LHRHa in advanced prostate cancer.

1. Metastasis-Free Survival (MFS):

2. 3-year MFS: 87% (tE2) vs. 86% (LHRHa) | HR: 0.96 (95% CI 0.81–1.14)

3. Met non-inferiority (NI margin HR ≤1.16).

2. Overall Survival (OS):

1. HR: 0.89 (95% CI 0.74–1.07), favoring tE2.

2. Safety/QoL:

1. Fewer hot flushes (44% vs. 89%) and better bone mineral density (+6.9% lumbar spine BMD vs. -2.1% with LHRHa at 1 year).

2. Higher gynecomastia (85% vs. 42%).

3. STAMPEDE Trial:

1. Design: Phase 3 sub-protocol (n=1,360) comparing tE2 patches + androgen receptor pathway inhibitors (ARPIs) vs. LHRHa + ARPIs.

2. PSA Response: Similar PSA ≤0.2 ng/mL rates: 61% (tE2) vs. 61% (LHRHa).

3. Toxicity: Lower hypertension (5% vs. 17%) and reduced hot flushes (grade 2: 5% vs. 20%).

4. Clinical Implications: Non-Inferior Efficacy:

5. tE2 achieved comparable castration rates (testosterone ≤1.7 nmol/L in 85% vs. 85% in PATCH) and survival outcomes.

6. Safety Advantages: tE2 preserved bone health and improved metabolic parameters (vs. LHRHa-associated osteoporosis and diabetes risk).

7. Quality of Life: Better physical function (EORTC-QLQ-C30 scores) and sexual activity rates (22% sexually active vs. 13% with LHRHa).

4. Summary Table

Trial Non-Inferiority Outcome Key Secondary Benefits Limitations

PATCH ✔️ MFS, OS Bone health, fewer hot flushes Higher gynecomastia

STAMPEDE ✔️ PSA response, OS Lower hypertension Small ARPI subgroup (n=79)

5. Conclusion: Both trials confirm tE2 as a non-inferior alternative to LHRHa, with distinct toxicity profiles favoring tE2 for bone/metabolic health and QoL. Adoption may expand patient choice in ADT regimens.

6. Sources:

1. PATCH: NCT00303784

2. STAMPEDE: NCT00268476

7. References:

1. Ruth E. Langley et al. "Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme" The Lancet, 2021.

thelancet.com/journals/lanc...

2. Nicholas David James et al. "Transdermal Estradiol Plus Androgen Receptor Pathway Inhibitors Versus Luteinizing Hormone-Releasing Hormone Agonists Plus Androgen Receptor Pathway Inhibitors in Advanced Prostate Cancer: A Randomized Phase III Substudy of STAMPEDE" Journal of Clinical Oncology, 2025.

ascopubs.org/doi/10.1200/JC...

3. Duncan Gilbert et al. "PATCH Trial Evaluates Transdermal Estradiol in Non-Metastatic Prostate Cancer" UroToday, 2024.

urotoday.com/categories-med...

4. Loss of Estradiol by Androgen Deprivation in Prostate Cancer Patients Shows the Importance of Estrogens in Males | Journal of the Endocrine Society | Oxford Academic academic.oup.com/jes/articl...

[Lizzo30]

It's a no brainerBut big pharma won't like it