Compared to LHRHa, transdermal oestradiol (tE2) lowers testosterone more rapidly, maintains bone mineral density, and improves metabolic outcomes and quality of life (QL). Importantly, transdermal administration avoids the cardiovascular (CVS) toxicity of oral oestrogen.
Methods
Open-label, randomised phase 3, non-inferiority (NI) comparison of LHRHa v tE2 patches. Eligibility: histologically confirmed newly diagnosed high-risk M0 [locally advanced or node positive (+)] prostate cancer or those relapsing with PSA≥4ng/ml and doubling in <6 months, PSA ≥20ng/ml or N+. Treatment: standard LHRHa v tE2 100mcg/24h patches changed twice weekly for ≥2 years, (prostate radiotherapy and docetaxel permitted). Primary outcome: metastasis-free survival (MFS) (time from randomisation to metastatic disease or death from any cause), designed to rule out a >4% reduction in 3-year MFS (85% power, 1-sided 5% α). Secondary outcomes: overall survival (OS), castration rates and toxicity.
Results
1360 men, [639 LHRHa, 721 tE2 (randomisation ratio 1:2 then 1:1)] recruited from PATCH (NCT00303784, n=1082) and STAMPEDE (NCT00268476, n=278) trial sites between 2007-2022. Baseline characteristics were well-balanced between randomised groups. LHRHa 3-year MFS 86% (giving a target NI hazard ratio (HR) of 1.31). tE2 3-year MFS 87% HR 0.96 (95% CI 0.81-1.14) in favour of tE2, excluding a 2% reduction in MFS. OS HR 0.89 (CI 0.74-1.07) in favour of tE2. Prostate cancer, CVS and 2nd malignancy deaths similar between randomised groups. Sustained castration rates (testosterone ≤1.7nmol/L over 1 year (n=1066), with tE2 use confirmed as oestradiol ≥250 pmol/L, 85% both groups. LHRHa v tE2 any grade: gynaecomastia 42% v 85%, hot flushes 89% v 44%.
Conclusions
Prostate cancer outcomes and overall survival are non-inferior when tE2 is used to commence androgen suppression and this approach should be considered a standard of care. tE2 provides men with choices about the expected side-effect profile and route of administration. These data complement those showing improved metabolic parameters and overall QL scores with tE2 v LHRHa.
Clinical trial identification
PATCH trial – ISRCTN70406718, registration date 12/09/2005 STAMPEDE trial – ISRCTN78818544, registration date 03/08/2004.