LBA69 - Prostate cancer efficacy results from a randomised phase III evaluation of transdermal oestradiol (tE2) versus luteinising hormone releasing hormone agonists (LHRHa) for androgen suppression in non-metastatic (M0) prostate cancer

Background

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 2^nd 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.

Editorial acknowledgement

Legal entity responsible for the study

University College London.

Funding

Cancer Research UK and Medical Research Council.

Disclosure

N. Clarke: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca; Financial Interests, Personal, Invited Speaker: Ipsen, Bayer, Pfizer, Janssen; Non-Financial Interests, Leadership Role, Principal Investigator The Propel Trial: AstraZeneca. N.D. James: Financial Interests, Personal, Advisory Board, Advice around PARP inhibitors: AstraZeneca; Financial Interests, Personal, Advisory Board, Prostate cancer therapies: Janssen, Clovis, Novartis; Financial Interests, Institutional, Advisory Board, Assisted with submissions regarding licencing for abiraterone: Janssen; Financial Interests, Personal, Advisory Board, Docetaxel: Sanofi; Financial Interests, Institutional, Advisory Board, Providing STAMPEDE trial data to facilitate licence extensions internationally for docetaxel: Sanofi; Financial Interests, Personal, Advisory Board, Bladder cancer therapy: Merck; Financial Interests, Personal, Advisory Board, Advice around novel hormone therapies for prostate cancer: Bayer; Financial Interests, Personal, Invited Speaker, Lecture tour in Brazil August 2022 - speaking on therapy for advanced prostate cancer: Merck Sharp & Dohme (UK) Limited; Financial Interests, Institutional, Coordinating PI, Funding for STAMPEDE trial: Janssen, Astellas; Financial Interests, Institutional, Coordinating PI, Funding for RADIO trial bladder cancer: AstraZeneca. M.K. Parmar: Financial Interests, Institutional, Full or part-time Employment, Director at MRC Clinical Trials Unit at UCL: Medical Research Council Clinical Trials Unit at UCL; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca, Astellas, Janssen, Baxter, GSK; Financial Interests, Institutional, Research Grant: Clovis, Abcodia Pvt Ltd, Akagera, Amgen, Aspirin Foundation, Bayer, BMS US, Bri-BioCepheid, Cipla, CSL Behring, Eli-Lilly, Emergent Biosolutions, Gilead Sciences, Grifols, Johnson & Johnson, Pfizer, Sanofi, ViiVHealthcare, Micronoma, Modus Theraputics, Mylan, Serum Institute of India, shionogi, SyntenyBiotechnology, Takeda, Tibotec, Transgene, Virco and Xenothera; Non-Financial Interests, Advisory Role, Euro Ewing Consortium: University College London; Non-Financial Interests, Advisory Role, rEECur: University of Birmingham; Non-Financial Interests, Advisory Role, CompARE Trial: University of Birmingham; Non-Financial Interests, Advisory Role, ROSSINI Trial Platform: University of Birmingham. All other authors have declared no conflicts of interest.