OBJECTIVES: To compare quality of life (QoL) outcomes at 6 months between men with advanced prostate cancer (PCa) receiving either transdermal oestradiol (tE2) or LHRH agonists (LHRHa) for androgen deprivation therapy (ADT). PATIENTS AND METHODS: Men with locally advanced or metastatic PCa participating in an ongoing randomised, multi-centre UK trial comparing tE2 versus LHRHa for ADT were enrolled into a QoL sub-study. tE2 was delivered via 3 or 4 transcutaneous patches containing 100mcg of oestradiol/24 hours. LHRHa was administered as per local practice. Patients completed questionnaires based on EORTC QLQ-C30 with prostate-specific module QLQ PR25. The primary outcome measure was global QoL score at 6 months, compared between randomised arms. RESULTS: 727 men were enrolled between August 2007 and 5 October 2015 (412 tE2, 315 LHRHa) with QoL questionnaires completed at both baseline and 6 months. Baseline clinical characteristics were similar between arms: median age 74 years (interquartile range [IQR] 68-79), median PSA 44 ng/ml (IQR 19-119), and 40% (294/727) had metastatic disease. At 6 months, patients on tE2 reported higher global QoL than LHRHa (mean difference +4.2, 95% CI 1.2 to 7.1, p=0.006), less fatigue and improved physical function. Men in the tE2 arm were less likely to experience hot flushes (8% vs 46%), and report a lack of sexual interest (59% vs 74%) and sexual activity, but had higher rates of significant gynecomastia (37% vs 5%). The higher incidence of hot flushes among LHRHa patients appear to account for both the reduced global QoL and increased fatigue in the LHRHa arm compared to tE2 arm. CONCLUSION: Patients receiving tE2 for ADT had better 6-month self-reported QoL outcomes compared to those on LHRHa, but increased likelihood of gynecomastia. The ongoing trial will evaluate clinical efficacy, and longer term QoL. These findings are also potentially relevant for short-term neoadjuvant ADT. This article is protected by copyright. All rights reserved.