Transdermal oestradiol (tE2) patches as androgen deprivation therapy (ADT): Efficacy and safety of combining with androgen receptor pathway inhibitors (ARPIs) in metastatic (M1) prostate cancer—Randomised comparison from the STAMPEDE trial platform.

21 Background: Recent phase III data (n=1360) has shown that starting ADT with tE2 patches is non-inferior in terms of metastasis-free survival (with similar overall survival) to luteinising hormone releasing hormone analogues (LHRHa) for locally advanced (M0) prostate cancer. For both M0 and M1 patients, tE2 has advantages in terms of reported quality of life, bone mineral density, hot flushes and metabolic outcomes compared to LHRHa, with no excess of thromboembolic events. However, there is currently no data on the use of androgen receptor pathway inhibitors (ARPIs) (abiraterone, enzalutamide or apalutamide) with tE2. Methods: STAMPEDE [NCT00268476] is a multi-arm, multi-stage platform trial. This embedded phase 2 randomised study assessed efficacy and toxicity in participants (pts) randomly allocated (1:1) to tE2 patches (releasing 100mcg/24hrs, 3 patches changed twice weekly once testosterone ≤1.7ng/ml) or LHRHa (standard doses) and scheduled to receive ARPIs. Primary outcome measure was the proportion of pts reaching a PSA nadir of ≤0.2ng/ml during the first 6 months. Other PSA parameters, testosterone ≤1.7ng/ml at 12 weeks with tE2, and adverse events within the first 12 months (including hypertension, hot flushes and gynaecomastia) were assessed. Results: Between Oct-2020 and Mar-2023, 79 pts with histologically confirmed M1 prostate cancer (median (IQR) age 69 (65-75), median (IQR) baseline PSA 43.3 (11.5-296.2)) received either LHRHa+ARPI (n=41) or tE2+ARPI (n=38). Baseline characteristics were similar between the 2 groups. The proportion of pts achieving PSA ≤0.2ng/ml was LHRHa+ARPI 25/41 (61%) and tE2+ARPI 23/38 (61%). LHRHa v tE2: PSA90 (93% v 95%) and PSA50 (100% v 100%). 31/34 (91%) men treated with tE2 had testosterone ≤1.7ng/ml at 12 weeks. Hot flushes: LHRHa (grade 1: 32%, grade 2: 20%) v tE2 (grade 1: 24%, grade 2: 5%). Gynaecomastia: LHRHa (grade 1: 10%, grade 2: 0%) v tE2 (grade 1: 35%, grade 2: 8%) and any grade hypertension LHRHa v tE2 17% versus 5%. Conclusions: PSA responses were similar in pts treated with tE2+ARPI or LHRHa+ARPI further supporting the use of tE2 patches for ADT in prostate cancer management. tE2 patches provide patients with ADT choices about expected toxicity profiles, including reduced hot flushes (and subsequent impact on quality of life), and mode of administration. Clinical trial information: NCT00268476 .