To compare the efficacies of exemestane and fulvestrant as first-line monotherapies for postmenopausal Chinese women having advanced oestrogen-receptor positive (ER+)/ human epidermal growth factor receptor 2 (HER2)-breast cancer (ER+/HER2- ABC) after a previous treatment for ≥2 years with an adjuvant non-steroidal aromatase inhibitor.In this randomised, open-label, multi-centre, parallel-controlled phase 2 FRIEND study, 145 postmenopausal ER+/HER2- ABC patients were assigned into fulvestrant (500 mg on days 0, 14 and 28, and then at every 28 ± 3 days, n = 77) and exemestane (25 mg/day, n = 67) groups. The primary outcome was progression-free survival (PFS), while the secondary outcomes were disease control rate, objective response rate, time to treatment failure, duration of response and overall survival. Exploratory end-points included gene mutation-related outcomes and safety.Fulvestrant was superior to exemestane regarding median PFS times (8.5 versus 5.6 months, p = 0.014, HR = 0.62, 95% confidence intervals: 0.42-0.91), objective response rates (19.5% versus 6.0%, p = 0.017) and time to treatment failure (8.4 versus 5.5 months, p = 0.008). The incidence of adverse or serious adverse events in the two groups was virtually identical. The most frequent mutations in 129 analysed patients were detected in the oestrogen receptor gene 1 (ESR1) (18/14.0%), PIK3CA (40/31.0%) and TP53 (29/22.5%) genes. Fulvestrant produced significant longer PFS times compared to exemestane but only for patients with an ESR1-wild type (8.5 versus 5.8 months) (p = 0.035), although there was a similar trend also for the ESR1 mutation without statistical significance. All patients with c-MYC and BRCA2 mutations had longer PFS times in the fulvestrant versus the exemestane group (p = 0.049, p = 0.039).Fulvestrant significantly increased overall PFS for ER+/HER2- ABC patients and was well tolerated.NCT02646735, https://clinicaltrials.gov/ct2/show/NCT02646735.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.