Background: The CDK4/6 inhibitor palbociclib (P) in combination with letrozole (L) has become a standard first-line treatment for patients (pts) with luminal metastatic breast cancer (MBC) (PALOMA-1 & 2 trials). Meanwhile, the anti-estrogen fulvestrant (F) showed to be superior to anastrozole in the same population (FALCON trial). We aimed to identify the best endocrine agent to combine with P in this first-line scenario. Methods: A total of 486 pts with ER[+]/HER2[-] MBC with no prior therapy in the advanced setting and endocrine sensitive criteria (relapse > 12 months [mo] after the end of adjuvant endocrine therapy or diagnosed with “de novo” metastatic disease) were randomly assigned (1:1 ratio) to receive P (oral 125 mg/day [d]; 3 wks on/1 wk off) plus F 500 mg/d (I.M Days 0, 14, 28, and then every 28 d) or PL (oral 2.5 mg/d). Pts were stratified by visceral involvement and type of disease presentation (“de novo”/recurrent). Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety. 254 events were needed with 80% power to detect a hazard ratio (HR) ≤0.7 in favor of PF (2-sided α = 0.05). Results: By March 9th, 2020, 256 PFS events occurred. Pts characteristics were well balanced. Median age was 62 years (range: 25–90), 56.6% were ECOG 0, 40.7% had “de novo” metastatic disease, 48% had visceral disease, and 43.6% with ≥3 organ sites involved. At median follow-up of 32 mo, median PFS was 27.9 mo (95% confidence interval [CI], 24.2-33.1) with PF and 32.8 mo (95% CI, 25.8-35.9) with PL (HR: 1.1; 95% CI, 0.9-1.5; P = 0.321). No differences were observed for pts with or without visceral involvement (HR: 1.3 and HR: 0.97 respectively, interaction P = 0.275), and for “de novo” or recurrent metastatic disease (HR: 1.1 and HR: 1.1 respectively, P = 0.979). The 4-year OS rate was 67.6% in PF and 67.5% in PL arm (HR: 1; 95% CI, 0.7-1.5; P = 0.986). No differences were observed in ORR or CBR between arms. Grade ≥3 adverse events were similar in both arms, being neutropenia and leukopenia the most frequent. No treatment-related deaths were reported. Conclusion: This study was not able to identify an improvement in PFS for PF over PL in patients with endocrine-sensitive ER[+]/HER2[-] MBC. As both arms demonstrated comparable 4 years-OS, PF is a reasonable alternative to PL in this setting. Clinical trial information: NCT02491983.