Background: Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) in combination with ET has become a standard first-line treatment for pts with endocrine-sensitive, HR[+]/HER2[-] ABC. The optimal treatment after progression on a CDK4/6i remains unknown. This study aims to determine if P maintenance with an alternative ET improves the antitumor activity of second-line treatment in this patient population. Methods: A total of 198 pts with HR[+]/HER2[-] ABC who had disease progression to first-line P plus ET (aromatase inhibitor or fulvestrant) were included. Pts were eligible if they had clinical benefit to the first-line treatment defined as response or stable disease ≥24 weeks, or who had progressed on a P-based regimen in the adjuvant setting with disease progression after at least 12 months of treatment but no more than 12 months following P treatment completion. Pts were randomly assigned (2:1 ratio) to receive P plus second-line ET (letrozole or fulvestrant, based on prior ET) or second-line ET alone. Stratification factors were prior ET and the presence of visceral involvement. Primary endpoint was investigator-assessed progression-free survival (PFS) determined by RECIST v.1.1. Secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), overall survival, and safety. The 2-sided log-rank test (α = 0.05) had an 80% power to detect a hazard ratio ≤0.59 in favor of P maintenance. Results: Between April 2019 and October 2022, 136 and 62 pts were randomized to receive P+ET and ET, respectively. Pts characteristics were well balanced. Median age was 59 years (range: 33-85), 61.1% were ECOG 0, 61.1% had visceral disease, and 89.9% received aromatase inhibitor + P as first-line treatment for metastatic disease. At median follow-up of 8.7 months and 155 PFS events, median investigator-assessed PFS was 4.2 months (95% CI 3.5–5.8) in the P+ET vs. 3.6 months (95% CI 2.7–4.2) in the ET arm (hazard ratio 0.8, 95% CI 0.6–1.1, p=0.206). This result was consistent across all stratification subgroups. 6-month PFS rate was 40.9% and 28.6% for P+ET and ET, respectively. Among 138 pts with measurable disease, no significant differences were observed in ORR (6.4% vs. 2.3%) or CBR (33.0% vs. 29.5%) for P+ET and ET, respectively. Grade 3-4 adverse events were higher in pts treated with P+ET (45.2% vs. 8.3%) and no new safety signals were identified. No treatment-related deaths were reported. Conclusions: For HR[+]/HER2[-] ABC pts, maintaining P with a second-line ET beyond progression on prior P-based therapy did not significantly improve PFS compared with second-line ET alone. Planned biomarker analysis may help identify which pts are more likely to benefit from this therapeutic approach. Clinical trial information: NCT03809988.