Abstract Introduction: CDK4/6 inhibitors (CDK4/6i) are integral to managing HR+/HER2- advanced breast cancer (ABC), with approvals in both first-line (1L) and second-line (2L). The phase 3 SONIA trial found that 1L CDK4/6i therapy improved time to first progression (PFS1) but not overall survival (OS) or time to second progression (PFS2) compared to reserving CDK4/6i for 2L. Because most patients in SONIA received palbociclib, optimal timing remains uncertain for other CDK4/6i. We computationally analyzed phase 3 trial results to investigate whether CDK4/6i yield intrinsically greater PFS1, PFS2, or OS benefits in 1L versus 2L settings. Methods: We analyzed PFS and OS from pivotal phase 3 trials investigating palbociclib, abemaciclib, and ribociclib in HR+/HER2- ABC (Table). Using PFS distributions from 2L trials, we computed expected 1L PFS under the null hypothesis that CDK4/6i prolong time to progression, relative to endocrine therapy alone, by the same absolute durations at 1L or 2L. For OS, we investigated confounding from incomplete crossover in 1L trials, where a fraction of control arm patients did not receive CDK4/6i post-progression. We used 2L survival distributions to simulate OS with 100% crossover where all control patients receive CDK4/6i at 2L, testing the null hypothesis that CDK4/6i extend OS equally at 1L and 2L. For each CDK4/6i, we simulated trials with the same design as SONIA to compare expected PFS2, and time on therapy, for 1L vs 2L CDK4/6i. Results: Expected 1L PFS derived from 2L trial data did not significantly differ from observed 1L PFS for any CDK4/6i (P values ≥ 0.25, Cox proportional hazards), suggesting similar efficacy in delaying progression at 1L or 2L. For each CDK4/6i, simulated OS when all control arm patients cross-over to 2L CDK4/6i did not significantly differ from observed OS of 1L CDK4/6i (Table), suggesting that CDK4/6i prolongs OS similarly at 1L or 2L. For each CDK4/6i, simulated trials of 1L versus 2L CDK4/6i strategies did not predict significant differences in PFS2, but did predict longer time on CDK4/6i therapy at 1L, as observed in SONIA (Table). Conclusions: Analysis of PFS and OS results of phase 3 trials in 1L and 2L settings indicate that approved CDK4/6 inhibitors confer comparable durations of PFS2 and OS when added to endocrine therapy at either 1L or 2L in HR+/HER2- ABC. These results suggest that reserving CDK4/6i for 2L administration is a clinically valid approach without significant detriment to survival outcomes and may be preferable for many patients due to improved tolerability and affordability. Citation Format: N. Schlachter, L. A. Carey, A. Palmer. Equivalent survival benefits from first-line and second-line use of CDK4/6 inhibitors in HR+/HER2- advanced breast cancer: A computational analysis of phase 3 trials abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-08-25.
Schlachter et al. (2026) studied this question.