Abstract PS1-10-29: Complete tumor response during first-line endocrine therapy (ET) plus Cyclin Dependent Kinase 4/6 inhibitors (CDK4/6i) predicts excellent clinical outcomes in patients with Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative advanced Breast Cancer (HR+/HER2- aBC)

Abstract Background: The CDK4/6i palbociclib (P), ribociclib (R), and abemaciclib (A) combined with ET are the mainstay first-line therapy for patients (pts) with Hormone Receptor-positive, HR+/HER2- aBC. The impact of best tumor responses on long-term clinical outcomes has never been explored in this setting. Methods: PALMARES-2 (NCT06805812) is the largest, real-world (rw) study designed to investigate the effectiveness of first-line ET+CDK4/6i in pts with HR+/HER2- aBC treated in 25 Italian Institutions. Here, we investigated the impact of different types of radiologically and clinically assessed best tumor responses - complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) - on patient rw progression-free survival (rwPFS), time-to-chemotherapy (rwTTC), or overall survival (rwOS). Multivariable Cox regression models were used to adjust the association between the type of best tumor response and clinical outcomes for 16 clinically-relevant covariates. Logistic regression was used to identify variables predicting CR. Results: Of 3933 pts included in this analysis, 487 pts (12.4%) achieved CR, while 1620 (41.2%), 1535 (39.0%) and 292 (7.4%) pts achieved PR, SD and PD as best tumor response, respectively. Pts achieving CR had remarkably better rwPFS, rwTTC and rwOS when compared to pts achieving PR, SD or PD regardless of tumor endocrine sensitivity/resistance (Table). In the CR cohort, the three CDK4/6i were associated with similar rwPFS (R vs P: aHR 1.06, P =0.735; A vs P: aHR 0.93, P =0.763). Higher tumor expression of estrogen receptor alpha (ERα), as well as the presence of node or soft tissue metastases were associated with higher CR probability (OR: 1.10 per 10% increase, P=0.014; OR: 2.04, P=0.001; OR: 1.77, P=0.010, respectively). Conversely, higher tumor burden (OR 0.51 for each additional metastatic site, P 0.001), older age (OR: 0.79 per 10 years increase, P0.001), ECOG PS ≥1 (OR: 0.52, P0.001), higher Ki-67 expression (OR: 0.92 per 10% increase, P=0.025) and endocrine-resistant disease (OR: 0.78, P=0.047) were associated with lower CR probability. Among pts achieving CR, early CDK4/6i discontinuation because of toxicities was not associated with worse rwPFS (P=0.185) or rwOS (P=0.440). Conclusion: Achieving CR during first-line ET+CDK4/6i therapy is associated with excellent clinical outcomes in pts with HR+/HER2- aBC. These findings can guide clinicians in personalizing the management of pts with CR during ET+CDK4/6i, including CDK4/6i dose reduction/discontinuation in case of severe toxicities, or tailoring radiological disease re-evaluations. Citation Format: C. Vernieri, R. Caputo, M. Dieci, P. Vigneri, M. Giuliano, G. Curigliano, A. Toss, A. Botticelli, R. Pedersini, S. Cinieri, M. Lambertini, B. Tagliaferri, G. Rizzo, M. Sirico, M. Giordano, L. Gerratana, I. Meattini, A. Fabi, M. Piras, A. Zambelli, F. Pantano, A. Gennari, N. La Verde, D. Sartori, O. Garrone, D. Generali, F. Jacobs, F. De Braud, G. Pruneri, L. Provenzano, PALMARES-2 study group. Complete tumor response during first-line endocrine therapy (ET) plus Cyclin Dependent Kinase 4/6 inhibitors (CDK4/6i) predicts excellent clinical outcomes in patients with Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative advanced Breast Cancer (HR+/HER2- aBC) 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 PS1-10-29.