Background: Endocrine therapy (ET) combined with a CDK4/6 inhibitor is standard of care for hormone receptors-positive (HR+) advanced breast cancer (ABC). In France, 33% of BC are diagnosed in women aged 70 and older, contrasting with their constant underrepresentation in clinical trials. PALOMAGE, a prospective, observational, longitudinal real-life program, assessed the feasibility of ET combined with palbociclib (PAL), specifically in women aged ≥70 years with HR+ HER2- ABC. Methods: Depending on prior treatment for ABC and time of relapse, women were enrolled in two cohorts: ET-sensitive disease (no prior systemic treatment for ABC and no relapse within 1 year after adjuvant ET, cohort A) or ET-resistant disease (relapse on adjuvant ET or < 1 year after completion, or prior treatment for ABC, cohort B). Data collected at baseline and then every 3 months included: sociodemographic, clinical, biological, disease- and treatment-related, response, quality of life (QoL; EORTC QLQ-C30 and ELD14), geriatric (G8 and Geriatric-COre DatasEt [G-CODE]) and safety. Results of feasibility in cohort B (rate of PAL discontinuation at 6 months 28.8%) were reported at SABCS 2021. Here, we report results in cohort A, based on the rate of PAL discontinuation at 18 months for any reason as the primary endpoint. Secondary endpoints included time-to-treatment failure (TTF), progression-free survival (PFS), QoL, and safety. Results: For this analysis, 362 patients (from 130 sites) with sufficient data were considered: median age was 78 years (range: 70-94), ECOG was ≥2 in 19.2%, and visceral metastases was present in 39.8%. PAL starting dose was 125 mg, 100 mg, and 75 mg in 80.0%, 14.4%, and 5.6% of patients, respectively, and combined with an aromatase inhibitor in 93.6% or fulvestrant in 6.4%. Baseline scores showed G8 ≤14, ADL ≤5 and IADL ≤3 in 68.2%, 15.5% and 29.4% of patients, respectively. Among the 362 patients, 327 were evaluable for the primary endpoint. With a median follow-up of 20.7 months (95% CI: 18.8-22.0), the 18-month discontinuation rate for PAL was 41.9% (95% CI: 36.6%-47.2%), due to disease progression (20.8%), toxicity (7.7%), patient’s choice (6.7%), death (4.6%), or other reason (2.1%). Median TTF and PFS were 22.7 months (95% CI: 19.1–26.0) and 28.1 months (95% CI: 25.6-not reached), respectively. Safety profile showed (360 patients evaluable) 54.4% all grade neutropenia (1.1% febrile neutropenia). Impact of geriatric status on effectiveness and safety will be presented, together with the evolution of QoL. Conclusions: In a large real-life population of older women with G8 impaired in two thirds and with ET-sensitive ABC, discontinuation rate of PAL at 18 months was 41.9%, with a median PFS of 28.1 months, consistent with PALOMA2 results. Optimized ET combined with PAL is feasible in unselected older women with HR+ ET-sensitive ABC.