Background <p>In the real-world POLARIS study, patients with hormone receptor-positive (HR⁺)/human epidermal growth factor receptor 2-negative (HER2⁻) advanced/metastatic breast cancer (ABC) who had received palbociclib + endocrine therapy (ET) had a median real-world progression-free survival (rwPFS) of 20.9 months in the first line of therapy (1LOT) and 13.5 months in second or later LOTs (≥ 2LOT).</p> Objective <p>The aim of this study is to assess the relationship of prior anticancer treatments with clinical outcomes.</p> Patients and Methods <p>Kaplan–Meier estimates of rwPFS and overall survival (OS) are described by prior anticancer treatments in patients with HR⁺/HER2⁻ ABC who received palbociclib + ET.</p> Results <p>A total of 1250 patients received ≥ 1 palbociclib dose (1LOT: 901 [72.1%]; ≥ 2LOT: 349 [27.9%]). In the 1LOT group, 563 (62.5%) had received prior (neo)adjuvant treatments: 24.3% ET alone, 26.6% chemotherapy alone, 45.5% ET + chemotherapy, and 3.6% other treatments; both median rwPFS and OS were numerically longer in patients who had received ET alone (30.4 months and not reached, respectively) and had had no prior treatment (23.7 and 53.3 months, respectively) than in patients with prior chemotherapy alone (15.9 and 38.4 months, respectively). In the ≥ 2LOT group, patients with prior ET alone (21.5%; 19.8 months) or chemotherapy alone (16.6%; 15.5 months) in the (neo)adjuvant and/or metastatic setting had numerically longer median rwPFS than those with prior ET + chemotherapy (41.3%; 11.6 months); OS was comparable regardless of prior treatment.</p> Conclusions <p>Patients with HR⁺/HER2⁻ ABC who had received ET alone prior to palbociclib tended to have better clinical outcomes, while those with prior chemotherapy had less clinical benefit.</p> Trial Registration <p>ClinicalTrials.gov, NCT03280303.</p>