CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are the established first-line (1L) therapy for patients (pts) with hormone receptor (HR)-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC). Data supporting the best treatment choice at progression on CDK4/6i+ET is limited. We collected data from pts with HR+/HER2- mBC who received treatment after progression to CDK4/6i+ET in five Italian Institutions. Progression-free survival 2 (PFS2), the primary endpoint, was calculated from initiation of CDK4/6i to disease progression (PD) on subsequent line of therapy or patient death. The PFS2-PFS1 difference and PFS2/PFS1 ratio were also estimated. We compared outcomes between pts receiving chemotherapy (CT)- or ET-based regimens immediately after CDK4/6i+ET. As of January 2023, 511 pts were included. Median patient age was 59 years, 26.2% had de-novo mBC. CDK4/6i were administered mostly in the 1L (62.8%) or 2L (24.5%) settings. Most pts received palbociclib (69.3%), followed by ribociclib (22.5%) and abemaciclib (8.2%). At PD, more pts received CT (60.7%) than ET (39.3%). There was a significant imbalance between the two groups in terms of visceral involvement (61.2% versus 43.8% of pts treated with CT and ET at PD, respectively; p=0.0001) and prior lines of therapy (CDK4/6i+ET was given 1L to 71% of pts who subsequently received ET and to 55.8% of pts who received CT; p=0.004). Median follow-up was 33 months (mo). After adjusting for evidence of visceral metastasis and prior therapy, mPFS2 was 23.5 mo and 18.5 mo in pts receiving ET and CT, respectively (adjusted HR 0.69, 95% CI 0.55-0.86, p=0.001). Median OS was longer in pts receiving ET than CT (58.1 vs 39.7 mo, adjusted HR 0.52, 95% CI 0.38-0.70, p<0.0001). However, PFS2-PFS1 curves did not differ between the two groups (p=0.594), and more pts receiving CT had a PFS2/PFS1 ratio≥1.3 (78.7 vs 54.3%, p<0.0001). After progression to CDK4/6i, ET-based regimens are associated with longer PFS2 and OS when compared to CT. However, this likely reflects clinical benefit from previous CDK4/6i+ET. For pts with short PFS on CDK4/6i+ET, CT may be a more effective option.