Background: In patients with metastatic hormonal receptors (HR)-positive, HER2-negative breast cancer, CDK 4/6 inhibitors with hormonal therapy is the current standard first line therapy in patients without visceral crisis. Limited data is available about the outcome of second line therapy after CDK 4/6 inhibitors. In this study, we reported the survival outcome of second line systemic therapy after CDK 4/6 inhibitors in a single institute in Saudi Arabia. Methods: We retrospectively checked patients with metastatic HR-positive, HER2-negative breast cancer who received first line therapy with palbociclib in addition to an aromatase inhibitor in King Abdullah Medical City, Saudi Arabia. Patients who received second line systemic therapy were recruited. Different clinicopathological data were checked in addition to type of second line therapy, dates of starting 1^st and second lines therapy and dates of progression. We check progression-free survival (PFS) with second line therapy in relation to the type of second line therapy, duration of 1^st line therapy and other potential prognostic factors. Results: We recruited 59 eligible patients. Median PFS of the study group was 4 months (95% CI 2.9-5.1). No significant difference in PFS according to type of second line systemic therapy (chemotherapy: 4 months, everolimus with hormonal therapy: 6 months, hormonal monotherapy: 3 months, p=0.17). In addition, there was no significance difference in second line therapy PFS according to duration of 1^st line palbociclib-hormonal therapy (≤ 12 months: 4 months vs. >12 months: 5 months, HR 0.97, 95% CI: 0.55-1.7, p=0.92). Similarly, taking 6 months as a cutoff, no significant difference in PFS (≤ 6 months: 4 months, >6 months: 6 months, HR 0.73, 95% CI: 0.43-1.24, p=0.25). Similarly, no difference in second line PFS according to menopausal status, age at diagnosis (≤ 50 vs >50) or ER-Allred score (≤ 6 vs >6). Conclusions: Outcome of 2^nd line systemic therapy following first line palbociclib with hormonal therapy was poor in the study cohort. No significant difference in PFS according to type of systemic therapy, duration of first line therapy, or other clinicopathological factors.