Background: HR (hormone receptor)-positive, HER2 (Human Epidermal Growth Factor Receptor 2)-negative metastatic breast cancer represents the majority of advanced breast cancer cases. Although CDK4/6 (cyclin-dependent kinase) inhibitors combined with endocrine therapy have become the standard first-line approach, the optimal treatment strategy after disease progression remains unclear. Methods: We conducted a multicenter retrospective study of 218 patients treated across five tertiary oncology centers in Turkey who progressed on CDK4/6 inhibitors and subsequently received either endocrine therapy (ET) or chemotherapy (CT). Results: Endocrine therapy, administered in 65 patients—most commonly with everolimus-based combinations—was associated with a significantly longer overall survival (OS) compared with CT (18.0 vs 10.0 months, p = 0.011). While progression-free survival (PFS) showed a numerical advantage for ET (6.0 vs 4.9 months), the difference did not reach statistical significance. Multivariate analysis confirmed both treatment type and de novo metastatic presentation as independent predictors of survival. Conclusion: These findings demonstrate that, in real-world clinical practice, continued endocrine therapy beyond CDK4/6 inhibitors progression yields superior survival compared to chemotherapy, particularly in patients with de novo metastatic disease. Our results support the prioritization of endocrine-based approaches over chemotherapy in this setting and underscore the urgent need for prospective trials to refine treatment sequencing strategies for this large patient population.