Background: Of the estimated 232,670 new cases of breast cancer (BC) diagnosed in the U.S. in 2014, 40% will have occurred in women ≥ 65 years. In this population, the most common type of BC is estrogen receptor-positive (ER+), HER2-negative (HER2-) for which endocrine treatment (ET) is currently the treatment of choice. When tumors become refractory to ET, chemotherapy is often initiated; palliative measures might also be suitable. Palbociclib (P) is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In a randomized phase 2 trial (PALOMA-1/TRIO-18; NCT00721409), first-line P plus letrozole (L) showed median progression-free survival (PFS) benefit that was double that shown by L alone in patients (pts) with ER+ and HER2- advanced BC (Finn et al, Lancet Oncol, 2015; 16: 25-35). In the present subgroup analysis, we evaluated the effect of P + L versus L alone in pts aged ≥ 65 years. Methods: Postmenopausal women (N = 165) with advanced ER+, HER2- BC were randomized 1:1 to receive P (125 mg/day for 3 weeks, 1 week off) plus L (2.5 mg/day) or L alone (2.5 mg/day). Of the 76 pts aged ≥ 65 years, 37 were assigned to P + L and 39 were assigned L alone. The primary endpoint was investigator-assessed progression-free survival (PFS). Results: In pts ≥ 65 years, the median PFS was 26.6 months (95% CI 12.6 – NR) for the P + L arm and 7.7 months (95% CI 3.7 – 10.9) for the L arm (HR 0.505, 95% CI 0.269 – 0.948; one-sided p = 0.0155). In pts eligible for safety analysis, grade 3-4 neutropenia was reported in 56.8% in the P+L arm vs 2.7% in the L arm, leucopenia in 29.7% vs none, and fatigue in 10.8% vs none. In general, neutropenia associated with P+L was short-lived and did not require management with hematopoietic growth factors. Conclusions: The median PFS was > 3 times longer in the P+L arm than in the L alone arm for the subgroup of pts ≥ 65 years. The toxicity profile was consistent with that of entire study population. A phase III study evaluating P+L is ongoing; P+L is an important treatment option for elderly, as well as non-elderly, patients with ER+, HER2- advanced BC. Clinical trial information: NCT00721409