Background: Cell cycle inhibition is a target of interest for novel cancer therapeutics. P is an orally active inhibitor of CDK4/6, causing cell cycle arrest at the G1-S transition. In an interim analysis of a phase II first-line study in HR+ metastatic breast cancer (MBC), patients (pts) randomized to letrozole (L) plus P had prolonged progression-free survival compared with L alone (26.1 vs 7.5 mos, HR 0.37, p<0.001) (Finn et al SABCS 2012). The most common toxicity with P is neutropenia, typically non-cumulative and uncomplicated. Given observed benefits of LP in HR+ MBC, exploring the feasibility of P in the adjuvant setting is warranted. Methods: This is a phase II single arm trial evaluating the feasibility of 2 yrs of combination P and adjuvant ET. Eligible pts are postmenopausal, with HR+ stage II (not T2N0)-III invasive breast cancer. Pts must have demonstrated tolerance of adjuvant aromatase inhibitor (AI) by completion of 3-24 mos of AI without significant adverse events (AE), with plan for at least 2 more yrs of AI. Pts will receive P at 125 mg daily, 3 wk on/1 wk off in a 28d cycle, plus continuous physician’s choice AI (L, anastrozole, or exemestane), for planned duration 2 yrs. Neutropenia monitoring occurs every 2 wks for the first 3 cycles, then monthly for the duration of treatment. Pts may be removed from study for toxicity, non-adherence, or other events related to tolerability; pts who recur or complete 2 yrs of therapy will be censored for the primary endpoint. The primary objective is to evaluate the treatment discontinuation rate at 2 yrs; if the rate is >50%, the treatment duration will not be considered feasible, whereas a rate <33.3% would be considered feasible and worthy of further study for efficacy. Discontinuation rates at 2 yrs will be estimated by Kaplan Meier with 95% confidence bands. The total sample size is 120 pts, providing 92% power to reject the null hypothesis using a one-sided alpha = 0.025, and accounting for a censoring rate of up to 20% over the 2 yrs. Secondary endpoints include AE graded by CTCAE 4.0 and adherence to oral therapy. Two interim analyses for futility are planned when 66% and 100% of pts have received 6 mos of therapy. Clinical trial information: NCT02040857.