Background: Palbociclib (P) is a cyclin-dependent kinase inhibitor approved for the treatment of ER+/HER2- locally advanced (LA) or MBC and, in combination with endocrine therapy, was shown to be superior, in terms of PFS, to endocrine therapy alone in both a phase II trial comparing P+letrozole (L) to L alone (PALOMA-1) as well as in a phase III trial comparing P+ fulvestrant (F) to F alone (PALOMA-3). In the phase II FIRST study PFS was greater in the high-dose F (HDF) arm compared to anastrozole (A) as 1L therapy for ER+ MBC. The phase III FALCON study has recently completed accrual and compares HDF to A as 1L treatment. With two new (L+P and HDF) standards of care shaping up as 1L endocrine therapy for ER+/Her2- LA/MBC, exploring the combination of P+HDF in the 1L setting seems mandatory. Methods: The PARSIFAL phase II study is an open-label, randomized, controlled, multicenter study with the primary aim of assessing 1-year PFS of P+HDF vs. P+L in women with ER+ LA/MBC. 304 eligible pts will be enrolled in 53 centers and 9 countries (Europe and Middle East). Pts must be postmenopausal women > 18 years old, an ECOG score ≤ 2, and histologically confirmed recurrent ER+/HER2- LA/MBC. Pts may not have received prior chemotherapy for LA/MBC and are randomized to receive 125 mg capsules of P taken once daily from D1 to D21 of every 28D cycle together with either HDF 500 mg/5mL i.m. injection administered on D1 (Cycle 1 loading dose also requires D14 administration also on) or 2.5 mg tablets of L once daily from D1 to D28. Treatment is given until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first. For both combinations, secondary objectives are to: evaluate safety and tolerability; compare times to progression (TTP); and compare overall survival (OS) and clinical response results. The trial is in progress (start: Aug 2015, end: Jul 2017) and 62 pts have been accrued in 4 countries. A series of complementary prospective molecular studies are planned in order to evaluate predictive/prognostic biomarkers to P and endocrine therapy. Clinical trial information: 2014-004698-17.