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Purpose: The CDK4/6 inhibitor palbociclib inhibits cyclin A, which is overexpressed in endometrial cancer. Combining palbociclib with endocrine therapy improves efficacy in hormone receptor-positive breast cancer. We investigated palbociclib combined with endocrine therapy for estrogen receptor-positive advanced/recurrent endometrial cancer., Patients and Methods: This placebo-controlled double-blind, randomized phase II screening trial (NCT02730429) enrolled women with measurable/evaluable estrogen receptor-positive endometrioid endometrial cancer that was primary metastatic or had relapsed after ≥1 prior systemic therapy. Patients were randomized in a 1:1 ratio, stratified by number of prior chemotherapy lines, measurable versus evaluable non-measurable disease, and prior medroxyprogesterone/megestrol acetate treatment, to receive oral letrozole 2.5 mg on days 1-28 plus either oral palbociclib 125 mg or placebo on days 1-21, repeated every 28 days until disease progression or unacceptable toxicity. The primary end point was investigator-assessed progression-free survival (PFS)., Results: Among 77 patients randomized between February 16, 2017, and December 21, 2018, 73 were treated (36 with palbociclib-letrozole, 37 with placebo-letrozole). Median follow-up was 21.9 (95 % CI, 16.7 to 22.3) months. Median PFS was 8.3 (95 % CI, 4.6 to 11.2) versus 3.1 (95 % CI, 2.7 to 6.8) months, respectively. In a landmark analysis at 12 months the PFS hazard ratio was 0.57 (95 % CI, 0.32 to 0.99; P = .044). Grade ≥ 3 adverse events were more common with palbociclib-letrozole (67 %) than placebo-letrozole (30 %), most commonly neutropenia (44 % v 0 %, respectively)., Conclusion: These results support a potential role of the palbociclib-letrozole combination as treatment for hormone receptor-positive advanced/recurrent endometrial cancer. Based on these encouraging results, phase III evaluation of letrozole combined with a CDK4/6 inhibitor is planned., Clinical Trial Information: NCT02730429., Competing Interests: Declaration of competing interest MRM reports leadership roles and stock for Karyopharm Therapeutics and Sera Prognostics; honoraria from Roche, AstraZeneca, Genmab/Seattle Genetics, GSK, Merck, Mersana, Takeda, Zai Lab, Geneos, and Allarity Therapeutics; consulting/advisory roles for AstraZeneca, Genmab, Karopharm Therapeutics, Pfizer, and GSK; research funding (to institution) from AstraZeneca, Boehringer Ingelheim, Pfizer, Tesaro, Clovis Oncology, Ultimovacs, Apexigen, and GSK; grants and personal fees from Tesaro, AstraZeneca, Pfizer, and Clovis Oncology; travel/accommodation/expenses from AstraZeneca, Karyopharm Therapeutics, Pfizer, Roche, Tesaro, and SeraCare; and other relationships with ENGOT, GCIG, and ESGO. LB reports speaker's bureau participation for GSK and MSD and research funding from AstraZeneca. FM reports honoraria from Roche/Genentech, Novartis, Pfizer, AstraZeneca, Clovis Oncology, Eisai, Genomic Health, PharmaMar, Amgen, MSD Oncology, Seagen, Myriad Genetics, Pierre Fabre, GSK, Agendia, Lilly, Gilead, Daiichi Sankyo, and Immunomedics; consulting/advisory roles for Pfizer, Genomic Health, CureVac, Amgen, Eisai, GSK, Gilead, Seagen, Clovis Oncology, AstraZeneca, Roche, Vaccibody, and Immunomedics; research funding from Roche/Genentech, Novartis, AstraZeneca, Tesaro, Clovis Oncology, MSD Oncology, Vaccibody, Gilead, and GSK; and travel/accommodation/expenses from Roche, Pfizer, AstraZeneca, and Gilead Sciences. RdPC reports employment and stock ownership from Y-mAbs Therapeutics and consulting/advisory role for Karyopharm. MGM reports consulting/advisory roles for AstraZeneca; speakers' bureau for GSK and MSD Oncology; and travel/accommodation/expenses from AstraZeneca, GSK, and MSD Oncology. AA reports consulting/advisory roles and travel/accommodation/expenses from GSK and MSD. BA reports honoraria from Roche, AstraZeneca, MSD, GSK, Eisai Europe, Novartis, Lilly, and Pfizer; consulting/advisory roles for Roche, MSD, Sanofi Aventis GmbH, GSK, and Eisai Europe; and travel/accommodation/expenses from Roche, AstraZeneca, GSK, Lilly, and Daiichi Sankyo/AstraZeneca. VS reports honoraria from AstraZeneca, MSD Oncology, GSK, PharmaMar, and Novocure; consulting/advisory roles for AstraZeneca and Novocure; and travel/accommodation/expenses from GSK and PharmaMar. AR reports consulting/advisory roles for AstraZeneca, GSK, Boehringer Ingelheim, MSD, and Pharma&; speakers' bureau for AstraZeneca, GSK, MSD, and Pharma&; and travel/accommodation/expenses from AstraZeneca. KL reports honoraria from AstraZeneca; consulting/advisory roles for Eisai, MSD, GSK, and Nycode; research funding (inst) from GSK; and is Deputy Medical Director of NSGO-CTU. FT reports research funding and personal fees from AstraZeneca, Clovis, Eisai, ImmunoGen, MSD, SAGA diagnostics, and Tesaro/GSK. MPBG reports consulting/advisory roles for AstraZeneca, GSK, MSD Oncology, Eisai Europe, Clovis Oncology, PharmaMar, and Pharma&; speakers' bureau for AstraZeneca Spain, GSK, Eisai Europe, and MSD Oncology; and travel/accommodation/expenses from AstraZeneca, GSK, and MSD Oncology. JEK reports employment (immediate family member) with MSD; consulting/advisory roles for AstraZeneca, MSD, and GSK; and travel/accommodation from AstraZeneca, Eisai, PharmaMar, and GSK. JS reports honoraria from AstraZeneca, Eisai, Clovis Oncology, Olympus Medical Systems, Johnson & Johnson, PharmaMar, Pfizer, Teva, Tesaro, MSD Oncology, GSK, and Bayer; consulting/advisory roles for AstraZeneca, Clovis Oncology, PharmaMar, Merck, Pfizer, Tesaro, MSD Oncology, Lilly, Novocure, Johnson & Johnson, Roche Diagnostics, NGRESS-Health, Riemser, Sobi, GSK, Novartis, and Alkermes; research funding (inst) from AstraZeneca, Clovis Oncology, Merck, Bayer, PharmaMar, Pfizer, Tesaro, MSD Oncology, and Roche; travel/accommodation/expenses from AstraZeneca, Clovis Oncology, PharmaMar, Roche Pharma AG, Tesaro, MSD Oncology, and Olympus. No other potential conflicts of interest were reported., (Copyright © 2024. Published by Elsevier Inc.)