title: Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer.
abstract: BACKGROUND
  Growth of hormone-receptor-positive breast cancer is dependent on cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), which promote progression from the G1 phase to the S phase of the cell cycle. We assessed the efficacy of palbociclib (an inhibitor of CDK4 and CDK6) and fulvestrant in advanced breast cancer.
  
  
  METHODS
  This phase 3 study involved 521 patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that had relapsed or progressed during prior endocrine therapy. We randomly assigned patients in a 2:1 ratio to receive palbociclib and fulvestrant or placebo and fulvestrant. Premenopausal or perimenopausal women also received goserelin. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, objective response, rate of clinical benefit, patient-reported outcomes, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 195 events of disease progression or death had occurred.
  
  
  RESULTS
  The median progression-free survival was 9.2 months (95% confidence interval [CI], 7.5 to not estimable) with palbociclib-fulvestrant and 3.8 months (95% CI, 3.5 to 5.5) with placebo-fulvestrant (hazard ratio for disease progression or death, 0.42; 95% CI, 0.32 to 0.56; P<0.001). The most common grade 3 or 4 adverse events in the palbociclib-fulvestrant group were neutropenia (62.0%, vs. 0.6% in the placebo-fulvestrant group), leukopenia (25.2% vs. 0.6%), anemia (2.6% vs. 1.7%), thrombocytopenia (2.3% vs. 0%), and fatigue (2.0% vs. 1.2%). Febrile neutropenia was reported in 0.6% of palbociclib-treated patients and 0.6% of placebo-treated patients. The rate of discontinuation due to adverse events was 2.6% with palbociclib and 1.7% with placebo.
  
  
  CONCLUSIONS
  Among patients with hormone-receptor-positive metastatic breast cancer who had progression of disease during prior endocrine therapy, palbociclib combined with fulvestrant resulted in longer progression-free survival than fulvestrant alone. (Funded by Pfizer; PALOMA3 ClinicalTrials.gov number, NCT01942135.).
authors.affiliation: From Royal Marsden Hospital, London (N.C.T.); National Cancer Center, Goyang-si, South Korea (J.R.); Institut Gustave Roussy, Villejuif, France (F.A.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S. Loi); Sunnybrook Odette Cancer Centre, Toronto (S.V.); Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); Brustzentrum der Universität München, Munich (N.H.), and German Breast Group Forschungs, Neu-Isenburg (S. Loibl) - both in Germany; Pfizer, New York (C.H.B., M.K.), La Jolla, CA (K.Z., S.R.), and Milan (C.G.); and Thomas Jefferson University, Philadelphia (M.C.).
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Turner
authors.forename: Jungsil
authors.initials: J
authors.lastname: Ro
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
authors.forename: Sunil
authors.initials: S
authors.lastname: Verma
authors.forename: Hiroji
authors.initials: H
authors.lastname: Iwata
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.forename: Cynthia
authors.initials: C
authors.lastname: Huang Bartlett
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: Carla
authors.initials: C
authors.lastname: Giorgetti
authors.forename: Sophia
authors.initials: S
authors.lastname: Randolph
authors.forename: Maria
authors.initials: M
authors.lastname: Koehler
authors.forename: Massimo
authors.initials: M
authors.lastname: Cristofanilli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D001943:Breast Neoplasms / Q000188:drug therapy*; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004958:Estradiol / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis
chemical_list: D015415:Biomarkers; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D004958:Estradiol; D000077267:Fulvestrant; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human; C500026:palbociclib