title: A Phase I/Ib Study of Enzalutamide Alone and in Combination with Endocrine Therapies in Women with Advanced Breast Cancer.
abstract: Purpose:Several lines of evidence support targeting the androgen signaling pathway in breast cancer. Enzalutamide is a potent inhibitor of androgen receptor signaling. Preclinical data in estrogen-expressing breast cancer models demonstrated activity of enzalutamide monotherapy and enhanced activity when combined with various endocrine therapies (ET). Enzalutamide is a strong cytochrome P450 3A4 (CYP3A4) inducer, and ETs are commonly metabolized by CYP3A4. The pharmacokinetic (PK) interactions, safety, and tolerability of enzalutamide monotherapy and in combination with ETs were assessed in this phase I/Ib study.Experimental Design:Enzalutamide monotherapy was assessed in dose-escalation and dose-expansion cohorts of patients with advanced breast cancer. Additional cohorts examined effects of enzalutamide on anastrozole, exemestane, and fulvestrant PK in patients with estrogen receptor-positive/progesterone receptor-positive (ER+/PgR+) breast cancer.Results:Enzalutamide monotherapy (n= 29) or in combination with ETs (n= 70) was generally well tolerated. Enzalutamide PK in women was similar to prior data on PK in men with prostate cancer. Enzalutamide decreased plasma exposure to anastrozole by approximately 90% and exemestane by approximately 50%. Enzalutamide did not significantly affect fulvestrant PK. Exposure of exemestane 50 mg/day given with enzalutamide was similar to exemestane 25 mg/day alone.Conclusions:These results support a 160 mg/day enzalutamide dose in women with breast cancer. Enzalutamide can be given in combination with fulvestrant without dose modifications. Exemestane should be doubled from 25 mg/day to 50 mg/day when given in combination with enzalutamide; this combination is being investigated in a randomized phase II study in patients with ER+/PgR+breast cancer.Clin Cancer Res; 23(15); 4046-54. ©2017 AACR.
authors.affiliation: West Cancer Center, Memphis, Tennessee.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Schwartzberg
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tennessee.|Tennessee Oncology, PLLC, Nashville, Tennessee.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Yardley
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Elias
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tennessee.|Florida Cancer Specialists, Sarah Cannon Research Institute, Sarasota, Florida.
authors.forename: Manish
authors.initials: M
authors.lastname: Patel
authors.affiliation: Department of Internal Medicine, Yale University, New Haven, Connecticut.
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tennessee.|Tennessee Oncology, PLLC, Nashville, Tennessee.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: Ayca
authors.initials: A
authors.lastname: Gucalp
authors.affiliation: Medivation, Inc. (Medivation, Inc., was acquired by Pfizer, Inc., in September 2016), San Francisco, California.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Peterson
authors.affiliation: Medivation, Inc. (Medivation, Inc., was acquired by Pfizer, Inc., in September 2016), San Francisco, California.
authors.forename: Martha E
authors.initials: ME
authors.lastname: Blaney
authors.affiliation: Astellas Pharma, Inc., Northbrook, Illinois.
authors.forename: Joyce L
authors.initials: JL
authors.lastname: Steinberg
authors.affiliation: Medivation, Inc. (Medivation, Inc., was acquired by Pfizer, Inc., in September 2016), San Francisco, California.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Gibbons
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. trainat@mskcc.org.|Weill Cornell Medical College, New York, New York.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Traina
mesh_terms: D000328:Adult; D000368:Aged; D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D001549:Benzamides; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D009570:Nitriles / Q000008:administration & dosage; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D001549:Benzamides; D009570:Nitriles; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014230:Triazoles; D010669:Phenylthiohydantoin; D000077384:Anastrozole; C540278:enzalutamide; D051544:Cytochrome P-450 CYP3A