Phase I Study of the Prolactin Receptor Antagonist LFA102 in Metastatic Breast and Castration-Resistant Prostate Cancer.
Despite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical efficacy.Increased serum prolactin levels may be a biomarker for prolactin receptor inhibition.Results from the pharmacokinetic and pharmacodynamics (PD) studies suggest that inappropriately long dosing intervals and insufficient exposure to LFA102 may have resulted in lack of antitumor efficacy.Based on preclinical data, combination therapy of LFA102 with those novel agents targeting hormonal pathways in metastatic castration-resistant prostate cancer and metastatic breast cancer is promising.Given the PD evidence of prolactin receptor blockade by LFA102, this drug has the potential to be used in conditions such as hyperprolactinemia that are associated with high prolactin levels.



Prolactin receptor (PRLR) signaling is implicated in breast and prostate cancer. LFA102, a humanized monoclonal antibody (mAb) that binds to and inhibits the PRLR, has exhibited promising preclinical antitumor activity.



Patients with PRLR-positive metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) received doses of LFA102 at 3-60 mg/kg intravenously once every 4 weeks. Objectives were to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) to investigate the safety/tolerability of LFA102 and to assess pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.



A total of 73 patients were enrolled at 5 dose levels. The MTD was not reached because of lack of dose-limiting toxicities. The RDE was established at 60 mg/kg based on PK and PD analysis and safety data. The most common all-cause adverse events (AEs) were fatigue (44%) and nausea (33%) regardless of relationship. Grade 3/4 AEs reported to be related to LFA102 occurred in 4% of patients. LFA102 exposure increased approximately dose proportionally across the doses tested. Serum prolactin levels increased in response to LFA102 administration, suggesting its potential as a biomarker for PRLR inhibition. No antitumor activity was detected.



Treatment with LFA102 was safe and well tolerated, but did not show antitumor activity as monotherapy at the doses tested.
Huntsman Cancer Institute, Division of Medical Oncology, Department of Medicine, University of Utah, Salt Lake City, Utah, USA neeraj.agarwal@hci.utah.edu.
Neeraj
N
Agarwal
Roi Albert II Institute, Medical Oncology Service, University Clinic Saint Luc and Institute of Experimental and Clinical Research (Pôle Molecular Imaging, Radiotherapy & Oncology), Catholic University of Louvain, Brussels, Belgium.
Jean-Pascal
JP
Machiels
Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Cristina
C
Suárez
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Nancy
N
Lewis
Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, USA.
Michaela
M
Higgins
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.
Kari
K
Wisinski
Jules Bordet Institute, Brussels, Belgium.
Ahmad
A
Awada
Oncology Unit, Department of Oncology, Hematology and Respiratory Disease, University Hospital Policlinico of Modena, Modena, Italy.
Michela
M
Maur
Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA.
Mark
M
Stein
Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA.
Andy
A
Hwang
Rebecca
R
Mosher
Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA.
Ernesto
E
Wasserman
Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA.
Gang
G
Wu
Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA.
Hefei
H
Zhang
Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA.
Renata
R
Zieba
Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA.
Mohamed
M
Elmeliegy
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D011981:Receptors, Prolactin / Q000037:antagonists & inhibitors* / Q000502:physiology
D061067:Antibodies, Monoclonal, Humanized; C583731:LFA102 monoclonal antibody; D011981:Receptors, Prolactin