Pharmacodynamic study of the oral hedgehog pathway inhibitor, vismodegib, in patients with metastatic castration-resistant prostate cancer.
OBJECTIVE
Hedgehog (Hh) pathway signaling has been implicated in prostate cancer tumorigenesis and metastatic development and may be upregulated even further in the castration-resistant state. We hypothesized that antagonism of the Hh pathway with vismodegib in men with metastatic castration-resistant prostate cancer (mCRPC) would result in pathway engagement, inhibition and perhaps induce measurable clinical responses in patients.


METHODS
This is a single-arm study of oral daily vismodegib in men with mCRPC. All patients were required to have biopsies of the tumor and skin (a surrogate tissue) at baseline and after 4 weeks of therapy. Ten patients were planned for enrollment. The primary outcome was the pharmacodynamic assessment of Gli1 mRNA suppression with vismodegib in tumor tissue. Secondary outcomes included PSA response rates, progression-free survival (PFS), overall survival (OS) and safety.


RESULTS
Nine patients were enrolled. Gli1 mRNA was significantly suppressed by vismodegib in both tumor tissue (4/7 evaluable biopsies, 57%) and benign skin biopsies (6/8 evaluable biopsies, 75%). The median number of treatment cycles completed was three, with a median PFS of 1.9 months (95% CI 1.3, NA), and a median OS of 7.04 months (95% CI 3.4, NA). No patient achieved a PSA reduction or a measurable tumor response. Safety data were consistent with the known toxicities of vismodegib.


CONCLUSIONS
Hh signaling, as measured by Gli1 mRNA expression in mCRPC tissues, was suppressed with vismodegib in the majority of patients. Despite this pharmacodynamic response that indicated target inhibition in some patients, there was no apparent signal of clinical activity. Vismodegib will not be developed further as monotherapy in mCRPC.
Huntsman Cancer Center, University of Utah, 2000 Circle of Hope Dr, Salt Lake City, UT, 84112, USA.
Benjamin L
BL
Maughan
Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 20993, USA.
Daniel L
DL
Suzman
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans St. CRB1 1M45, Baltimore, MD, 21287, USA.
Brandon
B
Luber
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans St. CRB1 1M45, Baltimore, MD, 21287, USA.
Hao
H
Wang
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans St. CRB1 1M45, Baltimore, MD, 21287, USA.
Stephanie
S
Glavaris
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans St. CRB1 1M45, Baltimore, MD, 21287, USA.
Robert
R
Hughes
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans St. CRB1 1M45, Baltimore, MD, 21287, USA.
Rana
R
Sullivan
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans St. CRB1 1M45, Baltimore, MD, 21287, USA.
Rana
R
Harb
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans St. CRB1 1M45, Baltimore, MD, 21287, USA.
Karim
K
Boudadi
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans St. CRB1 1M45, Baltimore, MD, 21287, USA.
Channing
C
Paller
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans St. CRB1 1M45, Baltimore, MD, 21287, USA.
Mario
M
Eisenberger
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans St. CRB1 1M45, Baltimore, MD, 21287, USA.
Angelo
A
Demarzo
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans St. CRB1 1M45, Baltimore, MD, 21287, USA.
Ashely
A
Ross
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans St. CRB1 1M45, Baltimore, MD, 21287, USA. eantona1@jhmi.edu.
Emmanuel S
ES
Antonarakis
D000368:Aged; D000813:Anilides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000071676:Zinc Finger Protein GLI1 / Q000235:genetics
D000813:Anilides; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines; D000071676:Zinc Finger Protein GLI1; D017430:Prostate-Specific Antigen
Gli; Hedgehog; Metastatic castration-resistant prostate cancer; Vismodegib