The authors conducted a prospective randomized (Sonidegib vs. observation) open-label translational clinical trial in 14 men with high-risk localized prostate cancer undergoing radical prostatectomy. The primary endpoint was the proportion of patients in each arm who achieved at least a two-fold reduction in GLI1 mRNA expression in post-treatment versus pre-treatment tumor tissue. The authors hypothesized that >70% of men in the Sonidegib arm would achieve this primary endpoint. Secondary endpoints included the effect of pre-surgical treatment with Sonidegib on disease progression following radical prostatectomy, and safety.
There were 7 men per arm randomized to either neoadjuvant Sonidegib or observation for 4 weeks prior to prostatectomy. Six of seven men (86%) in the Sonidegib arm (and none in the control group) achieved a GLI1 suppression of at least two-fold. In the Sonidegib arm, drug was detectable in plasma and in prostatic tissue; and median intra-patient GLI1 expression decreased by 63-fold, indicating potent suppression of Hedgehog signaling. Sonidegib was well tolerated, without any Grade 3-4 adverse events observed. Disease-free survival was comparable among the two arms (HR 1.50, 95%CI 0.26–8.69, p = 0.65), although the sample size and event rate were small.
Dr. Hughes concluded that the Hedgehog pathway activity (as measured by GLI1 expression) was detectable at baseline in men with localized high-risk prostate cancer. Sonidegib penetrated into prostatic tissue and induced a >60-fold median suppression of the Hedgehog pathway. However, at this point in time the oncological benefit of Hedgehog pathway inhibition in prostate cancer remains unclear.
Presented by: Robert M. Hughes, B.S. The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD
Co-Authors: Stephanie Glavaris ¹, Kamyar Ghabili MD¹, Ping He ², Nicole Anders ², Rana Harb ², Luigi Marchionni MD, PhD², Edward Schaeffer MD, PhD¹, Alan Partin MD, PhD¹, Mohamad Allaf MD¹, Trinity Bivalacqua MD, PhD¹, Carolyn Chapman ¹, Tanya O'Neal ¹, Angelo DeMarzo MD, PhD¹, Paula Hurley PhD¹, Michelle Rudek PhD, PharmD³, Emmanuel Antonarakis MD¹ and Ashley Ross MD, PhD¹
Affiliation: ¹The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD; ²The Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD; ³The Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD
Written by: Zachary Klaassen, MD, Society of Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre @zklaassen_md at the 18th Annual Meeting of the Society of Urologic Oncology, November 20-December 1, 2017 – Washington, DC