Pharmacodynamic and pharmacokinetic neoadjuvant study of hedgehog pathway inhibitor Sonidegib (LDE-225) in men with high-risk localized prostate cancer undergoing prostatectomy.

// Ashley E. Ross 1, 2, 3, * , Robert M. Hughes 1, 2, 3, * , Stephanie Glavaris 1, 2, 3 , Kamyar Ghabili 1, 2, 3 , Ping He 3, 4 , Nicole M. Anders 3, 4 , Rana Harb 3 , Jeffrey J. Tosoian 1 , Luigi Marchionni 2, 3 , Edward M. Schaeffer 1, 2, 3 , Alan W. Partin 1, 2, 3 , Mohamad E. Allaf 1, 2, 3 , Trinity J. Bivalacqua 1, 2, 3 , Carolyn Chapman 1, 2, 3 , Tanya O’Neal 1, 2, 3 , Angelo M. DeMarzo 1, 3, 5 , Paula J. Hurley 1, 2, 3 , Michelle A. Rudek 3, 4, 6 and Emmanuel S. Antonarakis 1, 2, 3 1 James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA 2 Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA 3 Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA 4 Analytical Pharmacology Core Laboratory, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA 5 Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA 6 Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD, USA * These authors have contributed equally to this work Correspondence to: Emmanuel S. Antonarakis, email: eantona1@jhmi.edu Keywords: prostate cancer; Hedgehog; Sonidegib (LDE-225); GLI1 ; clinical trial Received: July 21, 2017 Accepted: September 15, 2017 Published: October 26, 2017 ABSTRACT Purpose: To determine the pharmacodynamic effects of Sonidegib (LDE-225) in prostate tumor tissue from men with high-risk localized prostate cancer, by comparing pre-surgical core-biopsy specimens to tumor tissue harvested post-treatment at prostatectomy. Methods: We conducted a prospective randomized (Sonidegib vs. observation) open-label translational clinical trial in 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. Secondary endpoints included the effect of pre-surgical treatment with Sonidegib on disease progression following radical prostatectomy, and safety. Results: Fourteen men were equally randomized (7 per arm) 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). Conclusions: 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 suppression of the Hedgehog pathway. The oncological benefit of Hedgehog pathway inhibition in prostate cancer remains unclear.