Pharmacodynamic and pharmacokinetic neoadjuvant study of hedgehog pathway inhibitor Sonidegib (LDE-225) in men with high-risk localized prostate cancer undergoing prostatectomy
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Ashley E. Ross1,2,3,*, Robert M. Hughes1,2,3,*, Stephanie Glavaris1,2,3, Kamyar Ghabili1,2,3, Ping He3,4, Nicole M. Anders3,4, Rana Harb3, Jeffrey J. Tosoian1, Luigi Marchionni2,3, Edward M. Schaeffer1,2,3, Alan W. Partin1,2,3, Mohamad E. Allaf1,2,3, Trinity J. Bivalacqua1,2,3, Carolyn Chapman1,2,3, Tanya O’Neal1,2,3, Angelo M. DeMarzo1,3,5, Paula J. Hurley1,2,3, Michelle A. Rudek3,4,6 and Emmanuel S. Antonarakis1,2,3
1James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA
2Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
3Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
4Analytical Pharmacology Core Laboratory, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
5Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA
6Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD, USA
*These authors have contributed equally to this work
Emmanuel S. Antonarakis, email: [email protected]
Keywords: prostate cancer; Hedgehog; Sonidegib (LDE-225); GLI1; clinical trial
Received: July 21, 2017 Accepted: September 15, 2017 Published: October 26, 2017
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.
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