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, Robert M. Hughes, Stephanie Glavaris, Kamyar Ghabili, Ping He, Nicole M. Anders, Rana Harb, Jeffrey J. Tosoian, Luigi Marchionni, Edward M. Schaeffer, Alan W. Partin, Mohamad E. Allaf, Trinity J. Bivalacqua, Carolyn Chapman, Tanya O'Neal, Angelo M. DeMarzo, Paula J. Hurley, Michelle A. Rudek, Emmanuel S. Antonarakis

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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 presurgical 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.

Original languageEnglish (US)
Pages (from-to)104182-104192
Number of pages11
JournalOncotarget
Volume8
Issue number61
DOIs
StatePublished - 2017

Keywords

  • Clinical trial
  • GLI1
  • Hedgehog
  • Prostate cancer
  • Sonidegib (LDE-225)

ASJC Scopus subject areas

  • Oncology

Fingerprint

Dive into the research topics of 'Pharmacodynamic and pharmacokinetic neoadjuvant study of hedgehog pathway inhibitor Sonidegib (LDE-225) in men with high-risk localized prostate cancer undergoing prostatectomy'. Together they form a unique fingerprint.

Cite this