Neoadjuvant Sonidegib Active in High-Risk Prostate Cancer

Robert M. Hughes, BS

In a study of neoadjuvant sonidegib (LDE-225; Odomzo) in men with high-risk localized prostate cancer undergoing prostatectomy, hedgehog pathway activity was detectable at baseline, according to a study presented by lead author Robert M. Hughes, BS, at the 2017 Society of Urologic Oncology Annual Meeting.

Investigators evaluated the Hedgehog inhibitor sonidegib to determine its pharmacodynamic effect in this population. In the analysis, researchers compared presurgical core-biopsy specimens to tumor tissue collected following neoadjuvant treatment at the time of prostatectomy, said Hughes, from the James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins School of Medicine.

Sonidegib is FDA-approved as a treatment option for patients with locally advanced basal cell carcinoma that has recurred following surgery. It’s inhibition of the Hedgehog pathway is what lead investigators in this study to evaluate it in patients with high-risk prostate cancer.

“Numerous preclinical as well as retrospective studies have demonstrated a reactivation of Hedgehog pathway in aggressive prostate cancer,” said Hughes.

In this prospective randomized study, 14 men with a median age of 63, median pretreatment PSA of 8, and median Gleason score of 9, were randomized to either neoadjuvant sonidegib (n = 7) or observation (n = 7) for 4 weeks prior to prostatectomy. Patients had stage ≥T3 disease.

Sonidegib was administered orally at 800 mg daily. The primary endpoint of this trial was reduction in GLI1 mRNA expression by at least two-fold.

Hughes stated that there were no significant differences in tumor or GLI1 expression between the 2 arms at baseline, but after 4 weeks of treatment, 86% of men (n = 6) in the treatment arm achieved the primary endpoint.

“We were able to decide Hedgehog pathway activity at baseline in treatment-naive men with localized high-risk prostate cancer,” said Hughes. “The drug successfully penetrated the tumor and inhibited GLI1 expression at least 2-fold in the majority of treated men.”

Sonidegib was found in the tissue and plasma of treated men and median intra-patient GLI1 expression decreased by 63-fold, demonstrating a potent suppression of the Hedgehog pathway.

Although disease-free survival was comparable (hazard ratio, 1.50; 95% CI, 0.26-8.69, P = .65), this did not power any conclusion on outcomes as it was not a primary endpoint of the study, said Hughes.

Sonidegib was well tolerated and did not induce any grade 3 or higher adverse events. Grade 1/2 adverse events in the sonidegib arm included nausea (n = 3), increased ALT (n = 2), and CK increase (n = 2), as well as 1 incident each of fatigue, arthralgia, increased AST, dry mouth, dysgeusia, myalgia, and musculoskeletal pain. In the control arm, grade 1/2 adverse events included 1 case each of fatigue, hyperglycemia, and thrombocytopenia.

In his concluding remarks, Hughes said the oncologic benefit of Hedgehog pathway inhibition in prostate cancer remains unclear.

Hughes R, Glavaris S, Ghabili K, at al. Pharmacodynamic and pharmacokinetic neoadjuvant study of hedgehog pathway inhibitor sonidegib (LDE-225) in men with high-risk localized prostate cancer undergoing prostatectomy. Presented at the 18th Annual Meeting of the Society of Urologic Oncology; November 29 to December 1, 2017; Washington, DC.