IGF-1 axis changes with ADT and docetaxel in metastatic prostate cancer.

Abstract

Androgen deprivation therapy (ADT) forms the cornerstone of treatment in locally-advanced and metastatic prostate cancer (PCa). Since the growth hormone-insulin like growth factor (GH-IGF-1) axis has been implicated in prostate tumorigenesis, we aimed to evaluate the association between IGF-1 and its binding proteins on outcomes in men with metastatic PCa treated with ADT, with or without docetaxel (D). We analyzed serum samples for IGF-1 and its family proteins from baseline, 6 months post-randomization and at the time of progression in men enrolled to receive ADT +/- D in the phase 3 CHAARTED trial. The key outcomes were time to development of castrate-resistant prostate cancer and overall survival (OS). 560 patients had samples available for analysis. At 6 months, significant increases in IGF-BP1 (mean +27.4%, p=0.033), IGF-BP 3 (mean +10.3%, p<0.001) and IGF-BP4 (mean +31.1%, p<0.001) were seen in the ADT+D group, while the ADT group showed an increase in IGF-BP3 (mean +5.5%, p=0.015). A higher IGF-1:IGF-BP1 ratio at baseline and after 6 months was associated with improved OS in both the ADT (baseline: HR=0.77, p=0.026; 6 months: HR=0.83, p=0.036) and ADT+D groups (baseline: HR=0.78, p=0.04; 6 months: HR=0.81, p=0.018). Patients with a log10IGF-1:IGF-BP1 ratio >1.3 at baseline had improved OS when meta-analyzed with data from a prior cohort (HR=0.71). Higher baseline and 6-month IGF-1:IGF-BP1 ratio was associated with better OS. Further exploration of the IGF-1 axis will be important to assess its role as a predictive biomarker and to target this axis in therapeutic trials.