A Phase II Pharmacodynamic Study of Preoperative Figitumumab in Patients with Localized Prostate Cancer

Abstract

Purpose: Activation of the insulin-like growth factor 1 receptor (IGF-IR) is implicated in prostate cancer development and progression. This study evaluated biologic and clinical effects of figitumumab, a fully human monoclonal IGF-IR antibody, in patients with localized prostate cancer.Experimental Design: Eligible patients received figitumumab 20 mg/kg intravenously every 3 weeks for 3 cycles followed by prostatectomy. The primary endpoint was IGF-IR expression inhibition as assessed by immunohistochemistry.Results: Sixteen patients were accrued. Median age was 63 years, median prostate-specific antigen (PSA) was 7.2 mg/L (range, 2.5-35), clinical stage was T1 in four patients and T2 in 12 patients, Gleason score 7 or >7 in 15 and one patients. Two patients received only 1 cycle (patient choice and grade III hyperglycemia). A PSA decline from baseline of !25% and !50% occurred in 15 (94%) and 5 (31%) of patients. Mean figitumumab concentration was 350.4 mg/mL (range, 26.3-492.8) in plasma and 51.3 mg/g (range, 27.4-79.6) in prostate tissue. Compared with pretreatment biopsies, IGF-IR expression decreased in the prostatectomy specimens in 14 of 16 patients. The mean IGF-IR immunohistochemistry visual score was 2.1 (SD ¼ 0.6) in biopsy and 1.1 (SD ¼ 0.5) in prostatectomy specimens (P < 0.0001). Androgen receptor expression was also decreased and there was a trend for a decrease in downstream IGF-IR signaling components.Conclusions: Figitumumab is biologically active in prostate cancer. PSA declines in treatment-naive patients were observed, potentially mediated by IGF-IR effects on androgen receptor expression. These results support the clinical relevance of IGF-IR signaling in prostate cancer and justify further clinical trials.

Phase II Randomized Study of Figitumumab plus Docetaxel and Docetaxel Alone with Crossover for Metastatic Castration-Resistant Prostate Cancer

“…Despite discontinuation of figitumumab clinical development, IGF-1R may still be considered to be a valid investigational target for the treatment of prostate cancer. Additional data on the effect of targeting IGF-1R have been reported in clinical studies (14,41), both in patients with localized prostate cancer (26) and particularly in patients with advanced CRPC (42,43). Moreover, studies indicate that SPOP mutated CRPC have high steroid receptor coactivator-3 levels which result in high IGF ligand levels.…”

“…Overall survival data were not collected. These findings are disappointing given the encouraging declines in PSA expression following treatment with single-agent figitumumab in a singlecenter, phase II study of 14 patients with localized prostate cancer (26). Nevertheless, a PSA response of 28% (90% CI, 15.5-43.9) was observed in patients treated with the combination after disease progression with docetaxel/prednisone alone, suggesting that IGF-1R blockade may have some activity in this disease.…”

“…In a phase Ib study that included 22 patients with advanced CRPC, figitumumab with docetaxel was well tolerated with promising antitumor activity (25). Moreover, figitumumab had antitumor activity as a single agent in newly diagnosed hormone-therapy na€ ve patients awaiting prostatectomy (26). Based on these findings, this randomized phase II study (NCT00313781) was undertaken to assess the efficacy of figitumumab in combination with docetaxel/prednisone in chemotherapy-na€ ve patients with metastatic CRPC.…”

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer

“…Inhibition of the IGF-1 signaling axis alone or in conjunction with ADT for the treatment of prostate cancer has shown favorable results in preclinical and early clinical trials (29)(30)(31). VCaP cells are particularly sensitive to IGF-1R inhibition both in vitro and in vivo, as demonstrated through administration of ganitumab, an antibody to IGF-1R that blocks IGF-1 and IGF-2 binding (29).…”

“…GH secretion, promoted by GHRH, stimulates the production of IGF-1 in the liver. IGF-1 is a potent mitogen and survival factor for prostate cancer cell lines and tumors whose actions can be blocked by targeting IGF-1 receptors (IGF1Rs) (29)(30)(31)(32). Decreased production of IGF-1 by inhibition of GHRH-R by GHRH antagonists occurs in vivo (33).…”