Phase II Study of Dovitinib in Patients with Castration-Resistant Prostate Cancer (KCSG-GU11-05)

Abstract

PurposeFibroblast growth factor (FGF) signals are important in carcinogenesis and progression of prostate cancer. Dovitinib is an oral, pan-class inhibitor of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, and fibroblast growth factor receptor (FGFR). We evaluated the efficacy and toxicity of dovitinib in men with metastatic castration resistant prostate cancer (mCRPC).Materials and MethodsThis study was a single-arm, phase II, open-label, multicenter trial of dovitinib 500 mg/day (5-days-on/2-days-off schedule). The primary endpoint was 16-week progression-free survival (PFS). Secondary endpoints were overall survival (OS), toxicity and prostate-specific antigen (PSA) response rate. Biomarker analyses for VEGFR2, FGF23, and FGFR2 using multiplex enzyme-linked immunosorbent assay was performed.ResultsForty-four men were accrued from 11 hospitals. Eighty percent were post-docetaxel. Median PSA was 100 ng/dL, median age was 69, 82% had bone metastases, and 23% had liver metastases. Median cycles of dovitinib was 2 (range, 0 to 33). Median PFS was 3.67 months (95% confidence interval [CI], 1.36 to 5.98) and median OS was 13.70 months (95% CI, 0 to 27.41). Chemotherapy-naïve patients had longer PFS (17.90 months; 95% CI, 9.23 to 28.57) compared with docetaxel-treated patients (2.07 months; 95% CI, 1.73 to 2.41; p=0.001) and the patients with high serum VEGFR2 level over median level (7,800 pg/mL) showed longer PFS compared with others (6.03 months [95% CI, 4.26 to 7.80] vs. 1.97 months [95% CI, 1.79 to 2.15], p=0.023). Grade 3 related adverse events were seen in 40.9% of patients. Grade 1-2 nausea, diarrhea, fatigue, anorexia, and all grade thrombocytopenia are common.ConclusionDovitinib showed modest antitumor activity with manageable toxicities in men with mCRPC. Especially, patients who were chemo-naïve benefitted from dovitinib.

Recent Advances in Prostate Cancer Treatment and Drug Discovery

“…Dovitinib is an FGF receptor kinase inhibitor which additionally blocks other receptors. A phase 2 study in mCRPC showed only limited efficacy [ 72 ].…”

Tumour-stroma ratio and 5-year mortality in gastric adenocarcinoma: a systematic review and meta-analysis

“…As the role of stroma in the growth of tumour has become more apparent, the interest in development of therapies that target stroma instead of tumour has grown 25,26 . For example, studies on antibodies against fibroblast growth factor, a signalling molecule for CAFs 27 , antibodies against transforming growth factor beta, a tumor growth enhancing factor produced by CAFs 28 , and T-cell immunotherapies targeting the stroma 29,30 are currently being developed in preclinical settings. While therapies targeting the stroma have not yet reached clinical use, they might become important in the future.…”

A Novel FGFR3 Splice Variant Preferentially Expressed in African American Prostate Cancer Drives Aggressive Phenotypes and Docetaxel Resistance

“…It will be of interest to compare FGFR3-L and FGFR3-S in terms of dimer structure, receptor orientation, transmembrane separation, conformation sampling, and monomer versus dimer status in future studies. Dovitinib is a multi-target RTK SMI that has shown antitumor activity in preclinical and clinical models of solid tumors, including prostate cancer (41)(42)(43)(44). While dovitinib failed a critical phase III trial in metastatic renal cell carcinoma, recent efforts have been taken to identify and select potential responders (e.g., patients with driver FGFR alterations) in future clinical trials.…”