773P - Multicenter, Randomized, Double-Blind Phase Ii Study of Sorafenib Compared to Placebo with Best Supportive Care After Failure of Docetaxel in Metastatic Castration-Resistant Prostate Cancer

Abstract

ABSTRACT Aim: In castration- and docetaxel-resistant prostate cancer cells, sorafenib has been shown to cause apoptosis through downregulation of myeloid cell leukemia-1, phosphorylation of Akt and inhibition of androgen receptor (AR) expression as well as of its constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain. We aimed to evaluate whether thus sorafenib may stabilize disease after failure of docetaxel in castration-resistant prostate cancer patients. Methods: In our phase 2, double-blind, placebo-controlled trial, 51 men with castration-resistant, docetaxel-refractory prostate cancer were randomly assigned to receive sorafenib 400mg twice daily or best supportive care for 12 weeks. The primary endpoint was the rate of patients who experienced stable disease (or partial response) for at least 12 weeks of treatment. Secondary efficacy variables were response rate according to RECIST criteria, progression-free survival and evaluation of biomarkers in serum. Results: In 8 (partial response: 2; stable disease: 6) out of 24 patients in the sorafenib group (33.3%) but only 2 (stable disease: 2) out of 27 patients in the placebo group (7.4%) tumor stabilization was observed (p = 0.024). Median progression-free survival and overall survival was in favour of the sorafenib group compared with placebo (100 versus 89 days; p = 0.019 and 369 versus 249 days; p= n.s.). In accordance with clinical results, serum values of M65, a prognostic biomarker of tumor progression, stabilized during sorafenib with a maximum effect at week eight (+5 %) while increasing with placebo (+41%). Rates of fatigue, diarrhea, appetite loss, hand-foot syndrome and hypertension were higher with sorafenib but well manageable. Conclusions: For the first time, sorafenib showed significant antitumor activity in patients with metastatic CRPC in the post-docetaxel setting. With activity against C-terminally truncated, constitutively active AR variants assumed to be present in abiraterone-resistant tumor cell clones it may be an option for new treatment sequences and combinations in future. Disclosure: G. Kramer: honorary fees from Advisory Boards: Amgen, Astellas, Bayer, Janssen, Ipsen, Sanofi-Aventis, Takeda, Roche, GSK, Novartis and research grant by Sanofi-Aventis;S.F. Shariat: Honorary fees for advisory boards for Janssen, Ipsen and Astellas;W. Loidl: Honorary fees for advisory boards for Sanofi-Aventis, GSK, Janssen, Roche, Novartis, Takeda, Astellas, Amgen, Ipsen, Bayer. All other authors have declared no conflicts of interest.