Bony metastatic disease responses to sorafenib (BAY 43–9006) independent of PSA in patients with metastatic androgen independent prostate cancer

Abstract

4506 Background: Sorafenib is a novel bis-aryl urea, multi-kinase inhibitor, approved for the treatment of advanced renal cell carcinoma. It inhibits b- and c-Raf kinase, PDGFR, c-kit, VEGFR, Flt-3 and p38 and demonstrates anti-proliferative and anti-angiogenic activity. Studies have shown a role for anti-angiogenic therapy for androgen-independent prostate cancer (AIPC). Evidence suggests that the Ras-Raf-MAPK-ERK signaling pathway is dysregulated in AIPC and might be targeted by sorafenib. Methods: 22 patients (pts) with progressive metastatic AIPC enrolled in an open-label, single arm phase II study. The primary objective was to determine if sorafenib is associated with a 50% 4 month probability of progression free survival as determined by clinical, radiographic, and PSA criteria. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. Clinical assessment and PSA measurement occurred every cycle with radiographic measurements every 2 cycles. Results: Baseline patient characteristics included a median (range) age of 64 (51–78), Gleason 8 (6–9), PSA 226.4 ug/l (2–1905), Alk Phos 108 u/l (48–259), Hb 12.7 g/dl (10.2–15.1). 60% of patients had received one prior chemotherapy regimen. Of the 19 pts with progressive disease, 10 progressed only by PSA criteria in the absence of evidence of clinical and radiographic progression. Two pts were found to have dramatic disappearance of bone metastatic lesions as demonstrated by bone scan, even though they met PSA progression criteria at the time the scans were obtained. Toxicities likely related to treatment include: one grade 3 hypertension and hand-foot syndrome; grade 1/2 toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and diarrhea. Conclusion: Sorafenib in AIPC is relatively well tolerated with 2 patients demonstrating evidence of improved bony metastatic lesions. Interpretation of this study is complicated by discordant radiographic and PSA responses. PSA may not be an adequate biomarker for monitoring sorafenib activity. Further study of sorafenib in metastatic AIPC using clinical and radiographic endpoints is warranted. No significant financial relationships to disclose.