Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC)：Results from a phase II randomized discontinuation trial.

Background: Cabozantinib (Cabo) is an inhibitor of MET and VEGFR2. MET signaling promotes tumor growth, invasion and metastasis. Methods: mCRPC patients (pts) with progressive measurable disease (mRECIST) received Cabo at 100 mg qd PO over a 12 week (wk) lead-in stage. Response was assessed q6 wks. Treatment wk 12 was based on response: pts with PR continued open-label Cabo, pts with SD were randomized to Cabo vs placebo, and pts with PD discontinued. Primary endpoint was objective response rate (ORR) per mRECIST in the lead-in stage. Up to 200 pts could be enrolled to target 70 randomizations. Bone scans (b-scans) were independently reviewed. Results: Accrual was halted at 168 pts based on an observed high rate of clinical activity. 100 pts are currently evaluable for the lead-in stage; median age 68, 47% with visceral disease, 78% with bone metastasis, and 47% docetaxel (D) pretreated. Median f/u was 4 months (range, 1-15); median PFS not yet reached. Most common related Grade 3/4 AEs were fatigue (11%), HTN (7%), and hand-foot syndrome (5%); no related Grade 5 AEs reported. Dose reductions for AEs occurred in 51% of pts, and discontinuations in 10%. Bone effects: 86% (56/65 pts evaluable by b-scan) had complete or partial resolution of lesions on b-scan as early as wk 6. Eight pts (12%) had SD and 1 pt (2%) had PD. In 28 pts receiving narcotics for bone pain, 64% had improved pain and 46% decreased or halted narcotics, per investigator. Median maximum rise in hemoglobin in anemic pts (Hb 11 g/dL) was 2.2 g/dL (range, 0.6-3.5). Osteoclast and osteoblast effects were observed: 55% had declines of 50% in plasma C-Telopeptide; 56% of pts with elevated tALP had declines of 50%. Soft tissue effects: Objective tumor shrinkage occurred in 84% of pts. ORR at wk 12 was 5%; 3 additional PRs await confirmation. PSA changes were independent of clinical activity. Overall, wk 12 disease control rate (PRSD) was 71%. Randomization was halted and pts unblinded due to high rates of b-scan resolution and pain relief. Conclusions: Cabo showed clinical activity regardless of prior D in mCPRC pts, particularly in pts with bone disease, as reflected by high rates of b-scan resolution and pain relief, in addition to improvements in Hb and tumor regression.