Phase II randomized, double-blind, placebo-controlled study of tivantinib in men with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC)

146 Background: Tivantinib is a putative non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that has additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to castration resistance. Methods: 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival. PCWG2 guidelines were utilized for determining eligibility and progression. Results: Of the 80 pts enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluated. Median age was 67 yrs (range: 43 to 85). Baseline characteristics were balanced between arms for ECOG PS, Gleason score, PSA, LDH, hemoglobin, Alk Phos, prior treatment, bone and organ involvement. More African Americans and those with lymph node involvement were randomly assigned to placebo. Median follow up is 8.2 months (range: 1.4 to 27.6). To date 59 patients have progressed. Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.6 mo vs 3.8 mo, respectively; HR = 0.53, 95% CI: 0.32 to 0.89; p=0.015). Toxicity was mild overall. Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia were recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. 8 deaths (3 P and 5 tivantinib) have been recorded and were all considered unrelated to therapy. Conclusions: Tivantinib significantly improved PFS in men with asymptomatic or minimally symptomatic mCRPC. Given the favorable toxicity profile and evidence of anti-tumor activity, investigation of tivantinib with other agents may be a rational strategy. Clinical trial information: NCT01519414.