Study Shows Tivantinib Boosts Progression-free Survival in Men with Prostate Cancer

The novel small molecule inhibitor tivantinib significantly improved progression-free survival in men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), according to clinical trial results presented at the American Society of Clinical Oncology’s 2015 Genitourinary Cancers Symposium.

Findings of the trial, which was conducted to determine tivantinib’s safety and efficacy in chemotherapy-naïve mCRPC, could aid further development of this agent.

Cleveland Clinic researchers participated in the multi-institutional Phase II randomized double-blind, placebo-controlled study.

Background

Tivantinib is an orally bioavailable non-ATP competitive inhibitor of the c-MET protein with potential antineoplastic activity. c-MET is overexpressed or mutated in many tumor cell types and plays key roles in tumor cell proliferation, survival, invasion and metastasis, and in tumor angiogenesis. As prostate cancer progresses and becomes more advanced, it demonstrates higher c-MET expression. Tivantinib binds to c-MET and disrupts c-MET signal transduction pathways, which may induce cell death in tumor cells overexpressing c-Met or expressing constitutively activated c-MET.

Study Methodology

Eighty men with asymptomatic or minimally symptomatic mCRPC were enrolled in the study, which was sponsored by the National Cancer Institute’s Cancer Therapy Evaluation Program

Prostate Cancer Working Group 2 guidelines were used to determine eligibility. Baseline characteristics were balanced between arms for Eastern Cooperative Oncology Group performance status, Gleason Score, prostate-specific antigen, lactate dehydrogenase, hemoglobin, alkaline phosphate, prior treatment and bone and organ involvement. Of those enrolled in the study, 78 participated. The participants received either tivantinib 360 mg PO BID (n = 52) or placebo (n = 26).

Results

To date, 59 patients have progressed and there have been eight deaths; none of the deaths was considered to be related to therapy. The median follow-up was 8.2 months.

“Patients treated with tivantinib had significantly better progression-free survival (PFS) versus those treated with placebo,” says Cleveland Clinic prostate cancer oncologist Jorge A. Garcia, MD. The median PFS was 5.6 months for the tivantinib group versus 3.8 months for the placebo group. “Toxicity was mild overall,” says Dr. Garcia. “These results demonstrate that alternative non-androgen receptor-dependent pathways remain important therapeutic targets in CRPC.”

Future Directions

Additional research is needed to better understand tivantinib’s effects and determine its therapeutic role, Dr. Garcia says.

“More work needs to be done so we can gain a further biological understanding of the importance of the c-MET pathway in prostate cancer,” he says. “We also need to continue defining the appropriate biologic and clinical phenotype of patients whose disease is driven by this particular pathway. The results of this trial could be used as a background to further develop this agent in prostate cancer. We need to conduct additional clinical trials giving this agent in combination with other existing agents.”