Trametinib in Treating Patients With Progressive Metastatic Hormone-Resistant Prostate Cancer

PRIMARY OBJECTIVES I. To assess the activity of trametinib in metastatic castration resistant prostate cancer (mCRPC) that has progressed on either enzalutamide or abiraterone acetate. SECONDARY OBJECTIVES I. Durability of prostate specific antigen (PSA) response as measured by the time to PSA progression as defined by Prostate Cancer Working Group 2 guidelines for PSA progression. II. Maximal PSA response. III. Quality of life by Functional Assessment of Cancer Therapy- Prostate (FACT-P). IV. Time to initiation of alternative antineoplastic therapy. V. Time to radiographic progression. VI. Objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. VII. Overall survival measured as time from enrollment until death. VIII. Safety and tolerability. IX. Analysis of trametinib target engagement of mitogen-activated extracellular signal-related kinase (MEK1/2) is assessed by presence of p-ERK, the primary phosphorylation target of activated MEK1/2, in pre-treatment and at progression radiographically directed metastatic tumor biopsies by immunohistochemistry evaluation of p-ERK. Markers of cell proliferation (Ki67) and apoptosis (p27) will also be assessed. XI. Investigation of molecular correlates to resistance and sensitivity to trametinib using pre-treatment and at progression metastatic biopsies. XII. Discovery of one or a set of possible discriminative networks that are associated with a response to trametinib. XII. Enrichment for patients in the second phase who have tumors exhibiting genomic features associated with a response to trametinib. XIV. Analyses of circulating tumor deoxyribonucleic acid (ctDNA) for genomic aberrations correlated to treatment response. OUTLINE: Patients receive trametinib orally (PO) once daily (QD). Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 2 and 4 weeks, and then every 4 weeks thereafter.