mTOR Inhibitors in Castration-Resistant Prostate Cancer: A Systematic Review.

BACKGROUND: The progression of prostate cancer to castration-resistant prostate cancer (CRPC) is often a result of somatic alterations in the PI3K/Akt/mTOR (mammalian target of rapamycin) pathway, suggesting that therapies targeting this pathway might lead to improved survival and efficacy. Here, we systematically evaluate the results of clinical trials investigating mTOR inhibition in CRPC and utilize preclinical data to predict clinical outcomes. METHODS: Trials included in the study were identified through PubMed and via review of conference abstracts cited by relevant review articles. The eligibility of trials was independent of sample size, clinical setting, or date. RESULTS: A total of 14 studies were eligible for qualitative analysis. The clinical setting was variable among studies, and all utilized an allosteric mTOR inhibitor as either a monotherapy or in combination. Molecular criteria were evaluated in three trials. Among most studies, the prostate-specific antigen level declined during treatment, but often increased shortly thereafter. Partial responses to treatment were minimal, and no complete responses were reported. Two studies exploring therapy with an mTOR inhibitor in combination with bicalutamide resulted in minimal efficacy. Overall, allosteric mTOR inhibition was deemed to be inadequate for the treatment of CRPC. CONCLUSION: Preclinical data suggest that a reciprocal feedback mechanism between PI3K and androgen receptor signaling is a potential mechanism behind the clinical inefficacy of mTOR inhibitors in CRPC, indicating combinatorial targeting of PI3K, mTORC1/2, and the androgen receptor might be more effective. Comprehensive analysis of preclinical data to assess clinical trial targets and efficacy may reduce the number of unproductive trials and identify potentially beneficial combinatorial therapies for resistant disease.