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Thus, new drugs are urgently needed. We investigated efficacy, toxicity and mechanism of action of marine triterpene glycoside frondoside A (FrA) using CRPC cell lines <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. FrA revealed high efficacy in human prostate cancer cells, while non\u2010malignant cells were less sensitive. Remarkably, proliferation and colony formation of cells resistant to enzalutamide and abiraterone (due to the androgen receptor splice variant AR\u2010V7) were also significantly inhibited by FrA. The marine compound caused cell type specific cell cycle arrest and induction of caspase\u2010dependent or \u2010independent apoptosis. Up\u2010regulation or induction of several pro\u2010apoptotic proteins (Bax, Bad, PTEN), cleavage of PARP and caspase\u20103 and down\u2010regulation of anti\u2010apoptotic proteins (survivin and Bcl\u20102) were detected in treated cells. Global proteome analysis revealed regulation of proteins involved in formation of metastases, tumor cell invasion, and apoptosis, like keratin 81, CrkII, IL\u20101\u03b2 and cathepsin B. Inhibition of pro\u2010survival autophagy was observed following FrA exposure. <jats:italic>In vivo<\/jats:italic>, FrA inhibited tumor growth of PC\u20103 and DU145 cells with a notable reduction of lung metastasis, as well as circulating tumor cells in the peripheral blood. Increased lymphocyte counts of treated animals might indicate an immune modulating effect of FrA. In conclusion, our results suggest that FrA is a promising new drug for the treatment of mCRPC. 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