In conclusion, this study provides solid evidence indicating that the combination of HT + metformin synergistically reduces the aggressiveness features of androgen-sensitive PCa cells (i.e., decrease in proliferation rate, migration capacity, and/or tumoursphere formation, and activation of apoptosis and cell cycle arrest) compared with the individual treatments with both drugs; these actions are likely mediated by a more pronounced alteration of distinct key oncogenic signalling pathways (i.e., the MAPK, AKT, and TGF-b pathways) that may result in these synergistic effects. Here, TGFB1 is linked to posterior cortical atrophy.