Molecular Targeted Therapies in Metastatic Prostate Cancer: Recent Advances and Future Challenges

SIMPLE SUMMARY: Recent studies have highlighted the importance of molecular targeted therapies in metastatic castration-resistant prostate cancer. These therapies, which aim to block specific molecules and related pathways in cancer cells, or in cells present in their microenvironment, and inhibit their proliferation, invasiveness and migration, while minimizing damage to healthy tissues, can be distinguished into four main categories: Prostate-Specific Membrane Antigen-targeted radionuclide therapies; DNA repair inhibitors; therapies targeting tumor neovascularization; and immune checkpoint inhibitors. The purpose of this review is to illustrate the characteristics, efficacy and limitations, of these therapies, some of which are already approved for clinical use while others are in clinical trials or at the pre-clinical stage of development, and to explore future research perspectives. Different solutions, from combined treatment with traditional drugs, to the use of nanomedicine for the selective release at the the tumor site, will be discussed, in order to improve their tolerability and therapeutic efficacy. ABSTRACT: Prostate cancer is the most frequent malignant tumor in men, and, despite the great improvements in survival in patients with localized cancer, the prognosis for metastatic disease remains poor. Novel molecular targeted therapies, which block specific molecules or signaling pathways in tumor cells or in their microenvironment, have shown encouraging results in metastatic castration-resistant prostate cancer. Among these therapeutic approaches, prostate-specific membrane antigen-targeted radionuclide therapies and DNA repair inhibitors represent the most promising ones, with some therapeutic protocols already approved by the FDA, whereas therapies targeting tumor neovascularization and immune checkpoint inhibitors have not yet demonstrated clear clinical benefits. In this review, the most relevant studies and clinical trials on this topic are illustrated and discussed, together with future research directions and challenges.