I. Endocrine therapy Prostate cancer is a tumor sensitive to endocrine therapy, and androgen suppression is the main strategy for treating prostate cancer. It was previously thought that the failure of denervation therapy was due to mutations in cancer cells whose growth was no longer dependent on androgens. Although denervation reduces serum testosterone to approximately 0.5 nmol/L, it does not affect the concentration of androgens in the adrenal glands, while prostate cancer tissue can synthesize androgens. Androgen receptors were found to be central to the biological features of metastatic CRPC and can be stimulated by low concentrations of androgens or activated by autocrine androgens from tumor cells [2]. cancer tissue samples from CRPC patients contain higher concentrations of testosterone than primary prostate cancer tissue samples, and the biotransformation of dihydroandrosterone to dihydrotestosterone in tumors activates androgen receptors in prostate cancer patients. Moreover, the gene expression of enzymes encoding steroidogenesis was altered in CRPC metastatic cancer compared with primary prostate cancer tissue, while the expression levels of many enzymes involved in steroidogenesis were upregulated. After exogenous androgen blockade, androgen biosynthetic enzymes gradually appear to be overexpressed in prostate cancer cells, resulting in increased androgen synthesis in the tumor, leading to actual concentrations of androgens in the tumor cell microenvironment exceeding those monitored in the blood, so that anti-androgen therapy still has therapeutic value in CRPC. [u1] Recently developed relevant drugs have started to be considered to target the androgen signaling pathway, and representative new drugs include abiraterone acetate and enzalutamide. As a new class of androgen biosynthesis inhibitors, abiraterone acetate is approved by the US Food and Drug Administration in combination with prednisone for the treatment of patients with metastatic CRPC previously treated with docetaxel chemotherapy. Abiraterone selectively inhibits cytochrome P450 C17 (CYP17) activity and inhibits androgen synthesis in the prostate, testis, and adrenal glands, thereby inhibiting prostate cancer cell[u2] growth[3]. A randomized, placebo-controlled clinical study of 1195 patients with metastatic CRPC previously treated with docetaxel chemotherapy evaluated the efficacy and safety of abiraterone acetate, which reduced the risk of death by 35% compared with placebo, with a median overall survival time of 14.8 months in the abiraterone acetate group and 10.9 months in the placebo group [4]. Abiraterone was shown to prolong overall survival in CRPC patients, and further studies[u3] confirmed a significant improvement in survival in metastatic CRPC not treated with chemotherapy.Orteronel[u4] (TAK-700), another CYP17 inhibitor, has been shown in animal studies to be more potent and highly selective in inhibiting androgen production, and theoretically has better clinical value than abiraterone acetate[u5]. Theoretically, it has better clinical value than abiraterone acetate [5], and its efficacy remains to be verified in clinical trials. Enzalutamide (MDV3100) is a novel androgen receptor (AR)[u5] antagonist that binds more tightly to the androgen receptor and inhibits nuclear translocation of the receptor and binding of the receptor to DNA, thereby inhibiting the AR signaling pathway and inducing tumor cell death. Currently, enzalutamide has been approved by the US Food and Drug Administration for the treatment of patients with advanced CRPC and has been shown to prolong survival [6]. The results of a phase III clinical trial that included 1199 patients with metastatic CRPC previously treated with docetaxel confirmed that the median overall survival in the enzalutamide group was 18.4 months compared with 13.6 months in the placebo group, and that enzalutamide significantly prolonged the survival of patients with CRPC after chemotherapy [7]. In addition, enzalutamide can be combined with other agents such as docetaxel, abiraterone, cabazitaxel, radium-223 and immunotherapy or in sequential therapy. ODM-201 is another new generation AR antagonist that, unlike other anti-androgen drugs, inhibits androgen receptor function mainly by blocking nuclear transport.The efficacy and safety of ODM-201 in prostate cancer patients also make it a very promising new drug [8]. The effectiveness and safety of ODM-201 in prostate cancer patients also make it a very promising new drug [8]. Recently, a new drug, Galeterone (TOK-001), has been used to treat CRPC while reducing prostate-specific antigen (PSA) expression levels in many [u6] patients. [u7] The drug exerts its anti-CRPC effects in 3 ways: by blocking the binding of testosterone to receptor proteins, reducing the amount of AR in tumors, and inhibiting CYP17 enzymes in the hormone signaling pathway. After receiving Galeterone treatment[u8], PSA levels were reduced by 30% in about 50% of patients, along with a significant reduction in tumor size[9]. II. Prostate cancer vaccine Provenge (Sipuleucel-T)[u9] is an autologous tumor cell vaccine for prostate cancer patients, made by sensitizing dendritic cells with a recombinant protein fusion of prostate acid phosphatase and granulocyte macrophage colony-stimulating biokines. It produces an antigen-specific immune response in patients with or without prior treatment [10]. The results of a multicenter, randomized, placebo-controlled phase III clinical study showed a 22% reduction in the risk of patient death in the treatment group compared to the placebo group [11]. Based on these findings, the FDA approved Sipuleucel-T in April 2010 for the treatment of patients with metastatic prostate cancer who had failed debulking therapy. Unlike previous vaccines for disease prevention, Sipuleucel-T is the first therapeutic vaccine approved by the FDA and has important clinical implications. GVAX is a cytogenetically transduced multi-antigen vaccine that modifies prostate cancer cell lines with granulocyte macrophage colony-stimulating factor genes, which are killed by radiation and then injected subcutaneously to induce a tumor-specific immune response, thereby specifically destroying tumor cells. This vaccine is a whole-cell vaccine that stimulates lymphocytes to produce[u10] an immune response against the tumor[12]. PROSTVAC-VF TRICOM[u11], on the other hand, is a PSA-based targeted vaccine with good efficacy in phase II studies and is currently undergoing an international multicenter phase III study. Recent studies have identified the cytotoxic T lymphocyte-associated antigen-4 (Cytotoxic T Lymphocyte Antigen-4) as a potential target for immunomodulatory therapy. [u12] Eprimar is a fully humanized antibody that binds to CTLA-4, blocking its activity and triggering a sustained immune response. Eprimar was found to elicit a sustained T-cell immune response that clinically benefits CRPC patients [13]. Recent studies have found that eprinomectin combined with androgen depot treatment has a better efficacy, with 55% of patients having a decrease in PSA levels to undetectable after 3 months of combined treatment, while only 38% of patients treated with androgen depot alone achieved the same efficacy [14], but the effect of long-term chemotherapy and corticosteroid treatment on the output of activated antigen-presenting cells and immune competence needs further study. Chemotherapy Currently, the standard treatment for CRPC is docetaxel combined with prednisone, and there is a lack of effective treatment after failure of docetaxel therapy. A phase III study comparing the efficacy of ADT alone and ADT combined with docetaxel in the treatment of patients with metastatic prostate cancer included 385 patients with metastatic prostate cancer and showed no statistically significant difference in overall survival between the two groups, concluding that docetaxel should not be used as part of first-line treatment for patients with non-destructive metastatic prostate cancer [15]. Cabazitaxel belongs to the paclitaxel class and is a novel microtubule inhibitor that remains effective in patients with paclitaxel resistance. Cabazitaxel is the first chemotherapeutic agent to improve the survival of patients with metastatic CRPC who have failed docetaxel therapy. A multicenter phase III clinical trial confirmed the efficacy of cabazitaxel in patients with CRPC[u13] with an overall patient survival time of 15.1 months and a 30% reduction in relative risk of death. (P = 0.001)[16]. The drug was approved by the FDA in 2010 for patients with CRPC whose disease has progressed despite doxorubicin treatment. IV. Molecularly targeted therapy Cabozantinib (cabozantinib) is an orally administered multi-receptor tyrosine kinase inhibitor that potently inhibits MET[u14] and vascular endothelial growth factor receptor 2, and MET and vascular endothelial growth factor signaling correlate with tumor angiogenesis, infiltration, and metastasis. The drug has been shown to be associated with pain relief, overall disease control, and PSA-only changes in patients with metastatic CRPC. [u15] Results from a recent phase II clinical study that included 171 patients with CRPC showed that patients in the cabozantinib group had a mean progression-free survival of 23.9 weeks compared with 5.9 weeks in the placebo group and a 67% improvement in bone pain symptoms compared with placebo [17]. Bevacizumab is is a humanized monoclonal antibody against vascular endothelial growth factor. A phase II clinical trial found that bevacizumab combined with doxorubicin in patients with CRPC resulted in a decrease in PSA in 55% of patients[u16] . However, another phase III clinical trial compared the efficacy of doxorubicin and prednisone combined with bevacizumab in patients with CRPC and found that the overall survival of patients with the combination of the three was 22.6 months, compared with 21.5 months in the doxorubicin and prednisone group (P = 0.181), which showed that the combination of bevacizumab did not end up improving the overall survival time of patients[u17] [18]. V. Other therapies Denosumab is a fully humanized immunoglobulin G2 monoclonal antibody prepared by DNA recombination technology, which targets nuclear factor-κB receptor activator ligands and disrupts the RANK/RANKL/OPG signaling system, thereby preventing bone tissue destruction and significantly delaying the time to bone metastasis in CRPC patients. [In November 2010, the US Food and Drug Administration approved the marketing of denosumab based on the results of three published randomized controlled phase III clinical studies[u19] . Endothelin is a peptide consisting of 21 amino acids, including three isomers: ET-1, ET-2, and ET-3. atrasentan is a potent, orally active, nonpeptide endothelin A (ETA[u20]) receptor A antagonist that is now in phase III clinical studies, and one of the indications is prostate cancer that has failed hormone therapy[19].