Abstract
Novel drugs, drug sequences and combinations have improved the outcome of prostate cancer in recent years. The latest approvals include abiraterone acetate, enzalutamide and apalutamide which target androgen receptor (AR) signaling, radium-223 dichloride for reduction of bone metastases, sipuleucel-T immunotherapy and taxane-based chemotherapy. Adding abiraterone acetate to androgen deprivation therapy (ADT) in order to achieve complete androgen blockade has proven highly beneficial for treatment of locally advanced prostate cancer and metastatic hormone-sensitive prostate cancer (mHSPC). Also, ADT together with docetaxel treatment showed significant benefit in mHSPC. Ongoing clinical trials for different subgroups of prostate cancer patients include the evaluation of the second-generation AR antagonists enzalutamide, apalutamide and darolutamide, of inhibitors of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, of inhibitors of DNA damage response, of targeted alpha therapy and of prostate-specific membrane antigen (PSMA) targeting approaches. Advanced clinical studies with immune checkpoint inhibitors have shown limited benefits in prostate cancer and more trials are needed to demonstrate efficacy. The identification of improved, personalized treatments will be much supported by the major progress recently made in the molecular characterization of early- and late-stage prostate cancer using “omics” technologies. This has already led to novel classifications of prostate tumors based on gene expression profiles and mutation status, and should greatly help in the choice of novel targeted therapies best tailored to the needs of patients.
Highlights
Despite recent diagnostic and therapeutic advances, prostate adenocarcinoma retains a high incidence in the male Western population and is responsible for about 20% of cancer-related deaths [1]
Adding abiraterone acetate to androgen deprivation therapy (ADT) in order to achieve complete androgen blockade has proven highly beneficial for treatment of locally advanced prostate cancer and metastatic hormone-sensitive prostate cancer
Mutations and deletions in genes from the PI3K pathway (e.g., PIK3CA, phosphatase and tensin homolog (PTEN)) and TP53 mutations are often concurrent with E26 transformation-specific (ETS) gene fusions, while deletion of chromodomain-helicase chromodomain-helicase-DNA-binding protein 1 (CHD1) is predominantly observed in the FOXA1 and speckle-type POZ protein (SPOP) subclasses [157]
Summary
Despite recent diagnostic and therapeutic advances, prostate adenocarcinoma retains a high incidence in the male Western population and is responsible for about 20% of cancer-related deaths [1]. Targeted alpha therapy with radium-223 dichloride has proven beneficial for the treatment of mCRPC with symptomatic bone metastases (Figure 1) [14] Despite these advances, the disease will relapse and resistance mechanisms including AR gene amplification, LBD mutations and splice variants, and local increase of androgen levels and altered levels of AR cofactors have been described, indicating that a more effective way of blocking AR signaling is likely to further improve the outcome [3,9,11,12]. Enzalutamide is a second-generation, competitive oral AR antagonist approved by the FDA for mCRPC treatment post- and pre-docetaxel therapy in 2012 and 2014, respectively [38] It strongly improves metastasis-free survival (MFS) in high-risk non-metastatic CRPC (nmCRPC) patients. Other approaches to block AR signaling deal with the binding function 3 located at the LBD surface and with a short region of the DBD for which small molecule inhibitors with in vitro or in vivo efficacy in several prostate cancer models have been identified [51,52]
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