Recent Advances in Prostate Cancer Treatment and Drug Discovery

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.

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

“…Enzalutamide is approved for metastatic and nonmetastatic castration‐resistant prostate cancer . It showed weaker activity in comparison to darolutamide in several instances, for example, for the mutations W742C/L and M896V/T (Table and Supporting Information Table 2).…”

“…Apalutamide was recently approved for nonmetastatic castration‐resistant prostate cancer . Its activity was comparable to enzalutamide with however a stronger antagonistic activity for the W742C/L and M896V/T mutations (Table and Supporting Information Table 2).…”

“…Treatment options for early disease stages include surgery, local irradiation and androgen deprivation therapy. Most men under androgen deprivation therapy will develop castration‐resistant prostate cancer and these tumors usually still respond to androgen receptor (AR) antagonists and androgen synthesis inhibitors . Unfortunately, therapy resistance, due to a variety of genomic alterations and adaptive responses of the tumor, is often observed .…”

Synergistic effects of hormone therapy drugs and usnic acid on hormone receptor‐positive breast and prostate cancer cells

“…The selective ER modulator Tamoxifen (Tam) is the most commonly used anticancer drug in the premenopausal period in patients with ER+ BC . On the other hand, luteinizing hormone–releasing hormone agonists or antagonists, AR agonists, androgen synthesis inhibitors, or antiandrogens are commonly used for hormone therapy in PC . However, the agents with better results, especially in castration‐resistant PC (CRPC), are new generation antiandrogens, including Enzalutamide (Enz) that is a second generation AR inhibitor approved for docetaxel resistant CRPC cases …”

Targeting the TMPRSS2/ERG fusion mRNA using liposomal nanovectors enhances docetaxel treatment in prostate cancer

“…A number of therapeutic modalities are used in the treatment of PCa depending on disease stage and tumor aggressiveness. The current standard of care for men with castrate‐resistant PCa failing second‐line androgen ablation therapies is docetaxel chemotherapy . In addition, docetaxel has been shown to be useful in metastatic hormone‐sensitive PCa .…”