The Current Therapeutic Landscape for Metastatic Prostate Cancer

Abstract

In 2024, there will be an estimated 1,466,718 cases of prostate cancer (PC) diagnosed globally, of which 299,010 cases are estimated to be from the US. The typical clinical approach for PC involves routine screening, diagnosis, and standard lines of treatment. However, not all patients respond to therapy and are subsequently diagnosed with treatment emergent neuroendocrine prostate cancer (NEPC). There are currently no approved treatments for this form of aggressive PC. In this review, a compilation of the clinical trials regimen to treat late-stage NEPC using novel targets and/or a combination approach is presented. The novel targets assessed include DLL3, EZH2, B7-H3, Aurora-kinase-A (AURKA), receptor tyrosine kinases, PD-L1, and PD-1. Among these, the trials administering drugs Alisertib or Cabozantinib, which target AURKA or receptor tyrosine kinases, respectively, appear to have promising results. The least effective trials appear to be ones that target the immune checkpoint pathways PD-1/PD-L1. Many promising clinical trials are currently in progress. Consequently, the landscape of successful treatment regimens for NEPC is extremely limited. These trial results and the literature on the topic emphasize the need for new preventative measures, diagnostics, disease specific biomarkers, and a thorough clinical understanding of NEPC.

Keywords: castration resistant prostate cancer; clinical trials; metastatic prostate cancer; neuroendocrine prostate cancer.

Figure 1

Clinical approach to prostate cancer: screening, diagnosis, and common therapies. A review of the current standard-of-care for PC, discussing diagnosis, standard lines of treatment, therapeutic resistance, and current clinical trials assessing novel therapies for patients with metastatic PC.

Figure 2

Circos plot of drug combinations in clinical trials for NEPC. The drugs are classified into broad groups based on their expected functions and linked based on combination use in a clinical trial. Each drug pair has both an outgoing and incoming link. Outgoing links are depicted with a flat end while incoming links are depicted with arrows that terminate earlier. Data used to create the plot (including drug abbreviations) are in Supplementary Table S1.

Figure 3

Timeline of selected novel target clinical trials for NEPC. Border colors indicate phase of the clinical trial (phase I, purple; phase II, blue; and phase III, orange). Fill colors indicate the status of the study (white, active/recruiting; green, completed; red, terminated; grey, unknown status).