Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC)

Abstract

Recently, the standard of care for metastatic Castration Resistant Prostate Cancer (mCRPC) has changed considerably. Persistent androgen receptor (AR) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer. Androgen receptor gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells, making them extremely sensitive to low levels of circulating androgens. Additionally, prostate cancer cells are able to maintain dihydrotestosterone (DHT) concentration in excess of serum concentrations to support tumor growth. For many years ketoconazole was the only CYP17 inhibitor that was used to treat mCRPC. However, significant toxicities limit its use. Newly approved chemotherapeutic agents such as Abiraterone (an oral selective inhibitor of CYP17A), which blocks androgen biosynthesis both within and outside the prostate cancer cells), and enzalutamide (blocks AR signaling) have improved overall survival. There are also ongoing phase III trials for Orteronel (TAK- 700), ARN- 509 and Galeterone (TOK-001), which targets androgen signaling. In this review, we will present the rationale for the newly approved hormonal treatments, their indications and complications, and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents. Finally, we will talk about the potential upcoming hormonal treatments for mCRPC.