Recent Developments in Treatments for Metastatic Castration-resistant Prostate Cancer—A Mechanistic Perspective

Abstract

Over the past decade, the treatment landscape in metastatic castration-resistant prostate cancer (CRPC) has markedly changed, with the introduction of three new chemotherapeutic agents. The mechanism of CRPC is not fully understood, but it may result from multiple pathways, including a loss or androgen receptor (AR) specificity and increased downstream signalling activity that provide multiple targets for therapeutic agents. For some years, docetaxel was the mainstay of treatment in CRPC, but recently, cabazitaxel (a microtubule inhibitor), sipuleucel-T (a cancer vaccine), and abiraterone acetate (a CYP17 inhibitor) were approved for CRPC treatment. In Phase III clinical trials, these agents have shown significant improvements in survival—over mitoxantrone (for cabazitaxel) and over placebo (for sipuleucel-T and abiraterone acetate)—and were well tolerated. There are also two treatments in late-stage development, MDV3100 (an oral AR antagonist) and radium-223 (an isotope that creates breaks in double-stranded DNA). These have also shown improvements in survival in Phase III trials; their regulatory approval is expected soon. The modes of actions of the existing and new drugs in CRPC are varied, but some are complementary and investigations of different combinations of these medications are much needed; they may enhance efficacy, further extend survival, and improve outcomes in this formerly untreatable disease.