Metastatic prostate cancer remains incurable, why?

Abstract

Metastatic prostate cancer patients present in two ways-with already disseminated disease at the time of presentation or with disease recurrence after definitive local therapy. Androgen deprivation therapy is given as the most effective initial treatment to patients. However, after the initial response, almost all patients will eventually progress despite the low levels of testosterone. Disease at this stage is termed castration resistant prostate cancer (CRPC). Before 2010, the taxane docetaxel was the first and only life prolonging agent for metastatic CRPC (mCRPC). The last decade has witnessed robust progress in CRPC therapeutics development. Abiraterone, enzalutamide, apalutamide and sipuleucel-T have been evaluated as first- and second-line agents in mCRPC patients, while cabazitaxel was approved as a second-line treatment. Radium-223 dichloride was approved in symptomatic patients with bone metastases and no known visceral metastases pre- and post-docetaxel. However, despite significant advances, mCRPC remains a lethal disease. Both primary and acquired resistance have been observed in CRPC patients treated by these new agents. It could be solely cell intrinsic or it is possible that the clonal heterogeneity in treated tumors may result from the adaptive responses to the selective pressures within the tumor microenvironment. The aim of this review is to list current treatment agents of CRPC and summarize recent findings in therapeutic resistance mechanisms.

Keywords: Drug resistance; Heterogeneity; Novel treatment; Prostate cancer.

Figure 1

A potential sequence of therapies for mCRPC patients in 2018. In mCRPC, the first-line treatment options include: Abiraterone, enzalutamide, sipuleucel-T or docetaxel. Additional options include: Bone anti-resorptive therapy with denosumab or zolendronic acid, and immunotherapy with pembroluzimab after DNA sequencing for DNA-MMR and MSI. If symptomatic bone metastases without organ involvement are present, radium-223 can be added. Cabazitaxel can be chosen as a second-line chemotherapy. MMR, mismatch repair; MSI, microsatellite instability; mCRPC, metastatic castration-resistant prostate cancer.