Clinical Review

Management of Castration-Resistant Prostate Cancer

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INTRODUCTION

Prostate cancer is the most common malignancy in men, with an estimated 165,000 new prostate cancer diagnoses and 29,000 prostate cancer deaths occurring in the United States in 2018.1 Due to the widespread use of screening prostate-specific antigen (PSA), prostate cancer has been mainly diagnosed when the tumor is confined to the prostate. Despite definitive treatment of localized prostate cancer, some men develop systemic disease, either biochemical failure, as defined by rising PSA level, or metastatic disease.1 Several factors have been demonstrated to predict risk of relapse, including higher pretreatment PSA, higher Gleason score, and a greater anatomic extent of disease.2 In addition, the incidence of de novo metastatic prostate cancer was recently noted to be increasing. This may be due to changes in the United States Preventive Services Task Force prostate cancer screening guidelines in 2012, which recommended against screening for prostate cancer in men of any age. The updated 2018 guidelines recommend a discussion of the risks versus benefits of screening for prostate cancer for all men aged 55 to 69 years,recommend against screening for men older than 70 years, and do not have recommendations for high-risk subgroups.3

Androgen deprivation therapy (ADT) has been the cornerstone of therapy since 1941 for men with hormone-sensitive systemic disease, both in biochemically relapsed and metastatic disease.4,5 While more than 90% of patients respond to initial ADT, castration resistance is inevitable in some men.6,7 Prostate cancer will become castration-resistant typically after 18 to 24 months of ADT, with the majority of patients developing castration-resistant prostate cancer (CRPC) within 5 years of initiation of ADT.8

PATHOGENESIS

CRPC (previously called androgen independent prostate cancer) is defined as progression of disease despite serum total testosterone levels less than 50 ng/dL. CRPC is characterized by a rising PSA level and/or radiographic progression. One mechanism of castration resistance is genetic modification of the androgen receptor (AR), including increased expression of the wild-type AR.9 Alternatively, mutations of the steroid-binding domain may play a role in the development of castration resistance by allowing the AR to become activated by non-androgen steroid hormones or even paradoxically by antiandrogens. Studies suggest, however, that AR mutations may be seen in only 10% of prostate cancers that have developed castration resistance.10 The AR-V7 splice variant of the AR lacks an androgen binding site altogether, and may play an important role in castration resistance. In one study, the presence of this splice variant in circulating prostate cancer tumor cells predicted resistance to enzalutamide and abiraterone as well as poor outcomes.11 Intratumoral androgen synthesis also may play a role in the development of CRPC.12,13

CRPC can be broadly categorized into 2 categories, metastatic (mCRPC) and nonmetastatic (nmCRPC; Figure). The exact proportion of patients entering CRPC at a nonmetastatic stage (M0) is largely unknown.14 In one study of patients at the time of diagnosis of CRPC, ≥ 84% of patients were shown to have metastases.8 In this article, we review key aspects of management of CRPC, including selection of first- and second-line therapy, and briefly discuss upcoming clinical trials.

Categories of castrate-resistant prostate cancer (CRPC).

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