CONTEXT: Recent studies focused on the molecular characterization of metastatic prostate cancer have identified genomic subsets and emerging resistance patterns. Detection of these alterations in patients has potential implications for therapy selection and prognostication.

OBJECTIVE: The primary objective is to review the current landscape of clinical and molecular biomarkers in advanced prostate cancer and understand how they may reflect underlying tumor biology. We also discuss how these features may potentially impact earlier stages of the disease.

EVIDENCE ACQUISITION: A literature search was performed of recent clinical biomarker/genomic studies focused on advanced metastatic prostate cancer as well as relevant preclinical studies investigating how these alterations influence therapy response or resistance.

EVIDENCE SYNTHESIS: Metastatic castration-resistant prostate cancer is commonly driven by androgen receptor signaling even after progression on potent hormonal agents, but other alterations may also be present or emerge during therapy resistance such as DNA repair gene aberrations or combined loss of tumor suppressor genes. Biological implications of these changes are context dependent, which may affect their detection and interpretation.

CONCLUSIONS: Molecular changes occur during prostate cancer progression and treatment resistance. Detection of genomic alterations has potential to influence therapy choice. Additional studies are warranted to elucidate the evolution of these changes and their impact in earlier stages of the disease.

PATIENT SUMMARY: We review the biology of advanced prostate cancer, and highlight opportunities and challenges for using biological or molecular assays to help guide individualized treatment decisions for patients.