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Although curative treatment for men with metastatic castration-resistant prostate cancer (mCRPC) has not yet been achieved, multiple therapeutic advances for CRPC patients have been realized. In 2004, a taxane-based chemotherapy, docetaxel, was established as the first therapeutic to prolong survival in patients with mCRPC^1,2; in the phase 3 trial TAX 327, 3-weekly docetaxel plus prednisone improved the median overall survival (OS) by 2.4 months in patients with mCRPC compared with mitoxantrone plus prednisone.² Since 2010, additional mCRPC treatments that prolong survival have been approved by the U.S. Food and Drug Administration (FDA): taxane chemotherapy (cabazitaxel), androgen receptor (AR)-directed therapies (abiraterone and enzalutamide), immunotherapy (sipuleucel-T), and bone-targeting radiotherapy (radium-223), completely altering the treatment paradigm.^3,4,5,6 Recently, the use of docetaxel plus androgen deprivation therapy (ADT) for high-volume castration-sensitive metastatic disease has demonstrated a significant survival benefit.^7,8

Optimal sequencing of therapies used to treat advanced prostate cancer remains controversial. Therapies targeting AR signaling may be recommended before chemotherapy in mCRPC because of their relative safety and tolerability profiles and ease of administration.^9,10 Hence, patients often undergo chemotherapy only after progressing on AR-targeted oral therapies, and thus presumably have a more advanced disease, possibly a concomitant decreased performance status, and may therefore be less suitable for, or tolerant of, chemotherapy. Selecting the optimal treatment strategy for sequencing or combining therapies to provide maximal OS and quality-of-life benefit is a significant challenge in the management of advanced prostate cancer. For example, early use of chemotherapy might be a better option for patients with specific disease characteristics, for example, visceral metastases or low prostate-specific antigen (PSA) and extensive tumor burden, suggestive of anaplastic or possible neuroendocrine features. Nonetheless, existing clinical data describing the relative benefits of different treatment strategies are usually retrospective and originate from a single institution.

In addition to concerns about ease of administration and patient tolerability, selecting the right treatment, at the right time, will avoid exposure to a clinically nonbeneficial therapy. Hence, can we improve precision therapeutic selection? Is there evidence for cross-resistance between or among treatments? Does resistance develop first at the molecular level, then at the clinical level? Can clinical factors and biomarkers predict resistance? These questions are pertinent to all clinicians managing advanced prostate cancer, especially to urologists specializing in advanced prostate cancer care. This article reviews data evaluating response and resistance to therapeutics currently used to treat mCRPC, and assays under investigation that may identify specific patient resistance patterns that may better inform therapeutic selection.

We searched MEDLINE and PubMed for literature to include in this review. Terms combined in our searches included, “prostate cancer,” “chemotherapy,” “docetaxel,” “cabazitaxel,” “abiraterone,” “enzalutamide,” “sipuleucel-T,” “radium-223,” “resistance,” “sequencing,” and “biomarker.” Identified publications were manually filtered for articles focusing on treatment sequencing, treatment resistance, and biomarkers in metastatic prostate cancer.