Prostate cancer is estimated to occur in 180,890 men in the USA in 2016 alone.1 Prostate cancer has been recognized since 1942 as being responsive to androgen deprivation therapy (ADT), but the response may be transient and the majority of patients progress to castration-resistant prostate cancer (CRPC) by developing resistance to ADT by various mechanisms.2 Approximately 20% of the patients may have de novo resistance to ADT.3 Chemotherapy has played a pivotal role in the setting of metastatic CRPC (mCRPC) since 2004 when docetaxel-based chemotherapy first showed modest improvement in survival compared with mitoxantrone-based therapy as first-line chemotherapy.3–5 Older agents, including estramustine, platinums, cyclophosphamide, and 5-fluorouracil, exhibit marginal-to-modest activity but have not been pursued in randomized trials.6–9 Mitoxantrone in combination with low-dose corticosteroids confers palliative benefits without overall survival (OS) benefit.3,10–13

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After a hiatus since the approval of docetaxel, multiple new orally administered antiandrogen drugs, such as abiraterone acetate and enzalutamide, have extended survival in the pre- and postdocetaxel settings.12,14–16 Additionally, an immunotherapeutic agent (sipuleucel-T) and a radiopharmaceutical (radium 223) have also extended survival modestly in minimally symptomatic or symptomatic bony disease settings, respectively.17,18 Moreover, a second and more potent taxane, cabazitaxel, has extended survival in postdocetaxel patients.19 The oral antiandrogen drugs have been rapidly adopted in the clinic due to the favorable therapeutic indexes and convenience, and chemotherapy has been generally relegated to later-line settings.

Cross-resistance between antiandrogen drugs and taxanes, as well as resistance to chemotherapy, is emerging as an important barrier to be overcome. Understanding the mechanisms of chemoresistance is of utmost importance as it can help in developing newer therapeutic agents and potentially synergistic combinations with better efficacy and improved survival.2 In addition, identifying patients who are potentially not likely to benefit from chemotherapy can prevent substantial morbidity in those patients. One challenging issue is that resistance is identified on the basis of disease progression, which is a soft end point in mCRPC, due to the frequent presence of nonmeasurable bone metastases. Indeed, the Prostate Cancer Working Group guidelines recommend 3 months of therapy before objective assessment, due to the occurrence of early prostate-specific antigen (PSA) and bone scan flares.20 Additionally, switching therapy based solely on PSA changes is not recommended. This review describes the current role of chemotherapy for treating mCRPC and mechanisms of resistance to chemotherapy.


Mechanism of action

Docetaxel is an antimitotic agent historically recognized to inhibit microtubule disassembly and has more recently been demonstrated to downregulate androgen receptor (AR) transcriptional activity. Docetaxel can inhibit the translocation of the AR to the nucleus in response to both androgens and ligand-dependent signaling pathways.21,22 Docetaxel also inhibits AR gene expression by acting on the gene promoter. It increases the levels of Forkhead box O1 (FOXO1), a strong transcriptional repressor of AR.23 The downregulation of AR activity, in addition to its historically recognized antimitotic effects, can explain the efficacy of microtubule inhibitors in prostate cancer.21 In addition, docetaxel also has anti-B-Cell lymphoma (BCL)-2 and anti-BCLX properties, thereby promoting apoptosis.21,24 Two Phase III clinical trials established docetaxel-based chemotherapy as the standard first-line chemotherapy based on an ~3-month increment in median OS compared to the mitoxantrone arm, which led to approval of the drug by the US Food and Drug Administration.4,5

Evidence for clinical benefit of docetaxel in mCRPC

The TAX 327 study (n = 1,006) demonstrated an improvement in median OS with docetaxel every 3 weeks plus prednisone compared to mitoxantrone plus prednisone: 18.9 months vs. 16.5 months (hazard ratio [HR]: 0.76; 95% confidence interval [CI]: 0.62–0.94; P = 0.009).4 Notably, patients receiving weekly docetaxel did not exhibit a survival extension compared to mitoxantrone. The most common toxicities of the every 3-week docetaxel arm were fatigue (53%), alopecia (65%), neutropenia (32%), and neuropathy (30%), although febrile neutropenia was uncommon (3%).4 A second landmark trial, the SWOG-9916 trial, also demonstrated improved survival for docetaxel plus estramustine compared to mitoxantrone plus prednisone, but this combination is not commonly used due to the gastrointestinal and cardiovascular toxicities of estramustine.5 Notably, analyses of both of these trials also demonstrated that PSA decline ≥30% within 3 months was a moderate surrogate for improved survival.25,26

Intermittent docetaxel treatment may be a reasonable strategy. While the above landmark Phase III trials aimed to deliver 10–12 cycles of docetaxel, in the ASCENT study (n = 250), patients who achieved a PSA ≤4 ng/mL could choose a chemotherapy holiday.11 Treatment was resumed when the PSA increased by ≥50% and was ≥2 ng/mL, or if there was other evidence for disease progression. The median duration of the treatment holiday was 18 weeks (range: 4–70 weeks) and 45.5% of patients exhibited a ≥50% PSA decline following the second course of treatment after the holiday.27

The combination of docetaxel with carboplatin yielded ≥50% PSA declines in ~20% of patients as second-line chemo therapy in mCRPC progressing after prior docetaxel-based chemotherapy (n = 34).28,29 However, owing to the lack of randomized trials, it is unclear if the addition of platinums confers a survival impact.