Management of docetaxel failures in metastatic castrate-resistant prostate cancer.

In 1941, Huggins et al noted the dramatic effects of surgical castration in the treatment of metastatic prostate cancer.1–2 This landmark development revolutionized the therapy of the disease, and over time, pharmacologic methods of castration were developed as an alternative to surgical methods.3 Huggins recognized early on that “despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease.”4 Though this disease state has undergone a number of nomenclature changes (including androgen-independent prostate cancer and hormone refractory prostate cancer), today we refer to this disease state as castration-resistant prostate cancer (CRPC), which may or not be metastatic. The onset of the metastatic CRPC (mCRPC) occurs at a median of about 9 years for years after androgen deprivation therapy (ADT) for patients initially treated with non-metastatic disease or 1–3 years after ADT for patients initial treated for metastatic disease.5–6 For decades, clinical trials failed to show a definitive advantage with novel therapies for mCRPC.7–8 Two pivotal trials examining docetaxel-based regimens were the first to demonstrate an OS benefit in patients with mCRPC. In TAX 327, patients were randomized to receive either mitoxantrone/prednisone or docetaxel/prednisone in one of two schedules.9 Ultimately, docetaxel at a dose of 75 mg/m2 intravenously (IV) every 3 weeks (q3wks) with prednisone daily led to a survival advantage over standard mitoxantrone/prednisone therapy (18.9 months vs 16.5 months, P=0.009). In Southwest Oncology Group (SWOG) trial 9916, patients were randomized to receive either docetaxel/estramusine or mitoxantrone/prednisone.10 Again, a survival advantage was noted with docetaxel-based therapy (17.5 months vs 15.6 months, P=0.02). The cumulative data from these studies led to the approval of docetaxel/prednisone based therapy for mCRPC on May 19, 2004.11 Over the ensuing years, a number of different approaches were taken to build on the success of docetaxel in patients with mCRPC. One such approach was to explore combinations of novel therapies with docetaxel. Unfortunately, to date, these studies have proven somewhat disappointing.12–19 A second approach to the patient with mCRPC has been to explore the efficacy of novel therapies either prior to or subsequent to docetaxel therapy. These efforts have thus far proven to be more fruitful than explorations of combination therapy.20 To date, the bulk of progress has been made in the post-docetaxel space – here, agents such as cabazitaxel, abiraterone, MDV3100, and radium-223 have all demonstrated statistically significant benefits in OS.21–24 Thus far, cabazitaxel/prednisone and abiraterone/prednisone are FDA approved. Although some agents (i.e., abiraterone, radium-223) may ultimately straddle pre- and post-docetaxel spaces,25 the current review will focus on the current post-docetaxel strategies. The clinical data related to each agent will be reviewed in detail so as to provide the physician with a framework with which to approach the docetaxel-refractory patient.