Cabazitaxel: a new drug for metastatic prostate cancer.

I n Western countries, prostate cancer is the most common malignancy in men and ranks third in mortality. In 2010, an estimated 217 730 new cases are anticipated in the United States, and about 32 050 men are expected to die from the disease. Until 2004, numerous clinical trials in men with metastatic castration-resistant prostate cancer (mCRPC) failed to demonstrate any significant change in overall survival. The only option for symptomatic patients at that time was mitoxantrone, a type II topoisomerase inhibitor that disrupts DNA synthesis and repair in cells, approved due to its beneficial effect on quality of life. Docetaxel with prednisone was the first chemotherapy regimen to demonstrate an improvement in overall survival in this patient population (18.9 months versus 16.5 months; hazard ratio (HR)50.76; P50.009) relative to mitoxantrone and prednisone. This regimen was approved by the US Food and Drug Administration (FDA) in 2004 for the treatment of mCRPC. It would be another 6 years, however, before any agent demonstrated a survival benefit in patients who progressed on docetaxel. Cabazitaxel is a second-generation semisynthetic taxane that inhibits microtubule depolymerization, leading to cell cycle arrest and cell death. Unlike other taxane compounds, cabazitaxel appears to penetrate the blood–brain barrier and is a poor substrate for the multidrug-resistant P-glycoprotein efflux pump that is a possible mechanism for taxane resistance. A company-sponsored phase III clinical trial of cabazitaxel versus mitoxantrone (TROPIC) was conducted in 28 countries in 755 patients with mCRPC previously treated with docetaxel. Eligible patients were at least 18 years of age (median: 68 years), had an ECOG performance status of 0–2, and had pathologically proven prostate cancer with documented disease progression during or after treatment with a cumulative dose of docetaxel .225 mg m. The median dose of docetaxel received pre-study was 576.6 mg m in the cabazitaxel group and 529.2 mg m in the mitoxantrone group. Patients with measurable disease were required to have documented disease progression by RECIST criteria, while patients with non-measurable disease were required to have rising serum prostate-specific antigen (PSA) concentrations or the appearance of at least one new radiographically demonstrable lesion. In addition, all patients were castrated by orchiectomy, luteinizing hormone–releasing hormone agonists, or both, and underwent antiandrogen withdrawal after biochemical recurrence for at least 4 weeks (6 weeks for bicalutamide). Patients were randomized to receive prednisone 10 mg per day with mitoxantrone 12 mg m or cabazitaxel 25 mg m. Patients in both arms of the trial appeared to be well balanced in terms of baseline characteristics and treatment histories. At the end of the trial, all significant measures of antitumor activity favored cabazitaxel. Tumor response rates by RECIST criteria were 14.4% for the cabazitaxel group versus 4.4% for the mitoxantrone group (P50.0005). Median progressionfree survival was 2.8 months with cabazitaxel and 1.4 months with mitoxantrone. Time to progression was also significantly longer with cabazitaxel (8.8 months versus 5.4 months; P,0.0001). PSA declines of at least 50% were seen in 39.2% of patients in the cabazitaxel group and 17.8% of patients in the mitoxantrone group (P50.0002). Most importantly, median overall survival was 15.1 months with cabazitaxel versus 12.7 months with mitoxantrone (HR50.72; P,0.0001). On the basis of guidelines recommending 12 weeks of treatment before adjustment of therapy for mCRPC, an amendment was made to the trial protocol after 59 patients had been enrolled to exclude patients previously receiving a cumulative dose of docetaxel ,225 mg m. Subgroup intentionto-treat analysis of overall survival consistently favored cabazitaxel in all subgroups, with no significant correlation between total previous dose of docetaxel and treatment response. Median time from last docetaxel dose to disease progression was similar in both groups (0.8 months for cabazitaxel versus 0.7 months for mitoxantrone). Time interval since last dose of docetaxel also did not correlate with treatment response. Unfortunately, cabazitaxel toxicity was significant in this post-docetaxel mCRPC population. In the cabazitaxel group, 18% of patients discontinued treatment because of adverse events (mostly neutropenia and renal failure), compared with 8% in the control group. Grade o3 neutropenia was seen in 81.7% of patients receiving cabazitaxel compared to 58% of patients receiving mitoxantrone. The most common (o5%) grades 3–4 adverse reactions were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue and asthenia. Deaths due to causes other than disease progression within 30 days of last dose of study drug were reported in 18 (5%) cabazitaxel-treated patients compared to only 3 (.1%) mitoxantrone-treated patients. The most common fatal adverse reactions in cabazitaxel patients were infections (n55) and renal failure (n54). Interestingly, the designated dose of cabazitaxel in this trial was higher than the starting dose of this agent (20 mg m) in breast cancer clinical trials that enrolled younger patients. Managing the toxicity of cabazitaxel and optimizing patient selection will be critical as this agent becomes more widely used. Cabazitaxel was granted fast-track designation by the FDA in November 2009. The new drug application submission was completed in March 2010 and was granted priority review in April 2010. Approval by the FDA occurred less than 3 months later, based on the results of the TROPIC study. Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Correspondence: Dr W L Dahut ([email protected]) Asian Journal of Andrology (2011) 13, 185–186 2011 AJA, SIMM & SJTU. All rights reserved 1008-682X/11 $32.00