Approval Summary

Abstract

Purpose: Docetaxel, a taxane previously approved for the treatment of breast cancer and non-small cell lung cancer, was approved by the United States Food and Drug Administration on May 19, 2004 for use in combination with prednisone for the treatment of metastatic androgen-independent (hormone-refractory) prostate cancer. The purpose of this summary is to review the database supporting this approval.Experimental Design: In a randomized, global study enrolling 1,006 patients, two schedules of docetaxel were compared with mitoxantrone ؉ prednisone as follows: MTZ q 3w, mitoxantrone 12 mg/m2 every 21 days ؉ prednisone 5 mg twice a day for a total of 10 cycles; TXT q 3w, docetaxel 75 mg/m 2 every 21 days ؉ prednisone 5 mg twice a day for a total of 10 cycles; and TXT qw, docetaxel 30 mg/m 2 days 1, 8, 15, 22, and 29 every 6 weeks ؉ prednisone 5 mg twice a day for a total of 5 cycles.Results: There was a statistically significant overall survival advantage shown for the TXT q 3w arm over MTZ q 3w (median survival 18.9 months versus 16.5 months, P ‫؍‬ 0.0094). No overall survival advantage was shown for TXT qw compared with MTZ q 3w. The most commonly occurring adverse events included anemia, neutropenia, infection, nausea, sensory neuropathy, fluid retention, alopecia, nail changes, diarrhea, and fatigue.Conclusions: This report describes the Food and Drug Administration review supporting this first approval of a combination therapy for hormone-refractory prostate cancer based on demonstration of a survival benefit.

Novel strategies in the treatment of castration-resistant prostate cancer (Review)

“…Based on these results, thrice-weekly docetaxel with prednisone therapy was approved by the FDA for the treatment of metastatic CRPC in May 2004 and is now widely accepted as the standard of care for chemotherapy in patients with CRPC (14)(15)(16). A recent update of the TAX 327 study, stemmed from an extended follow-up, is consistent with previously reported results.…”

“…Mitoxantrone, in combination with prednisone, was shown to play a role in the treatment of patients with CRPC (12,(14)(15)(16). A Canadian phase III study in patients with symptomatic CRPC demonstrated that, compared to prednisone alone, this combination resulted in a significant improvement in both response rate (29% versus 12%: p=0.01) and duration of palliation (43 versus 18 weeks: p<0.0001) (12).…”

“…In a phase III US Oncology study in patients with asymptomatic CRPC, mitoxantrone plus prednisone induced a significantly superior outcome in ≥50% PSA reduction (48% versus 24%: p=0.007), albeit with no difference in median time to treatment failure, median time to progression, or median survival (17). Although unable to achieve an improvement in OS, mitoxantrone was approved by the US Food and Drug Administration (FDA) for the palliative treatment of CRPC in 1996 (14)(15)(16).…”

Enzalutamide for Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer Who Have Previously Received Docetaxel: U.S. Food and Drug Administration Drug Approval Summary

“…It received full FDA approval in 2004 based on a 2.4-month improvement in median overall survival (OS) for docetaxel compared with mitoxantrone [HR ¼ 0.76; 95% confidence interval (CI), 0.62-0.94; P < 0.009; ref. 1,2]. Since then, docetaxel has been commonly used for patients with mCRPC, particularly for those with symptomatic or visceral disease.…”

Translating Clinical Trials into Meaningful Outcomes

“…The use of high response rates in nonrandomized trials has proved to be a very reliable basis for approving anticancer agents (13). On the other hand, randomized survival comparisons (particularly in unselected patients) can be very misleading (14), and have led to the approval of a wide range of agents that yield statistically significant results but provide limited benefits for unselected patients (Table 1) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Such survival-based randomized studies in unselected patients may miss a marked benefit in defined subpopulations, or alternatively it may result in a drug being widely applied even though it benefits only a small minority of patients (27).…”