Report from the FDA Approval Summary: Docetaxel in Combination with Prednisone for the Treatment of Androgen-Independent Hormone-Refractory Prostate Cancer

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 every 21 days prednisone 5 mg twice a day for a total of 10 cycles; and TXT qw, docetaxel 30 mg/m 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. INTRODUCTION Docetaxel (Taxotere, Aventis Pharmaceuticals, Bridgewater, NJ) is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules. Microtubules bundles without normal function are produced, and mitosis is inhibited. Docetaxel has been previously approved by the United States Food and Drug Administration (FDA) for locally advanced or metastatic breast cancer after anthracycline therapy, locally advanced or metastatic non–small-cell lung cancer after prior platinum-based chemotherapy, and for use in combination with cisplatin for newly diagnosed locally advanced or metastatic non–small cell lung cancer. After development of metastatic hormone-refractory disease, prostate cancer is incurable, with median survival of 9 to 12 months (1, 2). Historically, no single agent or combination regimen has shown a survival benefit in this setting. In 1996, mitoxantrone administered in combination with prednisone was approved by the FDA for the palliative treatment of metastatic or locally advanced disease that had progressed on standard hormonal therapy. This approval was based on results of a randomized trial comparing mitoxantrone plus prednisone to prednisone alone. A total of 161 patients were randomized in this trial, which used palliative response as a primary endpoint (3, 4). A second randomized trial of mitoxantrone plus hydrocortisone versus hydrocortisone alone conducted by the Cancer and Leukemia Group B provided supportive evidence of a palliative effect (4). Docetaxel has been evaluated in single arm studies in hormone-refractory prostate cancer, either as a single dose every 3 weeks or a weekly regimen. Prostate-specific antigen (PSA) declines, and radiographic responses in those patients with bidimensionally measurable lesions were noted (5–9). TAX327, a global multicenter trial, was designed to evaluate two docetaxel schedules with prednisone compared with a control arm of mitoxantrone plus prednisone. The design and findings of this study are outlined below.