CABAZITAXEL FOR PROSTATE CANCER

October 6, 2010 — The newly approved chemotherapeutic agent cabazitaxel (Jevtana, Sanofi-Aventis) combined with prednisone extends survival by more than 2 months for men with advanced multidrug-resistant prostate cancer.

The data from the international phase 3 TROPIC trial, which led to fast-track approval of the drug by the US Food and Drug Administration (FDA), were published in the October 2 issue of the Lancet. An accompanying editorial describes them as practice-changing.

Preliminary results were presented earlier this year at the American Society of Clinical Oncology 2010 Annual Meeting, and reported by Medscape Medical News at the time.

Principle investigator Johann de Bono, MD, from the Royal Marsden NHS Foundation and the Institute of Cancer Research in the United Kingdom, told Medscape Medical News that his team's most important finding was that prednisone plus cabazitaxel reduced the hazard of death by about 30%, compared with prednisone plus mitoxantrone, for metastatic castration-resistant prostate cancer. It was this survival benefit that led to FDA approval, Dr. de Bono emphasized. Only 5 drugs have shown this; the other 4 are [luteinizing hormone-releasing hormone] agonists, docetaxel, sipuleucel T, and abiraterone," he said.

However, cabazitaxel is the first drug to show a survival benefit in patients whose disease has progressed after standard chemotherapy with docetaxel and for whom there are currently no approved treatment options, he noted.

Dr. de Bono and colleagues compared overall survival in men with advanced multidrug-resistant prostate cancer (all previously treated with docetaxel) who were randomized to prednisone plus cabazitaxel (n = 378) or to prednisone plus mitoxantrone (n = 377). Patients in the cabazitaxel group received oral prednisone 10 mg/day plus cabazitaxel 25 mg/m2 intravenously over 1 hour every 3 weeks. Those in the mitoxantrone group received the same dose of prednisone and mitoxantrone 12 mg/m2 intravenously over 15 to 30 minutes every 3 weeks. The primary end point was overall survival.

Median survival was 15.1 months in the cabazitaxel group and 12.7 months in the mitoxantrone group. The hazard ratio for death was 0.70 for cabazitaxel vs mitoxantrone (P < .0001).

"Cabazitaxel treatment also improved median progression-free survival and time to tumor progression, and resulted in higher rates of tumor and serum prostate-specific antigen [PSA] response than did mitoxantrone," the authors note.

Median progression-free survival was 2.8 months with cabazitaxel and 1.4 months with mitoxantrone. Time to progression was also significantly longer with cabazitaxel (8.8 vs 5.4 months; P < .0001).

PSA response rates were 39.2% with cabazitaxel and 17.8% with mitoxantrone (P = .0002).

However, cabazitaxel caused more adverse events. Grade 3 or higher neutropenia occurred in 82% of cabazitaxel patients and in 58% of mitoxantrone patients. Grade 3 or higher diarrhea rates were 6% and less than 1%, respectively. Febrile neutropenia occurred in 28 cabazitaxel patients and in 5 mitoxantrone patients.

Dr. de Bono advised clinicians to treat advanced and docetaxel-resistant prostate cancer with cabazitaxel, but to exercise some caution.

"Monitor for neutropenia in course 1, and dose-reduce to 20 mg/m2 if grade 4 neutropenia lasting longer than 5 days is seen," Dr. de Bono said.

The authors conclude that "cabazitaxel is the first treatment to prolong survival for metastatic multidrug-resistant prostate cancer in the postdocetaxel setting. . . . On the basis of these results, cabazitaxel will become a standard of care for treatment of prostate cancer in this setting."

Data Are Practice-Changing

In an accompanying editorial, Tanya Dorff, MD, and David Quinn, MD, PhD, from the University of Southern California, Los Angeles, write: "The key result — a 2.4-month improvement for cabazitaxel over mitoxantrone — changes our practice."

"Cabazitaxel provides an added line of therapy for patients with castration-resistant prostate cancer," they explain.

The new drug, like docetaxel, is also a taxane, and the editorialists note that "taxane rechallenge does not provide a therapeutic breakthrough," but by "stretching survival without being curative, the horizon for patients with prostate cancer is promising."

Dr. de Bono added that "the main question raised for me is this: Do the taxanes work by impacting [androgen-receptor] signaling?"

However, the editorialists caution about the adverse effects encountered with the new drug. "First, during infusion, cabazitaxel is more likely to induce allergic-type reactions requiring prophylaxis, vigilance, and at times emergency attention. Second, cabazitaxel resulted in increased treatment-related mortality (4.9%), perhaps because of substantial neutropenia and diarrhea. . . . In this context, provision of well-structured contingency plans for management of diarrhea and febrile neutropenia is mandatory for patients treated with cabazitaxel." They recommend that such plans include patient education, access to acute specialized care, colon-stimulating factors, antibiotics, and supportive care.

This study was funded by Sanofi-Aventis. Dr. de Bono reports serving as a paid consultant for Sanofi-Aventis. Dr. Quinn reports receiving research funding from Sanofi-Aventis. Dr. Dorff has disclosed no relevant financial relationships.

Lancet. 2010;376:1119-1120, 1147-1154. Abstract, Abstract