Abiraterone for Advanced Prostate Caner
Castration has for long been a standard approach to treatment of men with advanced prostrate cancer. Orchiectomy and androgen deprivation with agents such as the luteinizing hormone-releasing hormone agonist drugs (e.g. Lupron) and anti-androgens (e.g Casodex) have predictable acitivity to block the effects of testosterone and/or to reduce the amount of testosterone synthesis. Inevitably, however, men with metastatic castration-resistant prostate cancer (CPRC), eventually have disease progression despite the very low levels of testosterone that such treatments induce.
A possible reason for this progression is that prostate cancer cells in these patients may have higher numbers of testosterone receptors and, therefore, are stimulated to multiply even in the presence of low testosterone in the body.
Until now, the options for treatment of CPRC patients have included second line hormonal interventions (which have not been shown to improve survival), docetaxel (Taxotere) chemotherapy, Provenge (sipuleucel-T) immunotherapy and Jevtana (cabazitaxel--a chemotherapy drug approved in 2010).
Based on a four month median survival benefit observed in a recently published pivotal clinical trial (http://www.nejm.org/doi/full/
Abiraterone is an inhibitor of cytochrome P450 17A1 (CYP17A1), an enzyme that is involved in the conversion of cholesterol to testosterone and synthesis of other hormones, and which appears to be overexpressed in prostate cancer cells.
In the multicenter clinical trial 1195 patients were randomized to either the combination of once-daily abiraterone plus prednisone, or the combination of placebo plus prednisone. Median overall survival (OS) was 14.8 months in the abiraterone group, versus 10. 9 months in the control group. The increase in median OS in abiraterone-treated patients was statistically significant. Abiraterone was shown to be a safe drug, and relatively few serious adverse events were observed in the abiraterone arm of the trial. Since abiraterone is an oral drug, this provides a significant advantage as well.
Patients who were treated previously with the antifungal, ketoconazole, were excluded from this trial, so it is possible that such patients may experience lower responses than ketoconazole-naïve patients.
For men with metastatic CPRC who failed docetaxel treatment, Zytiga (abiraterone acetate) represents an exciting and safe therapeutic option that results in improved survival. The possibility that abiraterone could assume a front line status is being tested in an on going Phase III trial in men with metastatic CRPC who have not yet received docetaxel treatment.
Copyright 2011 A. Richard Adrouny, M.D., F.A.C.P.
Improved Survival in Pancreatic Cancer
Pancreatic cancer affects many people (it is the fourth leading cause of cancer death in the United States) and unfortunately advanced pancreatic cancer generally has a terrible prognosis. The quest for treatment regimens providing survival benefit and/or improved quality of life (QOL) is ever present. Until recently, gemcitabine (Gemzar) alone or in combination with other drugs has been considered a front line approach.
Recently the French investigator Conroy and colleagues published the results of a randomized, multicenter Phase 2-3 clinical trial comparing treatment with either the 4-drug regimen, FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) or single agent gemicitabine in 342 patients with metastatic pancreatic cancer and good performance status (http://www.nejm.org/doi/full/
Median overall survival for FOLFIRINOX-treated patients was improved by nearly 5 months to 11.1 months versus 6.8 months for gemcitabine-treated patients. The one year survival for the FOLFIRINOX patients was nearly 50% as compared to only 20% in the gemcitabine group. Moreover, FOLFIRINOX therapy resulted in statistically significant improvements in progression-free survival and objective response rates. Therefore, FOLFIRINOX-treated patients exhibited notable survival advantages, as compared with gemcitabine-treated patients.
The FOLFIRINOX-treated group, however, experienced significantly more adverse events. In most categories of toxicity, both hematologic and non-hematologic, the FOLFIRINOX patients fared less well than the gemcitabine-treated group. Nevertheless, at 6 months of treatment, patients in the FOLFIRINOX group had a decline in quality of life that was only half that of the gemcitabine group (31% vs 66%).
Thus for patients with metastatic pancreatic cancer who have good performance status FOLFIRINOX represents a first-line, chemotherapeutic option that may provide extended survival and improved QOL.
