SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 220,800 new cases of prostate cancer will be diagnosed in 2015 and over 27,000 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention for hormone sensitive prostate cancer. Chemotherapy is usually considered for patients who progress on hormone therapy (Castrate Resistant Prostate Cancer-CRPC) and TAXOTERE® (Docetaxel) has been shown to improve Overall Survival (OS) of metastatic prostate cancer patients, who had progressed on Androgen Deprivation Therapy. Tumors in patients with CRPC are not androgen independent and continue to rely on Androgen Receptor signaling and two oral agents are presently available for metastatic CRPC. They include ZYTIGA® (Abiraterone) and XTANDI® (Enzalutamide). ZYTIGA® inhibits CYP 17A1 enzyme thus decreasing androgen biosynthesis and depletes adrenal and intratumoral androgens. XTANDI® competes with Testosterone and Dihydrotestosterone and avidly binds to the Androgen Receptor (AR), thereby inhibiting AR signaling and in addition inhibits translocation of the AR into the nucleus and thus inhibits the transcriptional activities of the AR. There is presently very little guidance with regards to the sequencing of these two oral agents after progression on TAXOTERE®, in patients with metastatic CRPC. ZYTIGA® was approved initially by the FDA in April 2011, for use in combination with prednisone for the treatment of patients with metastatic CRPC, who had received prior chemotherapy containing TAXOTERE®. Treatment with ZYTIGA® resulted in a 35% reduction in the risk of death and a 36% increase in median Overall Survival (OS) compared with placebo. Subsequently, XTANDI® was approved by the FDA on August 31, 2012 for the treatment of patients with metastatic CRPC who had previously received TAXOTERE®. XTANDI® improved median OS and reduced the risk of death by 37% when compared to placebo. Even though these two anti-androgen therapies improved OS in metastatic CRPC patients previously treated with TAXOTERE®, the proper sequence of administration of these two agents after TAXOTERE® failure, has remained unclear. At least 2 published studies have shown that the use of ZYTIGA® as third line therapy after progression on TAXOTERE® and XTANDI® resulted in inferior outcomes.
The purpose of this study was to evaluate the role of XTANDI® as third line therapy, in patients with metastatic CRPC, following progression on TAXOTERE® and ZYTIGA®. The authors searched large, established medical databases and selected 10 publications out of 1264 articles, in which metastatic CRPC patients were treated with XTANDI® as third line therapy, following progression on TAXOTERE® and ZYTIGA®. The study included 536 patients. The primary outcomes were PSA Response Rate of more than 50%, activity of XTANDI® based on previous response to ZYTIGA® and median Progression Free Survival (PFS) or Time To Progression. The secondary outcomes included safety and the median Duration of Response. The pooled Response Rate in this patient population with XTANDI® was 22.9%. However, in patients previously sensitive to ZYTIGA®, the Response Rate with XTANDI® was higher at 35%. The median PFS was 3.1 months and the median OS was 8.3 months. This pooled analysis gives some perspective on the initial choice of anti-androgen therapy in metastatic CRPC patients who progress on TAXOTERE®, with XTANDI® benefitting the most, in patients who respond to second line treatment with ZYTIGA®. It remains to be seen if this sequencing strategy can be confirmed in prospective trials. Enzalutamide After Docetaxel and Abiraterone Acetate Treatment in Prostate Cancer: A Pooled Analysis of 10 Case Series. Petrelli F, Coinu A, Borgonovo K, et al. Clinical Genitourinary Cancer 2015;13:193-198