BERKELEY, CA (UroToday.com) - Men with progressive metastatic castration-resistant prostate cancer (mCRPC) often have a poor prognosis, and it is not until recent years that new treatment options have become available for these patients, treatments that prolong survival but are less toxic. Biosynthesis of extragonadal androgen may be one factor that contributes to the progression of CRPC and this study was designed to evaluate whether a selective inhibitor of androgen biosynthesis, abiraterone acetate (AA), would prolong overall survival in patients with mCRPC who have received chemotherapy with docetaxel. As a selective androgen biosynthesis inhibitor, AA blocks the action of CYP17 thereby blocking androgen synthesis by the testes, adrenal glands, and within the prostate tumor.
This study included 1 195 patients with mCRPC previously treated with one or two regimens of chemotherapy, at least one of which contained docetaxel. The patients were randomized in a 2:1 ratio to receive either 1 000 mg of AA plus 5 mg prednisone twice daily (n=797) or placebo plus 5 mg prednisone twice daily (n=398) at 147 centers in 13 countries. The medication was administered as four 250 mg tablets (AA) or four placebo tablets orally once a day, to be taken at least 1 hour before or 2 hours after a meal, together with prednisone 5 mg orally twice a day. Patients were to discontinue treatment when all three criteria for disease progression were met: a 25% increase in PSA over baseline, radiographic progression, and clinical or symptomatic progression. Note that the study did not use PSA alone as reason for discontinuation of treatment. The primary endpoint was overall survival. The secondary endpoints included PSA-response rate, time to PSA progression, and progression-free survival based on radiographic evidence.
One interim analysis was planned after 67% of the required 797 total events were observed. At the time of the pre-planned interim analysis, the AA group had received a median of eight months treatment and the placebo group a median of four months treatment. The median follow-up in the overall study population was 12.8 months. The study demonstrated a median overall survival of 14.8 months in the AA group compared with 10.9 months in the placebo group, equal to 36% increase in median survival for AA compared with placebo. Treatment with AA also resulted in a 35.4% reduction in the risk of death compared with placebo (HR=0.65; 95% CI; 0.54 to 0.77; p < 0.001). The superior effect of AA plus prednisone on overall survival was consistent across all subgroups. At this point (August 2010), the independent data and safety monitoring committee recommended the study be unblinded.
All the secondary endpoints analyzed supported the superiority of AA over placebo. This included confirmed PSA response rate (29% vs. 6%, p < 0.001), time to PSA progression (10.2 months vs. 6.6 months, p < 0.001), and radiographic progression-free survival (5.6 months vs. 3.6 months, p < 0.001). Evaluation of exploratory endpoints at the interim analysis also favored AA relative to placebo, including time to 25% of patients having a skeletal event (9.9 vs. 4.9 months) and the rate of pain palliation (44% vs. 27%). Patients in the AA group had consistently improved pain palliation compared with the placebo group.
The most common adverse events were fatigue (AA 44% vs. placebo 43%), back pain (30% vs. 33%), nausea (30% vs. 32%), constipation (26% vs. 31%), bone pain (25% vs. 28%), and arthralgia (27% vs. 23%). Patients in the AA group experienced more mineralocorticoid related adverse events than patients in the placebo group due to the CYP 17 blockade. However, when taking low-dose prednisone, the mineralocorticoid excess is reduced. Most frequent were fluid retention and edema (31% vs. 22%, p=0.04), and hypokalemia (17% vs. 8%, p < 0.001). Cardiac events occurred at a similar rate in both groups and the difference was not significant (13% vs. 11%, p=0.14). Liver-function test abnormalities also occurred at a similar rate in both groups (10% vs. 8%). Adverse events resulting in treatment discontinuation occurred with similar frequency in both groups (19% vs. 23%, p=0.09). Adverse events resulting in death were seen in a lower proportion of patients in the AA group than the placebo group (12% vs. 15%).
An interesting comparison is to look at the serum testosterone levels after surgical or medical castration compared to serum testosterone levels after AA treatment. Surgical or medical castration leads to testosterone levels in the range of 20 to 50 ng/dL, while AA treatment reduces the levels to the range of 1 to 2 ng/dL. This could potentially lead to redefinition of the castrate levels of testosterone.
In summary, compliance with AA treatment was high in this study and the side effects were easily manageable and reversible, demonstrating a good safety profile. This study also showed that AA plus prednisone improved overall survival in patients with mCRPC who received prior docetaxel based chemotherapy. As a result, abiraterone acetate was approved by the FDA April 28, 2011, for the treatment of mCRPC after a patient has progressed on docetaxel. The recommended dose is 1 000 mg daily together with 5 mg prednisone twice daily. The marketed name for abiraterone acetate is ZYTIGA®.
Johann S. de Bono, et al. (for the COU-AA-301 Investigators). Abiraterone and Increased Survival in Metastatic Prostate Cancer. N Engl J Med. 2011; 364:1995-2005. doi: 10.1056/NEJMoa1014618
Written by Anna Forsberg, medical director for UroToday.com. Anna received a BSc in zoology from Louisiana State University, and a BSc in biomedicine and MSc in clinical drug development from Uppsala University in Sweden. She has worked almost 20 years in the global pharmaceutical and medical device world, involved with clinical research management and as a Medical Science Liaison (MSL) before joining UroToday as Medical Director. Her focus in clinical research and as a MSL has mainly been in the fields of urology and oncology.