A final analysis of a phase III trial comparing abiraterone acetate plus prednisone with a placebo in patients with metastatic castration-resistant prostate cancer (mCRPC) found that abiraterone significantly improved overall survival with positive responses seen in several subgroups of patients.Lancet Oncology
published the results of the phase III COU-AA-301 trial online on September 18.
Abiraterone acetate, which is marketed under its brand name Zytiga by Janssen Biotech, is a selective androgen biosynthesis inhibitor that is designed to target androgen receptors to block an enzyme, CYP17A1, which is heavily implicated in androgen receptor signaling and the synthesis of testosterone. Androgen deprivation therapies limit hormone production initially, but progression usually occurs because prostate cancer cells are able to synthesize testosterone on their own at levels that can cause disease progression, even after androgen deprivation. Abiraterone acetate is designed to block all sources of production of testosterone and therefore delay progression of the disease.
The study enrolled 1195 patients at 147 sites in 13 countries. These patients had been diagnosed with mCRPC and progressed after being treated with docetaxel, a standard of care for this group of patients. The study randomized patients to receive either abiraterone acetate 1000 mg once daily plus prednisone 5 mg twice daily (n = 797) or a placebo plus prednisone 5 mg twice daily (n = 398). The primary endpoint of the study was overall survival (OS). Though patients in the placebo arm were allowed to cross over into the abiraterone arm of the study after positive interim results, this study is a final analysis of data before crossover was allowed. This final analysis was performed after 775 of the prespecified 797 death events had occurred.
The final analysis found that after a median follow-up period of 20.2 months, the median OS in patients in the abiraterone arm of the study was 15.8 months (95% CI, 14.8–17.0) compared with 11.2 months in the placebo arm (95% CI, 10.4–13.1) (HR = 0.74, 95% CI, 0.64–0.86; P
Other endpoints also favored abiraterone. The median time to prostate-specific antigen (PSA) progression was 8.5 months in the abiraterone group (95% CI, 8.3–11.1) compared with 6.6 months (95% CI, 5.6–8.3) in the placebo arm (HR = 0.63; 95% CI, 0.52–0.78; P
< .0001). Abiraterone was also favored in terms of median radiologic progression-free survival (PFS), with the abiraterone arm achieving a median PFS of 5.6 months (95% CI, 5.6–6.5) compared with 3.6 months (95% CI, 2.9 – 5.5) in the placebo arm (HR = 0.66; 95% CI, 0.58–0.76; P
< .0001). PSA response was also higher in the abiraterone arm, with 235 of 797 (29.5%) achieving a response compared with 22 of 398 (5.5%) patients in the placebo arm (P
A subgroup analysis found that abiraterone acetate was favored across a wide variety of patient characteristics. Factors such as age, type of progression, baseline performance status, and region of the world from where the patients came from were all accounted for, and in all cases, patients who received abiraterone acetate performed better.
“Our work confirms that abiraterone acetate can be used as an effective and safe treatment for castration-resistant metastatic prostate cancer patients whose disease continues to progress after docetaxel treatment,” said lead author Karim Fizazi, MD, Institut Gustave Roussy in France, in a statement. “Furthermore, unlike current alternatives for this patient population, abiraterone plus prednisone therapy can be given orally in an outpatient setting, providing an additional benefit for both patients and clinicians.”
In a commentary that accompanied the study, Guru Sonpavde, MD, director of Urologic Medical Oncology at the University of Alabama, Birmingham, Comprehensive Cancer Center, praised the results, but he also stressed the need for further studies of the proper sequencing of abiraterone with other therapies, given that newer therapies like sipuleucel-T and enzalutamide have also been recently approved to treat prostate cancer.
“[This trial] represents an important advance in the therapy of metastatic castration-resistant prostate cancer,” wrote Sonpavde. “[Further] clinical trials investigating novel drugs and combinations should be strongly encouraged since all available options are palliative in nature.”
Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase III study [published online ahead of print September 18, 2012]. Lancet Oncol. DOI:10.1016/S0140-6736(08)61345-8.