Translating Basic Science into the Clinic: Approval of Abiraterone

On April 28, 2011, the US Food and Drug Administration (FDA) approved abiraterone acetate (Zytiga, Johnson & Johnson) for the treatment of metastatic castrationresistant prostate cancer (CRPC) for patients who have failed docetaxel therapy. Prostate cancer is a leading cause of cancer mortality and morbidity in the United States.^1,2 Each year approximately 215,000 men are diagnosed and 32,000 men die of the disease. Androgen ablation is the cornerstone for the treatment of metastatic prostate cancer, as a result of Huggins and Hodges’ Nobel Prize–winning work published in 1941. Depletion of circulating androgens either through surgical or medical castration is the first therapeutic maneuver for men failing definitive therapy (radical prostatectomy or external beam radiation). For several decades it was believed that the progression following androgen-deprivation therapy (ADT) was resistant to further hormonal manipulations.³

This paradigm started to change when prostate cancer gene–expression studies found that androgen-receptor activated genes, which are normally downregulated during ADT, become reactivated on transition to CRPC.^4,5 Furthermore, ADT strategies resulted in castrate concentrations of testosterone; however, it was found that low levels of circulating androgen persisted (mainly through peripheral conversion of adrenal steroids). In addition, gene upregulation is involved in androgen biosynthesis, including CYP 17.^6-8 Intratumoral enzymes involved in the conversion of upstream precursors of testosterone and dihydrotestosterone became a molecular target.

Clinical Trials
Cytochrome p450c17 is involved in androgen biosynthesis by 17-alphahydroxylation of C21 steroids and cleavage of C17,20 bond of C21 steroids.^3,9 These reactions are critical in the biosynthesis of dehydroepiandro - sterone and androstenedione. Abiraterone is a potent, selective, irreversible inhibitor of CYP 17A1.¹⁰ In the initial phase 1 trial of abiraterone conducted in chemotherapy-naïve CRPC patients, the drug was well tolerated. The dose (1000 mg/day) used in the phase 2 trial was determined after a plateau in the pharmacodynamic effects was observed When compared with baseline values during an additional phase 1/2 trial of abiraterone in chemotherapy-naïve patients, 67% of the patients achieved a decline in prostate-specific antigen (PSA) ≥50% and the median time to PSA progression (TTPP) on abiraterone alone for all phase 2 patients was 225 days.¹¹ Toxicities observed were attributed to changes in mineralocorticoid, which were manageable with lowdose corticosteroids.^11,12

The pivotal trial for abiraterone was conducted in the postchemotherapy setting for men with CRPC. In COUAA- 301, a large randomized, doubleblind, placebo-controlled phase 3 study, chemotherapy-refractory metastatic patients were treated with either abiraterone plus low-dose prednisone (n = 797) or prednisone plus placebo (n = 398). The median overall survival, the primary end point for this study, was 15.8 months and 11.2 months, respectively, after 775 events (hazard ratio, 0.740; 95% confidence interval, 0.638-0.859), and the benefit was observed across multiple subgroups, such as performance status, sites of metastatic disease, and number of previous chemotherapy regimens received. Other trial end points, including PSA change, TTPP, and radiographic progression- free survival (PFS), also resulted in superior outcomes. Patients on abiraterone achieved a PSA decline of >50% in 38% of the patients compared with 10% for placebo (P <.0001), had a significant delay in TTPP (10.2 vs 6.6 mo, P <.0001), and radiographic PFS (5.6 vs 3.6 mo, P <.0001). Although the incidence of adverse events was higher in patients receiving placebo, there were more patients who experienced grade 3 and 4 toxicities on the treatment arm (fluid retention, hypo kalemia, and hypertension).¹³

An Additional Option Treatment options for men with CRPC are limited, but abiraterone/ prednisone is a welcomed addition to the armamentarium. With this addition, we now have 5 FDA-approved regimens for the treatment of this disease (sipuleucel-T, docetaxel plus prednisone, cabazitaxel plus prednisone, and mitoxantrone plus prednisone). The real question is whether clinicians will move this treatment to the prechemo therapy setting. Abira-terone is a novel agent that inhibits androgen synthesis by selectively blocking CYP 17. The role of prednisone is of some concern, especially with prolonged use. None theless, this is a true example of translating basic laboratory observations into clinic advances.

References

1. Howlader N, Noone AM, Krapcho M, et al; eds. SEER cancer statistics review, 1975-2008. April 15, 2011. www.seer.cancer.gov/csr/1975_2008/index.html. Accessed May 3, 2011.
2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277-300.
3. Mohler JL, Pantuck AJ. Use of abiraterone for prostate cancer. J Urol. 2011;185:783-786.
4. Molina A, Belldegrun A. Novel therapeutic strategies for castration resistant prostate cancer: inhibition of persistent androgen production and androgen receptor mediated signaling. J Urol. 2011;185:787-794.
5. Scher HI, Sawyers CL. Biology of progressive, castration- resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 2005;23:8253-8261.
6. Chung BC, Picado-Leonard J, Haniu M, et al. Cytochrome P450c17 (steroid 17 alpha-hydroxylase/ 17,20 lyase): cloning of human adrenal and testis cDNAs indicates the same gene is expressed in both tissues. Proc Natl Acad Sci U S A. 1987;84:407-411.
7. Picado-Leonard J, Miller WL. Cloning and sequence of the human gene for P450c17 (steroid 17 alphahydroxylase/ 17,20 lyase): similarity with the gene P250c21. DNA. 1987;6:439-448.
8. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66:2815-2825.
9. Auchus RJ. The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinol Metab Clin North Am. 2001;30:101-119, vii.
10. Barrie SE, Potter GA, Goddard PM, et al. Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alpha-hydroxylase/ C17-20 lyase). J Steroid Biochem Mol Biol. 1994;50:267- 273.
11. Attard G, Reid AH, A’Hern R, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009;27:3742-3748.
12. Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26:4563-4571.
13. Pal SK, Sartor O. Phase III data for abiraterone in an evolving landscape for castration-resistant prostate cancer. Maturitas. 2011;68:103-105