BERKELEY, CA (UroToday.com) - The design, development, and recent approval of enzalutamide for use in metastatic castration-resistant prostate cancer highlights a shift in the treatment paradigm for this disease. Since the 1940s when it was shown that surgical orchiectomy could lead to prostate cancer regression,[1] androgen suppression, by targeting gonadotropin-releasing hormone, has been the cornerstone of treatment for metastatic prostate cancer. While this approach often produces a PSA response, resistance commonly develops rendering the disease castration-resistant, and shifting the therapeutic approach to taxane-based chemotherapy. The belief that once castration resistance ensues, the androgen receptor ceases to be a therapeutic target has recently been challenged. Studies have shown that prostate cancer growth remains dependent on androgen supply even after the disease becomes unresponsive to standard hormonal therapies.[2] Enzalutamide is an oral, second-generation androgen-receptor inhibitor that targets multiple steps in the androgen-signaling pathway.[3, 4] The efficacy and favorable side-effect profile were demonstrated in the Phase III AFFIRM trial in patients with metastatic castration-resistant prostate cancer who had failed prior docetaxel-containing regimens.[5] While the approval of enzalutamide currently resides in the post-docetaxel space, there are promising reports of this drug being used in an earlier setting[6, 7] as well as the recently presented PREVAIL trial in the pre-chemotherapy metastatic setting, and we will soon see the landscape of prostate cancer treatment changed forever.
This review article summarizes the historical context for the development of enzalutamide, the clinical trials leading to its approval, and its place in therapy amongst several recently approved agents for metastatic castration-resistant prostate cancer.
References:
- Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin. 1972;22(4):232-40.
- Attard G, Belldegrun AS, de BonoJS. Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer. BJU Int. 2005;96(9):1241-6.
- Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324(5928):787-90.
- Guerrero J, Alfaro IE, Gomez F, Protter AA, Bernales S. Enzalutamide, an androgen receptor signaling inhibitor, induces tumor regression in a mouse model of castration-resistant prostate cancer. Prostate. 2013;73(12):1291-305.
- Scher H, Fizazi K, Saad F, et al. Association of baseline corticosteroid with outcomes in a multivariate analysis of the Phase 3 AFFIRM study of Enzalutamide (ENZA), an androgen receptor signaling inhibitor (ARSI). Ann Oncol. 2012;23(Suppl 9):Abstr 899PD.
- Tombal B, Borre M, Rathenborg P, et al. Enzalutamide monotherapy: Phase II study results in patients with hormone-naïve prostate cancer. J Clin Oncol. 2013;31(Suppl)Abstr 5001.
- Smith MR, Borre M, Rathenborg P, et al. Efficacy and safety of enzalutamide (ENZA) monotherapy in hormone-naïve prostate cancer (HNPC). J Clin Oncol. 2013;31(Suppl 6):Abstr 63.
Written by:
Ashley Freeman, MD and Jeanny B. Aragon-Ching, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Division of Hematology/Oncology, Department of Medicine, George Washington University Medical Center, Washington, DC USA
Metastatic castration-resistant prostate cancer: Critical review of enzalutamide - Abstract
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