ZYTIGA in combination with prednisone was initially FDA indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel. Abiraterone acetate (ZYTIGA) is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.This effect is independent of previous exposure to docetaxel. However, the study that led to the FDA approval was in patients who received docetaxel as first line for hormone resistant prostate cancer(HRPC). On 21 July 2011 the European Committee for Medicinal Products for Human Use (CHMP) adopted the same indication as the FDA. More receently, ZYTIGA was FDA indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.
Because prostate cancer is a disease of the elderly, inability to tolerate docetaxel is a common clinical presentation of patient with HRPC. A second, large Phase III clinical trial was presented at the 48th annual meeting of the American Society of Clinical Oncology (ASCO)(2012). The COU-AA-302 Phase 3 study investigated the use of ZYTIGA® plus prednisone compared to placebo plus prednisone in asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer (mCRPC) who have not received chemotherapy. The data demonstrated a statistically significant improvement in radiographic progression-free survival (rPFS) in the ZYTIGA® plus prednisone arm of the study compared to the placebo plus prednisone (control) arm.
Phase II evidence is also generally positive. Ryan et al recommend the combination of a low-dose corticosteroid with abiraterone acetate in chemotherapy-naive patients to optimize the safety profile. Prechemotherapy phase I/II study of abiraterone acetate also found tumor responses after the addition of low-dose dexamethasone in patients who experienced progression while on single-agent abiraterone acetate. I reference several other papers that confirm activity in patients who did not receive docetaxel. NCCN update 2011 states as Category 2B that Zytiga is recommended in patients who are not candidates for docetaxel based chemotherapy. On 12/1012, FDA approved Zytiga for late-stage prostate cancer patients who have not yet received chemotherapy, based on study results showing it can extend life by up to five months when taken by men in that group.
Ryan CJ et al,(2010) Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol 28:1481–1488.
Reid AH et al, (2010) Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol 28:1489–1495.
Danila DC et al, (2010) Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol 28:1496–1501.
(2009) Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol 27:3742–3748.
Attard G et al, (2008) Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol26:4563–4571.