Future directions in the treatment of androgen-independent prostate cancer

Abstract

The rationale for evaluating the taxanes in hormone-refractory prostate cancer (HRPC) is strong. Preclinical data demonstrate that docetaxel is a potent inhibitor of bcl-2, an antiapoptotic gene implicated in the progression of HRPC and the development of chemotherapy resistance. The results of early clinical trials with docetaxel suggested that it could improve survival; trials in which docetaxel was combined with estramustine appeared even more promising. The Southwest Oncology Group intergroup trial (SWOG 9916) phase III was developed to compare the combination of docetaxel and estramustine to mitoxantrone-prednisone in men with HRPC. A total of 684 eligible patients were enrolled. Median survival was significantly improved with docetaxel-estramustine (17.5 months vs 15.6 months with mitoxantrone-prednisone, P = .02), and the relative risk of death was reduced by 20%. Progression-free survival was improved from 3.2 months with mitoxantrone-prednisone to 6.3 months with docetaxel-estramustine (P < .001). Significantly more patients treated with docetaxel-estramustine had a prostate-specific antigen response decline of at least 50% compared with those treated with mitoxantrone-prednisone (50% vs 27%, P < .001). Toxicity was more common in the docetaxel-estramustine arm, likely due to estramustine. Other docetaxel-based regimens under investigation include combinations with calcitriol, thalidomide, or bevacizumab. With docetaxel/prednisone approved by the US Food and Drug Administration (FDA) as first-line treatment of HRPC, ongoing and future trials will build on its success by evaluating a number of docetaxel-based combinations in various prostate cancer settings. Other novel agents, including the oral platinum analog satraplatin, are being investigated as second-line treatment for HRPC.