Prostate-specific antigen (PSA) response as a surrogate endpoint for overall survival (OS): Analysis of the TAX 327 Study comparing docetaxel plus prednisone with mitoxantrone plus prednisone in advanced prostate cancer

Abstract

4554 Background: The TAX 327 Study showed that metastatic hormone-refractory prostate cancer (HRPC) patients randomized to q3wk docetaxel (D) plus prednisone (P) had superior survival and higher PSA and pain response rates compared with q3wk mitoxantrone (M) plus P. We evaluated the relationship between PSA response and OS in this study to explore whether PSA response may be a surrogate endpoint for OS. Methods: Patients with histologically proven metastatic HRPC, clinical and/or PSA progression, were randomized to P (5 mg bid) plus either q3wk D (75 mg/m2 q3wks x 10 cycles), weekly D (30 mg/m2/wk x 5 of 6 wks x 5 cycles), or q3wk M (12 mg/m2 q3wks x 10 cycles). Only patients with a baseline PSA of at least 20 ng/mL were evaluated for PSA response (PSA decrease of at least 50% from baseline and confirmed at least 3 wks later). Results: A total of 1006 patients were randomized and median baseline PSA levels were similar among treatment arms (114, 108, and 123 ng/mL). A total of 873 patients (87%) were evaluable for PSA response (q3wk D, n=291; weekly D, n=282; M, n=300). No reductions in PSA levels on treatment were observed in 19% of D and 34% of M patients. PSA response rates were significantly higher with q3wk D and weekly D compared with M (45% and 48% vs. 32%, respectively; P<0.001 for both). Overall survival was improved in patients evaluable for PSA response receiving q3wk D, with a 25% reduction in the risk of death compared with M (HR, 0.75; 95% CI, 0.61 to 0.94; log rank, P=0.01). Although the weekly D arm had the highest PSA response rate, it was not associated with increased OS compared with M. Patients with a PSA response had a 60% reduction in mortality risk compared with PSA non-responders (HR, 0.40; 95% CI, 0.31 to 0.51; time-dependent Cox model, P<0.001). Approximately half the treatment effect on OS was accounted for by the PSA response. Conclusions: The beneficial effect of treatment on OS in the TAX 327 study is only partially explained by the PSA response. Therefore, PSA response cannot replace OS as the primary endpoint in Phase III trials in metastatic HRPC to confirm overall clinical benefit. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis sanofi-aventis Innovex, sanofi-aventis