Aims: AA is an androgen biosynthesis inhibitor that blocks CYP17 activity and improves overall survival(OS) in mCRPC patients post-docetaxel. Study COU-AA-302 evaluated the co-primary endpoints of radiographic progression-free survival(rPFS) and OS, in AA+prednisone(P) versus placebo(PL)+P in chemotherapy-naïve, asymptomatic or mildly symptomatic mCRPC patients.
Methods: 1088 patients (151 centers; 12 countries) were randomized 1:1 to AA(1 g)+P(5 mg BID) or PL+P; 132 patients enrolled across 18 sites in Australia. Median time-to-event endpoints were estimated using Kaplan-Meier method including LR statistic for inference. Lan-DeMets α-spending function was used for OS, with pre-specified alpha level 0.0008.
Results: Median follow up = 22.2 months. Clinical cutoff date(rPFS) was 20 Dec 2010 and 20 Dec 2011(other analyses). Median time for rPFS and OS was not reached(NR) for AA+P, while for PL+P these were 8.3 months, HR(95%CI) 0.43(0.35, 0.52), p<0.0001, and 27.2 months, HR(95%CI) 0.75(0.61, 0.93), p=0.0097, respectively. Median time to opiate use (cancer-related pain) was NR for AA+P and 23.7 months for PL+P, HR(95%CI) 0.69(0.57, 0.83), p=0.0001. Median time to chemotherapy initiation, to ECOG-PS deterioration and to PSA progression were statistically significant and favored AA+P versus PL+P, HR(95%CI):0.58(0.49, 0.69), p<0.0001; 0.82(0.71, 0.94), p=0.0053; and 0.49(0.42, 0.57), p<0.0001, respectively. Grade 3/4 AEs (AA+P, PL+P) (%): hypertension 3.9 versus 3.0; hypokalemia 2.4 versus 1.9; ALT↑ 5.4 versus 0.7; AST↑ 3.0 versus 0.9.
Conclusions: The Independent Data Monitoring Committee concluded that OS, rPFS and secondary endpoints favored AA arm and unanimously recommended unblinding the study and crossing patients from PL to AA at IA (43% of total events). IA results confirmed acceptable tolerability/safety profile of AA. This is the first randomized trial to demonstrate both OS and rPFS benefits in chemotherapy-naïve patients with mCRPC and that inhibition of persistent extragonadal androgen synthesis significantly delays initiation of cytotoxic chemotherapy.