Association of serum androgen and drug levels with response to abiraterone.

Abstract

208 Background: The association of serum ABI and androgen levels with clinical efficacy in men with CRPC is not well understood. Methods: We measured androgens, ABI and its key metabolites (D4A and 5α) in serum at 4, 8, and 12 weeks (wks) in 29 men with CRPC treated with ABI (for associations with PSA response and time to radiographic progression (TTP)); in 58 men from a study of ABI without prednisone; and in 22 men with localized PCa treated with neoadjuvant ABI for 3 months prior to definitive therapy (including prostate levels). Results: Median (Med) TTP was 36 mo (4-104). 52% had a PSA response (decline >30% at wk12), and 34% early progression (TTP < 6 mo). There was no difference in ABI (at wk4 or average of wks 4/8/12) in men with v without PSA response, or in men with early v late TTP. D4A and 5α at wk4 were higher in early v late progressors (2.9 v 1.5 ng/ml, p=0.05; 10.35 v 6.7 ng/ml, p=0.08). TTP was longer in the lowest v highest quartile of drug levels (ABI: 4wk 48 v 30 wks; 8wk 60 v 16 wks; D4A: 4wk 40 v 16 wks; 8wk 60 v 28 wks; 5a: 8wk 41 v 16 wks, p<0.05 all). The lowest quartile of pre-ABI androgens had shorter TTP (DHEAS 24 v 52 wks; T 30 v 52 wks, p<0.05 both). In both CRPC studies, men with pre-ABI DHEAS > Med had 2-5x higher levels of all steroids (DHEAS 110 v 22 ug/dl, DHEA 184 v 49 ng/dl, AED 46 v 26 ng/dl, and T 9 v 4.9 ng/dl, p<0.05 all). While markedly suppressed by ABI in both groups, levels remained detectable and higher in the ‘high’ group (DHEAS 5.4 v 1.6 ug/dl; DHEA 1.3 v 0.6 ng/dl; p<0.05 both) regardless of ABI levels (37.4 ng/ml, 2.75-89; 36.8 ng/ml, 8.7-121, p=ns). Androgens in serum and prostate after neoadjuvant ABI were higher in men with pre-ABI eugonadal serum DHEAS levels > v < Med, regardless of serum or tissue ABI levels on treatment. Conclusions: In men with pre-ABI serum DHEAS < Med, androgens were suppressed even at low serum ABI levels, whereas in men with pre-ABI DHEAS > Med, levels were not completely suppressed even at high ABI levels, explaining the minimal impact of dose escalated ABI and observed noninferiority of low dose ABI previously reported in men with CRPC. The shorter TTP in the highest quartiles of ABI, D4A and 5α may reflect increased conversion to the AR agonist metabolite 5α. Men with pre-ABI DHEAS > Med may warrant stratification to more potent/combination therapy. Clinical trial information: NCT01503229.