Androgen dynamics and serum PSA in patients treated with abiraterone acetate

Abstract

Background: We analyzed the potential of abiraterone acetate (henceforth abiraterone) to reduce androgen levels below lower limits of quantification (LLOQ) and explored the association with changes in PSA decline in metastatic castration-resistant prostate cancer (mCRPC) patients.

Methods: COU-AA-301 is a 2:1 randomized, double-blind, placebo-controlled study comparing abiraterone (1000 mg q.d.) plus low-dose prednisone (5 mg b.i.d.) with placebo plus prednisone in mCRPC patients post docetaxel. Serum testosterone, androstenedione and dehydroepiandrosterone sulfate from baseline to week 12 were measured by novel ultrasensitive two-dimensional liquid chromatography coupled to tandem mass spectrometry assays in a subset of subjects in each arm (abiraterone plus prednisone, n=80; prednisone, n=38). The association between PSA response (< or =50% baseline) and undetectable androgens (week 12 androgen level below LLOQ) was analyzed using logistic regression.

Results: A significantly greater reduction in serum androgens was observed with abiraterone plus prednisone versus prednisone (all P < or = 0.0003), reaching undetectable levels for testosterone (47.2% versus 0%, respectively). A positive association was observed between achieving undetectable serum androgens and PSA decline (testosterone: odds ratio=1.54; 95% confidence interval: 0.546-4.347). Reduction of androgens to undetectable levels did not occur in all patients achieving a PSA response, and a PSA response did not occur in all patients achieving undetectable androgen levels.

Conclusions: Abiraterone plus prednisone significantly reduced serum androgens, as measured by ultrasensitive assays and was generally associated with PSA response. However, androgen decline did not uniformly predict PSA decline suggesting ligand-independent or other mechanisms for mCRPC progression.

Figure 1

Box plots of serum androgen levels at baseline and at week 12. The horizontal line within the box indicates the median value and the open circle represents the mean value; the ends of the box show the 25 and 75% quartiles, and the whiskers show the minimum and maximum values. P-values for (a) testosterone, (b) androstenedione and (c) dehydroepiandrosterone sulfate (DHEAS) comparing treatment arms are <0.0001, 0.0003 and 0.0007, respectively.

Figure 2

Adjusted mean values (back-transformed) of serum androgens at baseline and week 12 in mixed-effect model, with the androgen level (after log transformation) regressed on treatment, visit and interaction between treatment and visit. Bars represent 95% confidence intervals. P-values for the adjusted mean difference for testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS) were 0.7322, 0.8432 and 0.3904 at baseline and <0.0001 for all androgens at week 12.

Figure 3

Waterfall plots for maximal PSA change in patients who did and did not achieve undetectable serum testosterone levels. If patient had decreased PSA value on at least one post-baseline visit, maximal PSA change=maximal PSA decrease. If patient had no decreased PSA value on any post-baseline visits, maximal PSA change=maximal PSA increase. *Truncated values.