Serum androgens as prognostic biomarkers in castration-resistant prostate cancer: results from an analysis of a randomized phase III trial

Abstract

Purpose: In the phase III study COU-AA-301, abiraterone acetate (AA) plus prednisone (P) prolonged overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel administration. In this article, we investigate the relationship between baseline serum androgen (SA) levels and OS.

Patients and methods: COU-AA-301 is a randomized, double-blind study of AA (1,000 mg every day) plus P (5 mg by mouth twice daily; n = 797) versus P alone (n = 398). Randomization was stratified by Eastern Cooperative Oncology Group performance status (0 to 1 v 2), pain (Brief Pain Inventory-Short Form over past 24 hours: 4 to 10, present; v 0 to 3, absent), prior chemotherapy (1 v 2), and progression (prostate-specific antigen v radiographic). Association of baseline SA (testosterone, androstenedione, dehydroepiandrosterone sulfate), was measured by ultrasensitive liquid-liquid extraction or protein precipitation and two-dimensional liquid chromatography coupled to mass spectrometry, with OS determined by bivariate and multivariable Cox models. OS was examined with SA as greater than median and less than or equal to the median.

Results: Median survival increased with each quartile increase in testosterone level regardless of treatment arm. SA levels at baseline strongly associated with survival (P < .0001) in bivariate and multivariable analyses. Longer survival was observed for patients with SA above median compared with below median in both the AA and P arms (eg, testosterone, AA; hazard ratio, 0.64; 95% CI, 0.53 to 0.77; P < .0001). Treatment with AA led to longer survival versus P alone in the above- or below-median group for all androgens.

Conclusion: SA, measured with a novel ultrasensitive assay in COU-AA-301, is prognostic for OS and may be useful for risk stratification in mCRPC clinical trials.

Trial registration: ClinicalTrials.gov NCT00638690.

Fig 1.

CONSORT diagram. A, androstenedione; AA, abiraterone acetate; DHEAS, dehydroepiandrosterone sulfate; ITT, intent-to-treat; P, prednisone; T, testosterone.

Fig 2.

Distribution of serum androgen levels at baseline in patients with metastatic castration-resistant prostate cancer enrolled onto the COU-AA-301 phase III trial. (A) Testosterone, (B) androstenedione, and (C) dehydroepiandrosterone sulfate (DHEAS).

Fig 3.

Overall survival as a function of baseline testosterone stratified by quartiles (Q). (*) Median overall survival in months. All analyses were adjusted by baseline stratification factors.

Fig 4.

Overall survival (OS) as a function of baseline androgen status stratified above median (AM) or below median (BM) in patients treated with abiraterone acetate (AA) plus prednisone (P) or placebo plus P. (A) Testosterone, (B) androstenedione, and (C) dehydroepiandrosterone sulfate. All analyses were adjusted by baseline stratification factors. HR, hazard ratio; mos, months.

Fig A1.

Representative liquid-liquid extraction or protein precipitation and two-dimensional liquid chromatography coupled to mass spectrometry chromatograms for testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS). (A), (C), and (E) represent calibrators at the lower limit of quantification for testosterone (0.2 ng/dL; signal to noise [S:N], 70), androstenedione (0.25 ng/dL; S:N, 102), and DHEAS (0.1 μg/dL; S:N, 494). (B), (D), and (F) represent specimens close to the Q1 androgen quartile for testosterone (2.5 ng/dL; S:N, 334), androstenedione (10.1 ng/dL; S:N, 3,355), and DHEAS (6.0 μg/dL; S:N, 18,008). cps. counts per second.

Fig A2.

Relationship of distribution of baseline androgen levels and estimate of median survival in all patients. (A) Testosterone; (B) androstenedione; (C) dehydroepiandrosterone sulfate (DHEAS).