Effects of abiraterone acetate on androgen signaling in castrate-resistant prostate cancer in bone

Abstract

Purpose: Persistent androgen signaling is implicated in castrate-resistant prostate cancer (CRPC) progression. This study aimed to evaluate androgen signaling in bone marrow-infiltrating cancer and testosterone in blood and bone marrow and to correlate with clinical observations.

Patients and methods: This was an open-label, observational study of 57 patients with bone-metastatic CRPC who underwent transiliac bone marrow biopsy between October 2007 and March 2010. Patients received oral abiraterone acetate (1 g) once daily and prednisone (5 mg) twice daily. Androgen receptor (AR) and CYP17 expression were assessed by immunohistochemistry, testosterone concentration by mass spectrometry, AR copy number by polymerase chain reaction, and TMPRSS2-ERG status by fluorescent in situ hybridization in available tissues.

Results: Median overall survival was 555 days (95% CI, 440 to 965+ days). Maximal prostate-specific antigen decline ≥ 50% occurred in 28 (50%) of 56 patients. Homogeneous, intense nuclear expression of AR, combined with ≥ 10% CYP17 tumor expression, was correlated with longer time to treatment discontinuation (> 4 months) in 25 patients with tumor-infiltrated bone marrow samples. Pretreatment CYP17 tumor expression ≥ 10% was correlated with increased bone marrow aspirate testosterone. Blood and bone marrow aspirate testosterone concentrations declined to less than picograms-per-milliliter levels and remained suppressed at progression.

Conclusion: The observed pretreatment androgen-signaling signature is consistent with persistent androgen signaling in CRPC bone metastases. This is the first evidence that abiraterone acetate achieves sustained suppression of testosterone in both blood and bone marrow aspirate to less than picograms-per-milliliter levels. Potential admixture of blood with bone marrow aspirate limits our ability to determine the origin of measured testosterone.

Fig 1.

Kaplan-Meier plot of proportion of patients (y-axis) discontinuing treatment over time (x-axis). Figure illustrates two different types of disease progression occurring either soon after initiation (gold box) or after prolonged treatment.

Fig 2.

Waterfall plot representing the percentage changes in serum prostate-specific antigen (PSA) concentrations. Maximal PSA reduction is represented on the right. Dashed lines represent 25%, −30%, and −90% PSA change.

Fig 3.

(A) Pretreatment intense nuclear androgen receptor (AR) expression in combination with CYP17 expression in the bone marrow–infiltrating tumor of a patient with treatment duration more than 4 months. (B) Pretreatment CYP17 expression in tumor is correlated with increased bone marrow aspirate (BMA) plasma testosterone (T) concentration in 19 cases with paired samples. MS, mass spectrometry.

Fig A1.

Correlation between circulating and bone marrow plasma testosterone by mass spectrometry. A strong correlation was found between circulating and bone marrow testosterone measured by mass spectrometry. Gold dots represent seven (17%) of 42 cases with higher bone marrow than circulating testosterone.