Clinical and Biological Characterisation of Localised High-risk Prostate Cancer: Results of a Randomised Preoperative Study of a Luteinising Hormone-releasing Hormone Agonist with or Without Abiraterone Acetate plus Prednisone

Abstract

Optimal therapeutic strategy remains an unmet need in localised high-risk prostate cancer (LHRPC). Androgen biosynthesis inhibition in the preoperative setting may improve outcomes. In this single-centre randomised trial, we looked at therapy outcomes of preoperative treatment with abiraterone acetate+prednisone (AAP)+luteinising hormone-releasing hormone agonist (LHRHa) or LHRHa alone followed by radical prostatectomy in 65 men. We did not see a significant difference of organ-confined carcinoma (p=0.27). However, tumour volume measures were significantly lower for AAP+LHRHa treatment (p≤0.001). Of note, lower tumour epithelium volume correlated with improved biochemical recurrence-free survival at ≥4-yr follow-up (p=0.0014). Tumours pretreated with AAP+LHRHa had lower proliferation and androgen signalling expression than LHRHa. On multivariate analysis, glucocorticoid receptor (GR) overexpression correlated with persistent tumours in AAP+LHRHa (p=0.018). The presence of nuclear androgen receptor splice variant (nARV7) correlated with persistent tumours in both arms. No new safety signals were observed. This is the first study investigating the role of preoperative AAP+LHRHa versus LHRHa alone in LHRPC. We report significant cytoreduction by tumour volume measures inversely correlating with biochemical relapse. Validation of these proposed tumour volume measures is planned. A potential role of GR in resistance to androgen biosynthesis inhibition warrants further study. PATIENT SUMMARY: This is the first study of abiraterone acetate plus leuprolide versus leuprolide alone in high-risk localised prostate cancer followed by prostatectomy. Patients in the combination arm had a significantly smaller tumour size.

Keywords: Abiraterone acetate; Androgen deprivation therapy; Androgen receptor; Androgen receptor splice variant; Glucocorticoid receptor; High-risk localised prostate cancer; Neoadjuvant; Preoperative; Radical prostatectomy; Tumour volume.

Fig. 1 -

Residual tumour quantification: (A) tumour volume, (B) tumour cell density, and (C) tumour epithelium volume. The bars represent the median for tumour quantification. AAP = abiraterone acetate plus prednisone; LHRHa = luteinising hormone-releasing hormone agonist.

Fig. 2 -

Differential expression of selected markers of interest between treatment arms. (A) Heatmap of markers ordered by domain of interest, including cell cycle regulation and neuroendocrine markers (CD56, chromogranin A, Ki67, PTCH), microenvironment interactions (Shh, p-cMET, p-Src, GR), and AR signalling (ARv7, CYP17, PSA, AR-C terminal, AR-N terminal). The expression of each marker in each sample is represented by the number of standard deviations above (red) or below (green) the mean for that gene across all samples. (B) Protein expression of select markers. AAP = abiraterone acetate plus prednisone; AR = androgen receptor, GR = glucocorticoid receptor, LHRHa = luteinising hormone-releasing hormone agonist; PSA = prostate-specific antigen.

Fig. 3 -

GR expression by immunohistochemistry in the AAP + LHRHa arm. (A) GR expression in tumour AAP + LHRHa-treated tumour samples. (B) Association of GR expression and tumour volume epithelium. (C) Association of GR expression and cortisol levels. Box plots represent 25th and 75th percentiles; whiskers extend to the minimum and maximum values. Median is indicated by the line within the box. AAP = abiraterone acetate plus prednisone; GR = glucocorticoid receptor; LHRHa = luteinising hormone-releasing hormone agonist.