Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study

Abstract

BackgroundThere is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC.MethodsWe optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naïve and 98 post-docetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naïve patients treated with enzalutamide (Secondary cohort; PREMIERE trial).ResultsIn the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naïve and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74–9.10; P < 0.001 and HR 3.81; 95% CI 2.28–6.37; P < 0.001, respectively], PFS (HR 2.18; 95% CI 1.08–4.39; P = 0.03, and HR 1.95; 95% CI 1.23–3.11; P = 0.01, respectively) and rate of PSA decline ≥50% [odds ratio (OR), 4.7; 95% CI 1.17–19.17; P = 0.035 and OR, 5.0; 95% CI 1.70–14.91; P = 0.003, respectively]. AR mutations [2105T>A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naïve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47–not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94–9.68; P < 0.001), radiographic-PFS (rPFS) (HR 8.06; 95% CI 3.26–19.93; P < 0.001) and OS (HR 11.08; 95% CI 2.16–56.95; P = 0.004). Plasma AR was an independent predictor of outcome on multivariable analyses in both cohorts.ConclusionPlasma AR status assessment using ddPCR identifies CRPC with worse outcome to enzalutamide or abiraterone. Prospective evaluation of treatment decisions based on plasma AR is now required.Clinical Trial numberNCT02288936 (PREMIERE trial).

Testosterone levels and androgen receptor copy number variations in castration‐resistant prostate cancer treated with abiraterone or enzalutamide

“…Our data analysis confirmed the negative prognostic and predictive impact of copy number alterations of the AR gene for both abiraterone and enzalutamide groups of patients, as already described in literature …”

Androgen Receptor-Dependent and -Independent Mechanisms Involved in Prostate Cancer Therapy Resistance

“…Among the patients in the study discovery cohort who had received docetaxel ( n = 98), AR amplification was associated with a worse rate of PSA decline of ≥50%, shorter PFS (HR = 1.95; 95% CI, 1.23–3.11; p < 0.01), and shorter OS (HR = 3.81; 95% CI, 2.28–6.37; p < 0.001). These results were confirmed in their replication cohort of enzalutamide-treated patients from the PREMIERE trial ( n = 100), where patients with AR amplification experienced shorter PSA PFS (HR = 4.33; 95% CI, 1.94–9.68; p < 0.001), and OS (HR = 11.08; 95% CI, 2.16–56.95; p < 0.004) [54]. Additional studies of liquid biopsies have also demonstrated that AR amplification in ctDNA is associated with resistance to abiraterone and enzalutamide [55,56].…”

Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer

“…Using so-called 'liquid biopsies', primary and acquired resistance to AR-targeted therapy has been linked to amplification or mutation of the AR gene (3)(4)(5)(6)(7), and also to the expression (in circulating tumor cells) of truncated AR splice variants that display ligand-independent activity (8,9). The impact of these biomarkers in first-line mCRPC patients has not been adequately studied and it is unclear whether the detection of AR alterations in patient ctDNA can outperform standard clinical prognostic factors.…”