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

V Conteduca, D Wetterskog, M T A Sharabiani, E Grande, M P Fernandez-Perez, A Jayaram, S Salvi, D Castellano, A Romanel, C Lolli, V Casadio, G Gurioli, D Amadori, A Font, S Vazquez-Estevez, A González Del Alba, B Mellado, O Fernandez-Calvo, M J Méndez-Vidal, M A Climent, I Duran, E Gallardo, A Rodriguez, C Santander, M I Sáez, J Puente, D Gasi Tandefelt, A Wingate, D Dearnaley, PREMIERE Collaborators, Spanish Oncology Genitourinary Group, F Demichelis, U De Giorgi, E Gonzalez-Billalabeitia, G Attard, V Conteduca, D Wetterskog, M T A Sharabiani, E Grande, M P Fernandez-Perez, A Jayaram, S Salvi, D Castellano, A Romanel, C Lolli, V Casadio, G Gurioli, D Amadori, A Font, S Vazquez-Estevez, A González Del Alba, B Mellado, O Fernandez-Calvo, M J Méndez-Vidal, M A Climent, I Duran, E Gallardo, A Rodriguez, C Santander, M I Sáez, J Puente, D Gasi Tandefelt, A Wingate, D Dearnaley, PREMIERE Collaborators, Spanish Oncology Genitourinary Group, F Demichelis, U De Giorgi, E Gonzalez-Billalabeitia, G Attard

Abstract

Background: There 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.

Methods: We 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).

Results: In 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.

Conclusion: Plasma 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 number: NCT02288936 (PREMIERE trial).

Keywords: abiraterone; androgen receptor; biomarker; castration-resistant prostate cancer; enzalutamide; plasma DNA.

© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.
Figure 1.
Association of plasma AR status with outcome in the primary cohort. Overall and progression-free survival for AR copy number normal, gain and mutated (Mut, p.L702H or p.T878A) chemotherapy-naïve (A, C) and post-docetaxel (B, D) castration-resistant prostate cancer patients treated with enzalutamide or abiraterone. Waterfall plots showing prostate-specific antigen (PSA) declines by AR copy number normal, gain and mutated (Mut, p.L702H or p.T878A) chemotherapy-naïve (E) and post-docetaxel (F) castration-resistant prostate cancer patients treated with abiraterone or enzalutamide (as marked). Bars clipped at maximum 100%.
Figure 2.
Figure 2.
Association of plasma AR status with outcome in PREMIERE cohort. Prostate-specific antigen (PSA) progression-free survival (A), radiographic (RAD) progression-free survival (B) and overall survival (C) for AR copy number normal versus AR gain patients. Waterfall plot (D) showing the magnitude of PSA decline by AR status. Bars clipped at maximum 100%.

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