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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-naþve and 98 postdocetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naþve patients treated with enzalutamide (Secondary cohort; PREMIERE trial). Results: In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naþve 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 decliné50% [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]. ARmutations [2105T=A (p.L702H) and 2632A➛G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naı^#245;e 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). [ABSTRACT FROM AUTHOR]

Abiraterone and enzalutamide represent the standard treatment in castration resistance prostate cancer (CRPC) patients, however, some patient displays primary resistance, and several studies investigated the role of the androgen receptor (AR) as a predictive biomarker of response to treatment (Conteduca, et al. Ann Oncol. 2017;28(7):1508-1516; Del Re, et al. BJU Int. 2019 doi: 10.1111/bju.14792). The present study is aimed at evaluating the role the AR in liquid biopsy to predict response to hormone treatment in CRPC patients. Six ml of plasma samples were collected from patients affected by castration-resistant prostate cancer before the beginning of first-line hormonal treatment. Circulating free DNA and exosome-RNA were isolated for analysis of AR-gain and AR-V7 by digital droplet PCR. Eighty-four CRPC were prospectively enrolled in this study. 40 patients received abiraterone and 44 patients received enzalutamide as first-line hormonal therapy. AR-gain was detected in 12 patients (14.3%) and 36% were AR-V7+ at baseline. Median PFS and OS were significantly longer in AR-V7- vs AR-V7+ patients (24.3 vs 5.4 months, p < 0.0001; not reached vs 16.2 months, p < 0.0001, respectively). Patients carrying of the AR-gain had a median PFS of 4.8 vs 24.3 months of non-gained AR patients (P < 0.0001). Median OS was significantly longer in AR-no gain vs AR-gain (not reached vs 8.17 months, p < 0.0001). A significant correlation between AR-V7 and AR-gain was observed (r = 0.28; p = 0.01). In the univariate model, known risk factors for progression such as AR-V7, AR-gain, neutrophil/lymphocyte ratio and metastatic spread to either bone or lymph nodes were analysed. In multivariable analysis, only AR-V7 and AR gain were confirmed as independent predictive biomarkers (p < 0.0001 and p = 0.004, respectively). The present study demonstrates that cfDNA and exosomal RNA are a reliable source of AR-variants and their detection predicts resistance to anti-hormonal therapy. The method is sensitive, fast and represents a convenient alternative to other potentially more expensive and less sensitive approaches. The authors. Has not received any funding. V. Conteduca: Travel/Accommodation/Expenses: Janssen; Travel/Accommodation/Expenses: Astellas; Travel/Accommodation/Expenses: Sanofi; Travel/Accommodation/Expenses: Bayer. U.F.F. De Giorgi: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Sanofi; Advisory/Consultancy: Astellas; Advisory/Consultancy: Byer; Advisory/Consultancy: BMS; Honoraria (self): Ipsen; Advisory/Consultancy: Janssen; Advisory/Consultancy: Merk; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Sanofi; Travel/Accommodation/Expenses: BMS; Travel/Accommodation/Expenses: Ipsen; Travel/Accommodation/Expenses: Janssen; Travel/Accommodation/Expenses: Pfizer. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Tumour DNA circulates in the plasma of cancer patients admixed with DNA from non-cancerous cells. The genomic landscape of plasma tumour DNA has been characterised in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome in mCRPC has not been extensively explored. Methods mCRPC plasma samples collected from three different centres were concurrently subject to targeted genomic and pan-genome methylation profiling. The treatment courses and outcomes were also obtained. Tumour fraction of each plasma sample was estimated based on heterogyzous SNPs located in two truncal genomic deletions (8q21 and 21q22). Targeted methylome was performed using pre-designed capture panel followed by deep sequencing. We integrated genomic information with methylation data to extract methylation signatures associated with genomically-determined tumour fraction or private to individual's tumour. Results Principal component analysis on the mCRPC plasma methylome indicated that the main contributor to methylation variance (principal component one, or PC1) was strongly correlated with genomically-determined tumour fraction (r=-0.96; P < 10-9), characterised by hypermethylation of targets of the polycomb repressor complex 2 components. Further deconvolution of the top PC1 correlated segments revealed that these segments comprised of methylation patterns specific to either prostate cancer or prostate normal epithelium. To extract information specific to an individual's cancer, we then focused on an orthogonal methylation signature which revealed enrichment for androgen receptor (AR) binding sequences and where hypomethylation of these segments associated with AR copy number gain. Individuals harbouring this methylation pattern had a more aggressive clinical course, including a significantly shorter overall survival (HR = 8.18, 95% CI = 1.93–34.76, P = 0.0044). Conclusions Plasma methylome analysis can accurately quantitate tumour fraction and identify distinct biologically-relevant mCRPC phenotypes associated with worse clinical outcome. Clinical trial identification Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy (REC 2192/2013) Royal Marsden, London, UK (REC 04/Q0801/6) PREMIERE trial (EudraCT: 2014-003192-28, NCT02288936). Legal entity responsible for the study The authors. Funding Cancer Research UK (CRUK), Prostate Cancer Foundation (PCF). Disclosure V. Conteduca: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Janssen-Cilag; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis. E. Gonzalez-Billalebeita: Honoraria (self): Astellas; Honoraria (self): Janssen-Cilag; Honoraria (self): Sanofi-Aventis. U.D. Giorgi: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Janssen-Cilag,; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis. G. Attard: Honoraria (self): Institute of Cancer Research; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Medivation; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Arno. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]