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Background: Genomic alterations in DNA damage response (DDR) genes are common in metastatic castration-resistant prostate cancer (mCRPC). Understanding how these genomic events impact prognosis and/or treatment response is vital for optimising clinical outcomes., Methods: Targeted sequencing was performed on 407 plasma samples from 375 men with mCRPC. Using the CLIA-certified PredicineCARE™ cell-free DNA (cfDNA) assay, pathogenic alterations in 152 key genes (including 27 DDR-related genes) were assessed, as was the presence and mechanisms of biallelic loss in BRCA2., Findings: At least one DDR alteration was present in 34.5% (129/375) of patients (including monoallelic alterations). The most frequently altered DDR genes were BRCA2 (19%), ATM (13%), FANCA (5%), CHEK2 (5%) and BRCA1 (3%). Patients with BRCA alterations, especially BRCA2, had significantly worse progression-free survival (PFS) (Hazard ratio (HR) 3.3 [95% CI 1.9-6.0]; Cox regression p < 0.001), overall survival (HR 2.2 [95% CI 1.1-4.5]; Cox regression p = 0.02) and PSA response rates to androgen receptor (AR) pathway inhibitors (32% vs 60%, chi-square p = 0.02). BRCA-deficient tumours were also enriched for alterations within multiple genes including in the AR and PI3K pathways. Zygosity of BRCA2 alterations had no discernible impact on clinical outcomes, with similarly poor PFS for monoallelic vs biallelic loss (median 3.9 months vs 3.4 months vs copy neutral 9.8 months)., Interpretation: These data emphasise that the BRCA genes, in particular BRCA2, are key prognostic biomarkers in mCRPC. The clinical utility of BRCA2 as a marker of poor outcomes may, at least in cfDNA assays, be independent of the zygosity state detected. Enrichment of actionable genomic alterations in cfDNA from BRCA-deficient mCRPC may support rational co-targeting strategies in future clinical trials., Funding: Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study., Competing Interests: Declaration of interests M.K received travel/accommodation from Celgene; D.C, T.Z, P.D and S.J are stockholders in Predicine, Inc.; L.G.H received research funding from Astellas Pharma, travel/accommodation from Astellas Pharma and Pfizer, honoraria from Janssen and Astellas and is on the scientific advisory board from Imagion; Kate Mahon received travel/accommodation from Astellas Pharma; E.M.K received honoraria from Janssen, research funding from Astellas Pharma and AstraZeneca, and travel/accommodations from Astellas Pharma, Pfizer, and Ipsen; A.A.A is a consultant for Astellas Pharma, Janssen, Novartis and Aculeus Therapeutics, is on the speakers bureau for Astellas Pharma, Janssen, Novartis, Amgen, Ipsen, Bristol Myers Squibb, Merck Serono and Bayer, received honoraria from Astellas Pharma, Janssen, Novartis, Tolmar, Amgen, Pfizer, Telix, Sanofi, Astra Zeneca, Merck Serono, Bristol Myers Squibb, Ipsen, Bayer, Pfizer, Noxopharm, Merck Sharpe Dohme, and Aculeus Therapeutics, is on the Scientific Advisory Board for Astellas Pharma, Novartis, Sanofi, AstraZeneca, Tolmar, Pfizer, Telix, Merck Serono, Janssen, Bristol Myers Squibb, Ipsen, Bayer, Merck Sharpe Dome, Amgen, and Noxopharm, travel/accommodations from Astellas, Merck Serono, Amgen, Novartis, Janssen, Tolmar, Pfizer and Bayer, and received research funding from Astellas (investigator), Merck Serono (investigator), Astra Zeneca (investigator), Bristol Myers Squibb (institutional), Astra Zeneca (institutional), Aptevo Therapeutics (institutional), Glaxo Smith Kline (institutional), Pfizer (institutional), MedImmune (institutional), Astellas (institutional), SYNthorx (institutional), Bionomics (institutional), Sanofi Aventis (institutional), Novartis (institutional), Ipsen (institutional), Exelixis (institutional), Merck Sharpe Dome (institutional), Janssen (institutional), Eli Lilly (institutional), Gilead Sciences (institutional), Merck Serono (institutional), Hinova (institutional)., (Copyright © 2023. Published by Elsevier B.V.)

Total plasma cell-free DNA (cfDNA) levels were recently shown to be prognostic in two large phase III trials of taxane chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). However, whether cfDNA concentration is predictive of treatment outcomes with androgen receptor pathway inhibitors (ARPIs) is unknown. We quantified plasma cfDNA levels at baseline (n = 74) and 4 weeks on treatment (n = 56) in a prospective cohort of mCRPC patients treated with the ARPIs abiraterone acetate or enzalutamide. Elevated total cfDNA concentration (log 10 ) at both baseline (hazard ratio [HR] 5.5, p < 0.001) and week 4 (HR 7.5, p < 0.001) was a significant negative prognostic factor for overall survival (OS), a finding maintained after adjustment for plasma circulating tumour DNA fraction. Unexpectedly, a rise in cfDNA concentration from baseline to week 4 was also associated with significantly improved OS (HR 0.14, p = 0.003). Conversely, patients with ≥29.8% decrease in cfDNA from baseline (optimal cut-point) had significantly shorter median OS than the rest of the cohort (10.5 vs 25.7 mo, p = 0.03). Collectively, our findings point to the potential prognostic utility of quantifying cfDNA in mCRPC and in particular suggest that dynamic changes in total cfDNA levels may be a novel early predictive biomarker for therapeutic outcome in ARPI-treated patients. PATIENT SUMMARY: We measured the levels of total cell-free DNA (cfDNA) in the plasma of patients with metastatic prostate cancer prior to and 4 weeks after starting new hormonal drugs. We found that patients with higher levels of cfDNA or a higher proportion of tumour-derived DNA at baseline had worse outcomes on hormonal therapies. Similarly, higher levels of cfDNA at 4 weeks into therapy were also associated with worse outcomes. However, a rise in total cfDNA levels at 4 weeks compared with baseline was linked with better outcomes. Measuring changes in cfDNA concentration may be a useful and technically straightforward early way to predict how patients will respond to treatment in metastatic prostate cancer., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Tumor tissue from metastatic castration-resistant prostate cancer (mCRPC) harbors frequent copy number variations (CNVs) in the PTEN-PI3K-AKT pathway. However, identifying CNVs in plasma cell-free DNA (cfDNA) has proven to be challenging. With emerging data supporting Akt inhibition in PTEN-deficient mCRPC, we profiled PTEN-PI3K-AKT pathway aberrations in patients with mCRPC using a novel cfDNA assay optimized for CNV detection., Methods: A next-generation sequencing-based cfDNA assay was used to profile 231 patients with mCRPC from two independent cohorts (Australian, n = 78; United States, n = 153). PTEN-PI3K-AKT pathway genomic aberrations were correlated with clinical outcomes, including progression-free survival and overall survival (OS)., Results: PTEN loss and PIK3CA gain were detected in 37% (85 of 231) and 17% (39 of 231) of patients, respectively. Poorer outcomes were observed in patients with PTEN-PI3K-AKT pathway aberrations, including those with dual PTEN loss and PIK3CA gain (hazard ratio 2.3, 95% CI 1.2 to 4.4). Cumulative CNV burden in the PTEN-PI3K-AKT and androgen receptor (AR) pathways was associated with significantly worse clinical outcomes (0 v 1 v ≥ 2 CNVs in Australian cohort: median OS 33.5 v 17.2 v 9.7 months, P < .001; 0 v 1 v ≥ 2 CNVs in US cohort: median OS 35.5 v 14.3 v 9.2 months, P < .001). Notably, 21% (31 of 146) of PTEN -neutral patients harbored alternative PTEN-PI3K-AKT pathway aberrations., Conclusion: PTEN-PI3K-AKT pathway CNVs were readily detected using our cfDNA assay, with the prevalence of PTEN loss comparable with tissue-based studies. Additional PTEN-PI3K-AKT pathway aberrations were found in one fifth of PTEN -neutral cases. Concurrent CNVs in the PTEN-PI3K-AKT and AR pathways portended poor survival, and identifying this high-risk patient subset for dual AR/Akt inhibition may optimize precision treatment with Akt inhibitors in mCRPC., Competing Interests: Arun A. Azad Honoraria: Janssen, Astellas Pharma, Novartis, Tolmar, Amgen, Pfizer, Bayer, Telix Pharmaceuticals, Bristol-Myers Squibb, Merck Serono, AstraZeneca, Sanofi, Ipsen, Merck Sharp & Dohme, Noxopharm Consulting or Advisory Role: Astellas Pharma, Novartis, Janssen, Sanofi, AstraZeneca, Pfizer, Bristol-Myers Squibb, Tolmar, Telix Pharmaceuticals, Merck Sharp & Dohme, Bayer, Ipsen, Merck Serono, Amgen, Noxopharm Speakers' Bureau: Astellas Pharma, Novartis, Amgen, Bayer, Janssen, Ipsen, Bristol-Myers Squibb, Merck Serono Research Funding: Astellas Pharma, Merck Serono, Novartis, Pfizer, Bristol-Myers Squibb, Sanofi, AstraZeneca, GlaxoSmithKline, Aptevo Therapeutics, MedImmune, Bionomics, Synthorx, AstraZeneca, Astellas Pharma, Ipsen, Merck Serono Travel, Accommodations, Expenses: Astellas Pharma, Sanofi, Merck Serono, Amgen, Janssen, Tolmar, Pfizer No other potential conflicts of interest were reported.Arun A. Azad Honoraria: Janssen, Astellas Pharma, Novartis, Tolmar, Amgen, Pfizer, Bayer, Telix Pharmaceuticals, Bristol-Myers Squibb, Merck Serono, AstraZeneca, Sanofi, Ipsen, Merck Sharp & Dohme, Noxopharm Consulting or Advisory Role: Astellas Pharma, Novartis, Janssen, Sanofi, AstraZeneca, Pfizer, Bristol-Myers Squibb, Tolmar, Telix Pharmaceuticals, Merck Sharp & Dohme, Bayer, Ipsen, Merck Serono, Amgen, Noxopharm Speakers' Bureau: Astellas Pharma, Novartis, Amgen, Bayer, Janssen, Ipsen, Bristol-Myers Squibb, Merck Serono Research Funding: Astellas Pharma, Merck Serono, Novartis, Pfizer, Bristol-Myers Squibb, Sanofi, AstraZeneca, GlaxoSmithKline, Aptevo Therapeutics, MedImmune, Bionomics, Synthorx, AstraZeneca, Astellas Pharma, Ipsen, Merck Serono Travel, Accommodations, Expenses: Astellas Pharma, Sanofi, Merck Serono, Amgen, Janssen, Tolmar, Pfizer No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Background: The androgen receptor (AR) remains a critical driver in metastatic castration-resistant prostate cancer (mCRPC). Profiling AR aberrations in both circulating DNA and RNA may identify key predictive and/or prognostic biomarkers in the context of contemporary systemic therapy., Objective: To profile AR aberrations in circulating nucleic acids and correlate with clinical outcomes., Design, Setting, and Participants: We prospectively enrolled 67 mCRPC patients commencing AR pathway inhibitors (ARPIs; n = 41) or taxane chemotherapy (n = 26). Using a first-in-class next-generation sequencing-based assay, we performed integrated cell-free DNA (cfDNA) and cell-free RNA (cfRNA) profiling from a single 10 ml blood tube., Outcome Measurements and Statistical Analysis: Kaplan-Meier survival estimates and multivariable Cox regression analyses were used to assess associations between clinical outcomes and the following AR aberrations: copy number variation, splice variants (AR-V7 and AR-V9) and somatic mutations., Results and Limitations: Cell-free DNA and cfRNA were successfully sequenced in 67 (100%) and 59 (88%) patients, respectively. Thirty-six (54%) patients had one or more AR aberrations. AR gain and cumulative number of AR aberrations were independently associated with clinical/radiographic progression-free survival (PFS; hazard ratio [HR] 3.2, p = 0.01 and HR 3.0 for 0 vs ≥2, p = 0.04) and overall survival (HR 2.8, p = 0.04 and HR 2.9 for 0 vs ≥2, p = 0.03). Notably, concurrent AR gain and AR splice variant expression (AR gain/AR-V+) was associated with shorter prostate-specific antigen PFS on both ARPIs (HR 6.7, p = 0.009) and chemotherapy (HR 3.9, p = 0.04). Importantly, key findings were validated in an independent cohort of mCRPC patients (n = 40), including shorter OS in AR gain/AR-V+ disease (HR 3.3, p = 0.02). Limitations include sample size and follow-up period., Conclusions: We demonstrate the utility of a novel, multianalyte liquid biopsy assay capable of simultaneously detecting AR alterations in cfDNA and cfRNA. Concurrent profiling of cfDNA and cfRNA may provide vital insights into disease biology and resistance mechanisms in mCRPC., Patient Summary: In this study of men with advanced prostate cancer, DNA and RNA abnormalities in the androgen receptor detected in blood were associated with poor outcomes on available drug treatments. This information could be used to better guide treatment of advanced prostate cancer., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)