Outperforms Other Androgen Receptor Biomarkers to Predict Abiraterone or Enzalutamide Outcome in Metastatic Castration-Resistant Prostate Cancer.

Purpose: To infer the prognostic value of simultaneous androgen receptor () and profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of signaling inhibitors (ARSi). Between March 2014 and April 2017, we recruited patients with mCRPC ( = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of and was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox regression models.

Results: Overall, no single perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18-3.00; = 0.008], and outperformed ARV expression and detection of genomic alterations. Using Cox coefficient analysis of clinical parameters and status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; < 0.0001), which was validated in an independent mCRPC cohort ( = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; < 0.0001).

Conclusions: In an all-comer cohort, tumor burden estimates and outperform any perturbation to infer prognosis.See related commentary by Rebello et al., p. 1699.