<i>TP53</i> Outperforms Other Androgen Receptor Biomarkers to Predict Abiraterone or Enzalutamide Outcome in Metastatic Castration-Resistant Prostate Cancer.

Abstract

To infer the prognostic value of simultaneous androgen receptor (<i>AR</i>) and <i>TP53</i> profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of <i>AR</i> signaling inhibitors (ARSi).<b>Experimental Design:</b> Between March 2014 and April 2017, we recruited patients with mCRPC (<i>n</i> = 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 <i>AR</i> splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of <i>AR</i> and <i>TP53</i> 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. Overall, no single <i>AR</i> 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. <i>TP53</i> inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18-3.00; <i>P</i> = 0.008], and outperformed ARV expression and detection of genomic <i>AR</i> alterations. Using Cox coefficient analysis of clinical parameters and <i>TP53</i> status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; <i>P</i> < 0.0001), which was validated in an independent mCRPC cohort (<i>n</i> = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; <i>P</i> < 0.0001). In an all-comer cohort, tumor burden estimates and <i>TP53</i> outperform any <i>AR</i> perturbation to infer prognosis.See related commentary by Rebello et al., p. 1699.