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Publication Detail
Blood Biomarker Landscape in Patients with High-Risk Nonmetastatic Castration-Resistant Prostate Cancer Treated with Apalutamide and Androgen-Deprivation Therapy as They Progress to Metastatic Disease
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Smith MR, Thomas S, Gormley M, Chowdhury S, Olmos D, Oudard SM, Feng FY, Rajpurohit Y, Urtishak KA, Ricci DS, Rooney OB, Lopez-Gitlitz A, Yu MK, Wyatt AW, Li M, Attard G, Small EJ
  • Publisher:
    American Association for Cancer Research
  • Publication date:
  • Journal:
    Clinical Cancer Research
  • Status:
  • Country:
    United States
  • Print ISSN:
  • PII:
  • Language:
PURPOSE: In the placebo-controlled SPARTAN study, apalutamide added to androgen-deprivation therapy (ADT) improved metastasis-free survival, second progression-free survival, and overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). Mechanisms of resistance to apalutamide in nmCRPC require evaluation. EXPERIMENTAL DESIGN: In a subset of patients from SPARTAN, aberrations were assessed at baseline and end of study treatment (EOST) using targeted next-generation sequencing or quantitative reverse transcription PCR. Circulating tumor (ct)DNA levels were assessed qualitatively. Select aberrations in androgen receptor (AR) and other common PC-driving genes were detected and summarized by treatment group; genomic aberrations were summarized in ctDNA-positive samples. Association between detection of aberrations in all patients and outcomes was assessed using Cox proportional-hazards models and multivariate analysis. RESULTS: In 247 patients, the overall prevalence of ctDNA, AR aberrations, and TP53 inactivation increased from baseline (40.6%, 13.6%, 22.2%) to EOST (57.1%, 25.4%, 35.0%) and was comparable between treatment groups at EOST. In patients who received subsequent androgen signaling inhibition after study treatment, detectable biomarkers at EOST were significantly associated with poor outcomes: ctDNA with PFS2 or OS [HR = 2.01 or 2.17, respectively; P < 0.0001 for both], any AR aberration with PFS2 [1.74; P = 0.024], and TP53 or BRCA2 inactivation with OS [2.06; P = 0.003; or 3.1; P <0.0001]. CONCLUSIONS: Apalutamide plus ADT did not increase detectable AR/non-AR aberrations over ADT alone. Detectable ctDNA, AR aberrations, and TP53/BRCA2 inactivation at EOST were associated with poor outcomes in patients treated with first subsequent androgen signaling inhibitor.
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