Data from 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

Abstract

<div>AbstractPurpose:<p>In the placebo-controlled SPARTAN study, apalutamide added to androgen-deprivation therapy (ADT) improved metastasis-free survival, second progression-free survival (PFS2), and overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). Mechanisms of resistance to apalutamide in nmCRPC require evaluation.</p>Patients and Methods:<p>In a subset of patients from SPARTAN, aberrations were assessed at baseline and end of study treatment (EOST) using targeted next-generation sequencing or qRT-PCR. Circulating-tumor DNA (ctDNA) levels were assessed qualitatively. Select aberrations in androgen receptor (AR) and other common PC-driving genes were detected and summarized by the 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.</p>Results:<p>In 247 patients, the overall prevalence of ctDNA, AR aberrations, and <i>TP53</i> inactivation increased from baseline (40.6%, 13.6%, and 22.2%) to EOST (57.1%, 25.4%, and 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; <i>P</i> < 0.0001 for both), any AR aberration with PFS2 (1.74; <i>P</i> = 0.024), and <i>TP53</i> or <i>BRCA2</i> inactivation with OS (2.06; <i>P</i> = 0.003; or 3.1; <i>P</i> < 0.0001).</p>Conclusions:<p>Apalutamide plus ADT did not increase detectable AR/non-AR aberrations over ADT alone. Detectable ctDNA, AR aberrations, and <i>TP53/BRCA2</i> inactivation at EOST were associated with poor outcomes in patients treated with first subsequent androgen signaling inhibitor.</p></div>