Androgen receptor (AR) aberrations in patients (Pts) with metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) plus androgen deprivation therapy (ADT) in TITAN

Abstract

Background: TITAN evaluated APA vs placebo (PBO),+ADT, in pts with mCSPC. APA improved overall survival (OS [HR, 0.67; 95% CI, 0.51-0.89; p=0.0053]) vs PBO. We evaluated AR aberrations at baseline (BL) and end of treatment (EOT) and assessed associations of EOT AR aberrations with outcomes in TITAN. Methods: From 265 pt samples (APA, n=116; PBO, n=149) available for evaluation, a subset was analyzed for circulating tumor (ct)DNA and AR aberrations (ARv7, AR amplification, AR ligand binding domain mutations) from cell-free (cf)DNA and cfRNA using next-generation sequencing and PCR, respectively. Associations with OS and duration on first subsequent therapy were assessed. Results: BL characteristics of pts were balanced between biomarker-positive groups. Among aberrations at BL, AR amplification was associated with longer duration of prior ADT (4.2 mo vs 1.6 mo, pts with vs without AR amplification; p=0.034). ctDNA %and frequency of AR aberrations increased from BL to EOT. At EOT, ctDNA%was similar in APA and PBO groups (60% and 66%), and AR aberrations were less frequent with APA vs PBO (Table). Regardless of treatment group, OS was significantly shorter with detection of any AR aberration at EOT (OS: 2.7 [1.1-6.6], p=0.0278, APA; 6.1 [1.9-20.3], p=0.0007, PBO). Detection of any AR aberration at EOT was significantly associated with duration on first subsequent therapy (2.0 [1.0-4.0], p=0.0386). Conclusions: In TITAN, AR amplification at BL was associated with even brief ADT exposure. AR aberrations were fewer at EOT with APA vs PBO. Pts with AR aberrations at EOT had worse outcomes vs pts without. Taken together, these findings suggest that early APA + ADT provides long-term benefits vs ADT alone without increased acquisition of AR aberrations. The detailed biological mechanisms underlying these findings need to be further studied. (Table Presented) .