Genetic Predictors of Progression and Skin Rash in Japanese mCSPC Patients Treated With Apalutamide: CUARTET Study

Despite promising evidence of the efficacy of the androgen deprivation therapy (ADT) plus apalutamide in metastatic castration-sensitive prostate cancer (mCSPC), it remains unknown how its effectiveness and safety are shaped by genetic factors, particularly among Asian populations. We evaluated whether baseline circulating tumor deoxyribonucleic acid (ctDNA) and germline variants predict outcomes and tolerability in the phase IV, open label, multicenter CUARTET trial in Japan. We enrolled 101 patients with mCSPC starting apalutamide with ADT; 99 contributed pretreatment plasma for ctDNA profiling across 73 prostate cancer driver genes and 86 provided genome-wide single nucleotide polymorphism (SNP) data. Primary endpoints were time to castration resistant prostate cancer (CRPC) and overall survival; skin rash incidence was assessed as a key adverse event. Cox models (adjusted for volume of disease) and exploratory machine-learning-assisted logistic regression were applied. ctDNA presence at baseline was associated with shorter time to CRPC (adjusted hazard ratio [HR] 3.18; 95% confidence interval [CI], 1.17-11.09) and overall survival (adjusted HR for all-cause mortality 3.95; 95% CI, 1.06-25.63). Among 55 paired samples, ctDNA presence increased from 61.8% pretreatment to 87.2% posttreatment, and alterations in androgen receptor and DNA repair pathways were enriched in patients who discontinued for progression. Any grade skin rash occurred in 59.4% and grade ≥ 3 in 5.9%. An exploratory genome-wide screen identified 12 SNPs associated with skin rash. This study demonstrated that baseline ctDNA predicts prognosis of Japanese patients with mCSPC receiving apalutamide with ADT and identified potential genetic predictors for treatment-related skin rash. Trial Registration: ClinicalTrials.gov identifier: jRCTs071200040.