Background: Apalutamide is an oral non-steroidal, potent, and highly selective androgen receptor antagonist. Alterations in androgen signaling, DNA repair, and other pathways impact on castration sensitivity and outcomes of androgen antagonists. Currently, there is limited data on the types or effects of variants in prostate cancer (PC)-related genes among Japanese mCSPC (castration-naïve or castration-sensitive) patients treated with apalutamide. Methods: CUARTET is a collaborative phase 4 study with a primary objective of evaluating genomic variants in 73 PC driver genes during apalutamide treatment and hence identify potential biomarkers. Men aged ≥20 years with mCSPC scheduled to start apalutamide at 20 participating institutions will be eligible. Patients previously treated with abiraterone, docetaxel, enzalutamide, apalutamide or darolutamide, are ineligible, as are those who received androgen-deprivation therapy or combined androgen blockade for >6 months before registration or neoadjuvant/adjuvant hormonal therapy for >36 months. The primary endpoint is the changes in genomic variants of 73 PC driver genes between pre- and post-treatment of apalutamide. Secondary endpoints, stratified by baseline genomic variants, include the proportion of patients with nadir prostate–specific antigen (PSA) ≤0.2 ng/mL, PSA–progression-free survival (PFS), PFS, overall survival, time to castration resistance, and PFS2. Other planned outcomes include safety, incidence/severity of apalutamide-related skin rash stratified by single nucleotide polymorphisms or human leukocyte antigen typing, and clinical outcomes in patients with only distant lymph node metastases. The first patient was enrolled in December 2020, and it is expected to enroll 100 patients during the 1.5-year registration period. Eighty-one patients have been enrolled in this study by July 2021. The patients will be followed up for a maximum of 4.5 years. Interim analyses are planned after the last patient has been registered. Results of CUARTET are expected to reveal the genomic variants, including those in androgen signaling-related genes, that are potentially involved in acquired resistance to apalutamide. The results will reveal biomarkers to aid treatment decision making for mCSPC patients, including the treatment options following apalutamide. Clinical trial information: NCT04601441.