Prognostic impact of intraductal carcinoma of the prostate and PTEN loss in metastatic castration-sensitive prostate cancer treated with androgen receptor pathway inhibitors.

[BACKGROUND] Intraductal carcinoma of the prostate (IDC-P) and phosphatase and tensin homolog (PTEN) alteration are established adverse features in prostate cancer. However, their coexistence and prognostic relevance in the era of androgen receptor pathway inhibitor (ARPI) therapy for metastatic castration-sensitive prostate cancer (mCSPC) remain unclear, particularly in Japanese populations. We evaluated the prevalence, concordance, and prognostic significance of IDC-P and PTEN loss in patients with mCSPC treated with ARPI plus androgen deprivation therapy (ADT).

[METHODS] We retrospectively analyzed consecutive patients with mCSPC who received ARPI plus ADT between February 2018 and June 2024 across three Japanese institutions. IDC-P was assessed on hematoxylin-eosin-stained biopsy specimens. PTEN loss was defined as ≥90% absence of cytoplasmic staining, consistent with the CAPItello-281 trial criteria. The primary endpoint was castration-resistant prostate cancer-free survival (CRPC-FS). Overall survival was evaluated as a secondary endpoint. Survival outcomes were assessed using Kaplan-Meier analysis and multivariable Cox regression modeling.

[RESULTS] In total, 121 patients were included. IDC-P was identified in 68.6% of biopsy specimens, and PTEN loss in 15.7%. Patients with IDC-P more frequently presented with CHAARTED high-volume and LATITUDE high-risk disease. During a median follow-up of 36 months, 44 patients (36.4%) developed CRPC. IDC-P was independently associated with shorter CRPC-FS [hazard ratio [HR] 2.4, 95% confidence interval (CI) 1.14-5.04; P = .02], whereas PTEN loss was not significantly associated with CRPC-FS or overall survival. Combined assessment of IDC-P and PTEN loss did not demonstrate additive prognostic value.

[CONCLUSION] In this multicenter Japanese cohort, IDC-P, but not PTEN loss, independently predicted earlier progression to CRPC in patients with mCSPC treated with ARPI plus ADT. The limited overlap between IDC-P and PTEN loss suggests distinct biological mechanisms in Japanese populations. IDC-P remains a strong morphologic indicator of aggressive disease, whereas PTEN loss may serve as a therapeutic biomarker for phosphoinositide 3-kinase/AKT-targeted strategies.