From Gleason Score to Molecular Classification: Redefining Therapeutic Strategy in Metastatic Castration-Resistant Prostate Cancer

Background: Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a resistant and highly aggressive phenotype associated with a dismal prognosis. With the widespread use of androgen receptor pathway inhibitors (ARPIs), the incidence of this condition has increased to 15–20% of CRPC cases. Early identification of at-risk patients remains an unmet clinical need.

Methods: This article provides a multidimensional classification framework through a systematic review and synthesis of evidence published in MEDLINE, EMBASE, and international conferences (ASCO, ESMO, AACR) up to 2026.

Findings: The Gleason score is not only an independent predictor of the risk of transformation to t-NEPC (HR=1.66, P=0.032), but also significantly associated with a higher frequency of DNA damage repair (DDR) gene mutations. Patients with Gleason ≥8 are not only 2.2 times more likely to harbor any DDR mutation (p=0.0028), but also 2.7 times more likely to harbor a BRCA1/2 or ATM mutation. Co-alteration of TP53/RB1 is associated with the worst overall survival (median OS = 11.40 months; HR=5.09, P<0.001). High PARP1 mRNA expression in 52,266 radical prostatectomy specimens was associated with distant metastasis (HR=1.67–1.81, all P<0.05) and in a phase II olaparib trial with improved PSA progression-free survival (HR=0.55, P=0.01). In the phase 1b DeLLpro-300 study, patients with DLL3-positive tumors had an overall response rate of 22.2% versus 0% in DLL3-negative patients.

Conclusion: Patients with Gleason ≥8 should be considered a high-risk subgroup, and comprehensive molecular evaluation should be performed before initiating ARPI.

keywords: Prostate cancer, castration-resistant, neuroendocrine, Gleason score, DDR mutation, PARP inhibitor, liquid biopsy, EZH2