CCL21 as a treatment-linked prognostic biomarker in metastatic castration-resistant prostate cancer.

Abstract

257 Background: Metastatic castration-resistant prostate cancer (mCRPC) is an immunologically “cold” tumor with a low-inflamed microenvironment and limited sensitivity to immune checkpoint inhibitors. Treatment selection still lacks validated blood biomarkers. C-C motif chemokine ligand 21 (CCL21) orchestrates lymphocyte trafficking and lymphoid niche formation; thus, circulating levels may mirror the patient’s systemic immune state. Yet, the serum dynamics of CCL21 in mCRPC before and after treatment and their clinical relevance remain poorly defined. Methods: Observational translational cohort in mCRPC. Patients received systemic treatment according to clinical guidelines: androgen receptor pathway inhibitors (ARPIs) or chemotherapy (CT). Serum was collected at baseline (≤14 days pre-start) and week 12 (pre–cycle 3). CCL21 was quantified by enzyme-linked immunosorbent assay (ELISA) in batched runs under standard operating procedures, blinded to clinical outcomes. Primary outcome was whether on-treatment CCL21 dynamics associate with overall survival (OS); secondary outcome assessed whether these dynamics differ by treatment class (ARPIs vs CT). CCL21 value was dichotomized into HIGH/LOW using the median as the threshold. OS was estimated by Kaplan–Meier and compared using log-rank. Statistical significance was set at p<0.05. Results: 98 patients with mCRPC were included: 47 received ARPI (48%), of which 35 abiraterone and 12 enzalutamide, and 51 CT (52%). Most patients had bone disease (94.9%); 54.1% had nodal involvement and 15.3% had visceral disease. 59 patients had Gleason ≥ 8. Classical prognostic factors in prostate cancer were comparable across treatment groups. Median CCL21 value was 423.61 at baseline and 465.33 at week 12. Survival analysis showed differences when CCL21 value at 12 weeks was used as classifier. Those patients with HIGH values had a worse prognosis. No significant differences were observed at baseline by treatment class. But at week 12, CCL21 levels showed differences regarding to prognosis by treatment class. Among patients receiving ARPI therapy, HIGH week-12 CCL21 value was associated with shorter OS (p=0.03); while no association was observed with CT. Conclusions: In mCRPC, serum CCL21 measured at week 12 showed treatment-related differences and association with OS. In patients receiving ARPI therapy, CCL21 emerges as a candidate biomarker to monitor treatment and inform therapeutic selection. External validation and definition of clinically actionable thresholds will be required for clinical implementation.