Optimizing the treatment pathway in post-docetaxel mCRPC: PSMA-RLT vs cabazitaxel.

BACKGROUND

The management of metastatic castration-resistant prostate cancer (mCRPC) after progression on androgen receptor pathway inhibitors (ARPI) and docetaxel presents a critical therapeutic choice between cabazitaxel and [177Lu]Lu-PSMA-617 radioligand therapy (PSMA-RLT). This review provides a comprehensive analysis of efficacy, toxicity, biomarkers, and treatment sequencing to guide clinical decision-making.

METHODS

A critical review of the scientific literature was conducted, integrating data from randomized clinical trials, real-world evidence (RWE) studies, and preliminary data presented at major scientific conferences.

FINDINGS: The head-to-head phase II TheraP trial demonstrated superior PSA response rates (66% vs 37%) and progression-free survival for [177Lu]Lu-PSMA-617 over cabazitaxel, without significant difference in overall survival (OS). In contrast, large RWE studies, including the ARON-3 study, consistently show a significant OS advantage for [177Lu]Lu-PSMA-617 (median OS 20.2 vs 14.8 months). [177Lu]Lu-PSMA-617 is associated with a more favorable safety profile, with a lower incidence of grade 3-4 adverse events (33% vs 53%) and superior patient-reported quality of life compared to cabazitaxel. PSMA-PET imaging serves as a key predictive biomarker, with a high SUVmean (≥10) identifying patients with the highest probability of response to PSMA-RLT. While both treatment sequences are clinically valid, a biological rationale may favor a PSMA-RLT -first approach. However, also cost-effectiveness analyses and local barriers play a role in the selection of the treatment pathway.

CONCLUSION

Available data suggest [177Lu]Lu-PSMA-617 as the preferred therapeutic option for the majority of patients with PSMA-positive mCRPC who progressed to ARPI and docetaxel. PSMA-RLT is preferred for most PSMA positive patients, with eligibility assessed individually rather than by rigid thresholds. Cabazitaxel remains a crucial treatment for patients with low PSMA expression, those ineligible for PSMA-RLT, or as an effective sequential therapy. Modern management of mCRPC demands a personalized, multidisciplinary approach to optimally balance survival gain with quality of life.