Impact of TP53 loss-of-function alterations on the response to PSMA radioligand therapy in metastatic castration-resistant prostate cancer patients
**Rationale**: PSMA-targeting radioligand therapy (PSMA-RLT) has shown potential in treating metastatic castration-resistant prostate cancer (mCRPC), particularly in PSMA-avid tumors. However, predicting treatment response remains difficult. Preclinical data suggest that abnormal p53 signaling may predict a poor response.
**Methods**: This pre-planned retrospective cohort study Alvelestat included 96 mCRPC patients treated with PSMA-RLT, who underwent molecular profiling through whole-genome sequencing and/or targeted next-generation sequencing. The response to PSMA-RLT was evaluated according to molecular subtypes, including TP53 mutation status.
**Results**: Patients with TP53 loss-of-function alterations had worse outcomes compared to those with TP53-wildtype. They experienced shorter median progression-free survival (3.7 vs. 6.2 months, P<0.001), a smaller reduction in PSA levels (-55% vs. -75%, P=0.012), and shorter overall survival after starting PSMA-RLT (7.6 vs. 13.9 months, P=0.003). Mutations in AR, MYC, BRCA1, BRCA2, as well as genes related to the PI3K or MAPK pathways and homologous recombination repair, were not linked to treatment response. Lactate dehydrogenase levels, along with TP53 status, were significantly associated with response. Transcriptome analysis of 21 patients revealed six p53 signaling genes whose low expression correlated with shorter progression-free survival (P<0.05). **Conclusion**: TP53 loss-of-function may serve as a prognostic marker for outcomes in mCRPC patients undergoing PSMA-RLT.