Impact of Loss-of-function Alterations on the Response to PSMA Radioligand Therapy in Metastatic Castration-resistant Prostate Cancer Patients

PSMA-targeting radioligand therapy (PSMA-RLT) has shown promise in metastatic castration-resistant prostate cancer (mCRPC), particularly in PSMA-avid tumours. However, predicting response remains challenging. Preclinical data suggests aberrant p53-signalling as a predictor of poor response. The patient population of this pre-planned retrospective cohort study consists of 96 patients with mCRPC who underwent treatment with PSMA-RLT and were molecularly profiled by whole-genome sequencing and or targeted next-generation sequencing. Response to PSMA-RLT was assessed per molecular subtype, including -mutational status. Patients with loss-of-function alterations had a shorter median progression-free survival (3.7 versus 6.2 months, <0.001), a lower median PSA change (-55% vs. -75%, =0.012) and shorter overall survival from initiation of PMSA-RLT (7.6 vs. 13.9 months, =0.003) compared to -wildtype patients. Pathogenic alterations in , , , or as well as in genes linked to the PI3K or MAPK pathways or genes involved in homologous recombination repair, were not associated with response. Only lactate dehydrogenase was, alongside -status, significantly associated with response. Transcriptome analysis of 21 patients, identified six p53 signalling genes whose low expression was associated to a shorter progression-free survival (<0.05). loss-of-function may serve as a prognostic factor for PSMA-RLT outcomes in patients with mCRPC.