Rationale: 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. Methods: 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 TP53-mutational status. Results: Patients with TP53 loss-of-function alterations had a shorter median progression-free survival (3.7 versus 6.2 months, P<0.001), a lower median PSA change (-55% vs. -75%, P=0.012) and shorter overall survival from initiation of PMSA-RLT (7.6 vs. 13.9 months, P=0.003) compared to TP53-wildtype patients. Pathogenic alterations in AR, MYC, BRCA1, or BRCA2 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 TP53-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 (P<0.05). Conclusion: TP53 loss-of-function may serve as a prognostic factor for PSMA-RLT outcomes in patients with mCRPC.
Theranostics. 2024 Aug 01*** epublish ***
Peter H J Slootbeek, María Victoria Luna-Velez, Bastiaan M Privé, Maarten J van der Doelen, Iris S H Kloots, Samhita Pamidimarri Naga, Hilde E Onstenk, James Nagarajah, Harm Westdorp, Inge M van Oort, Leonie I Kroeze, Jack A Schalken, Haiko J Bloemendal, Niven Mehra
Department of Medical Oncology, Radboud university medical center, Nijmegen, The Netherlands., Department of Urology, Radboud university medical center, Nijmegen, The Netherlands., Department of Nuclear Medicine, Radboud university medical center, Nijmegen, The Netherlands., Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.