[Molecular-Based Diagnostics and Therapy of Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)]

Metastatic hormone-sensitive prostate cancer (mHSPC) represents a biologically and clinically heterogeneous disease entity. While traditional clinical parameters such as metastatic burden and timing of metastasis remain prognostically relevant, molecular biomarkers are increasingly gaining importance for individualized treatment planning. Genetic alterations in tumor suppressor genes and DNA repair pathways, particularly BRCA, PTEN, and TP53 aberrations, are associated with more aggressive disease courses and poorer prognosis. At the same time, these molecular alterations provide novel therapeutic opportunities, including the use of PARP inhibitors and AKT inhibitors.In addition to genetic alterations, transcriptomic characteristics also play an important role. In particular, androgen receptor (AR) pathway activity influences prognosis and treatment response. Low AR activity and reduced PSMA expression have been associated with reduced sensitivity to hormonal therapies and increased biological heterogeneity. Conversely, high PSMA expression appears to correlate with improved responses to androgen deprivation therapy as well as PSMA-targeted radioligand therapies.Advanced imaging modalities such as PSMA PET imaging further contribute to a refined understanding of metastatic disease biology and increasingly challenge traditional disease classifications. Moreover, biomarkers including PSA nadir or circulating tumor DNA (ctDNA) may help identify progression patterns and guide future treatment intensification or de-escalation strategies.Overall, current evidence suggests that integrating genetic, transcriptomic, and imaging biomarkers may substantially improve the biological characterization of mHSPC. In the future, these approaches could enable a more accurate prognostic stratification and support the development of personalized therapeutic concepts.