Advances in Targeted Therapy for Metastatic Prostate Cancer.

Opinion statement: Over the past few years, treatment for advanced prostate cancer has begun shifting away from a one-size-fits-all approach toward biomarker-based therapies for select groups of patients. This review highlights the role of poly-ADP-ribose-polymerase (PARP) inhibitors in metastatic prostate cancer, emerging strategies to target the androgen receptor (AR), and innovative therapies aimed at cell surface proteins, including radioligand therapies, bispecific T cell engagers, and antibody-drug conjugates. For patients with homologous recombination repair (HRR)-mutated metastatic castration-resistant prostate cancer (CRPC), we favor combining a PARP inhibitor (PARPi) with an AR pathway inhibitor (ARPI), provided they can tolerate a more aggressive treatment strategy. In our opinion, patients with BRCA1 or BRCA2 mutations who are unable to handle combination therapy benefit from PARPi monotherapy. We are enthusiastic about the potential of ongoing clinical trials for new AR-directed therapies, such as AR ligand-directed degraders and CYP11A1 inhibitors, in metastatic CRPC. These treatments are expected to be most beneficial for patients whose cancer continues to rely on AR pathway signaling, suggesting they might also be effective in earlier stages of the disease. Progress in drug development and understanding of protein structures has led to new therapies that target cell surface proteins predominantly found in prostate cancer. We use ¹⁷⁷Lu-PSMA-617 for patients with PSMA avid metastatic CRPC who have progressed on an ARPI and a taxane chemotherapy. Additionally, we see promising potential in bispecific T-cell engagers (e.g., STEAP1-CD3 and PSMA-CD3) and novel radioligand therapies, including those utilizing actinium, to target these proteins. These advances show great promise in further enhancing survival for patients with metastatic prostate cancer.