Combination and Sequencing Strategies in Metastatic Castration-Resistant Prostate Cancer

Dr. Pedro Barata and Dr. Johann De Bono discuss ongoing questions surrounding combination approaches and optimal sequencing strategies for radiopharmaceutical therapies in metastatic castration-resistant prostate cancer (mCRPC). Dr. De Bono reviews the biologic rationale for combining PSMA-targeted radioligand therapies with androgen receptor pathway inhibitors, including the potential effects on DNA repair and radiosensitization. At the same time, he emphasizes that additional clinical evidence is still needed to determine whether combination strategies offer meaningful advantages over radiopharmaceutical monotherapy. The faculty also examine questions related to earlier versus later use of lutetium-based PSMA therapies, interpretation of emerging sequencing data, and the importance of understanding long-term outcomes beyond short-term tumor control. In addition, the discussion highlights ongoing concerns regarding delayed toxicities, including potential bone marrow suppression, myelodysplastic syndromes, acute leukemia, and renal effects associated with radiopharmaceutical exposure. Together, the segment provides a balanced overview of the evolving evidence and remaining uncertainties surrounding combination and sequencing strategies in mCRPC.