PSMA-directed radioligand therapy and radium-223 in prostate cancer bone metastases

Bone metastases are a major cause of pain, skeletal complications, marrow compromise and mortality in advanced prostate cancer. The therapeutic biology of skeletal disease is heterogeneous: malignant epithelial cells expressing prostate-specific membrane antigen (PSMA) coexist with osteoblasts, osteoclasts, reactive mineralising bone and variable marrow infiltration. Radium-223 dichloride is a bone-seeking alpha emitter with randomised evidence of overall-survival benefit in selected men with metastatic castration-resistant prostate cancer (mCRPC), whereas PSMA-targeted radioligand therapy delivers radiation to PSMA-expressing tumour deposits in bone and soft tissues. Their mechanistic complementarity has motivated sequential and concurrent strategies, but complementary localisation does not itself establish clinical synergy. This review critically integrates ALSYMPCA, ERA-223, PEACE-3, VISION, TheraP, PSMAfore, RALU and AlphaBet, together with radiobiology, molecular imaging, marrow and skeletal toxicity, dosimetry and evolving therapeutic sequencing. The final 133-patient retrospective RALU report describes the safety and outcomes observed after radium-223 followed by lutetium-177-PSMA in selected heavily pretreated patients; AlphaBet reports preliminary safety and antitumour activity with concurrent lutetium-177-PSMA-I&T and radium-223 in a single-arm early-phase study. Neither provides randomised evidence of an incremental survival benefit for dual-radionuclide treatment. Conversely, PEACE-3 establishes an overall-survival benefit for radium-223 combined with enzalutamide under contemporary bone-protective practice, whereas ERA-223 underscores the fracture hazards of inappropriate combinations. Future trials must integrate lesion-level imaging, whole-body disease phenotype, marrow reserve, patient-reported outcomes, competing systemic treatments and personalised radiation exposure. The most defensible clinical strategy is evidence-weighted selection of radionuclide therapy according to disease distribution and treatment history, with concurrent dual-radionuclide approaches restricted to appropriately governed trials.