Isotope Therapy for Castrate-Resistant Prostate Cancer: Unique Sequencing and Combinations

Radiopharmaceuticals used in the treatment of castrate-resistant prostate cancer are reviewed herein with an emphasis on sequential and combination therapies. Four bone-seeking radiopharmaceuticals had been approved in the United States. Three of these are β-emitters (phosphorus-32, strontium-89, samarium-153-ethylenediaminetetramethylene-phosphonic acid) that are approved for palliative purposes. One α-emitter (radium-223 [Ra]) is approved for prolongation of survival in bone metastatic castrate-resistant prostate cancer. Bone-seeking radiopharmaceuticals have been used in combination therapy with chemotherapy, hormones, and bisphosphonates for decades. Current combinations and clinical trials are primarily focused on Ra, given that overall survival benefit is associated with this radionuclide. Phase III trials with Ra were conducted in combination with a variety of standard hormonal therapies, bisphosphonates, and external beam radiation. Since the phase III Ra trials have been conducted, additional experience has been obtained with newer hormonal therapies such as abiraterone and enzalutamide, as well as with chemotherapies such as docetaxel. These therapies have been used both in combination with Ra and in sequence. Insights have arisen under each condition.A continuous evolution of radiopharmaceuticals is anticipated as these agents evolve in 2 distinct ways. First, current agents will evolve in combination with both current and emerging therapies, to create a better integrated and optimized approach. Second, radiopharmaceuticals that target the tumor (regardless of location) will continuously evolve. Therapies restricted to bone have inherent shortcomings, even in bone-tropic malignancies such as prostate cancer. Preliminary data with prostate-specific membrane antigen targeted β-emitters such as lutetium-177 are promising but need further evaluation. Prostate-specific membrane antigen targeted α-emitters are also in development. Given the molecular heterogeneity of tumor cells and the many shortcomings of molecularly targeted therapy, radiopharmaceuticals represent an attractive alternative approach given their capability of direct antitumor effects as well as their capability of microenvironmental disruption.