New mechanistic insights into possible radiobiologic and pathophysiologic explanations for unexpectedly impressive outcomes data observed for hormone-refractary metastatic prostate cancer patients treated with radium 223.

Abstract

10623 Background: The ALSYMPCA Trial of 223Ra (“Alpharadin”) for men with metastatic castrate-resistant prostate cancer was a Phase III randomized trial comparing 223Ra plus SOC vs best SOC. This trial was stopped early after 922 patients enrolled at over 100 centers achieved primary (overall survival) and all secondary endpoints including median survived (14 vs 11.2 m) time to first SRE (13.6 m vs 8.4 m) and time to PSA progression.These unexpectedly positive results prompted us to review some of the unique aspects of alpha-particle radiobiology and ultra-short range molecular targeting capabilities. Methods: Literature analysis. Results: The highly energetic alpha particles such as those released during decay of 223Ra (T1/2 = 11.4 mins) display unique radiobiologic and dosimetric aspects. The nuclear dose required in vitro for approximately 90% target cell kill is less than 1 Gy and electron micrographs shortly after exposure confirm bizarre blebbing and condensation of chromosomal material characteristic of apoptosis. Bovine aortic endothelial cells exposed to alpha particle radiation indicate that the radiobiologic effects depend heavily on cell culture condition with nonuniform DNA strand break damage observed in isolated detached cells. The subcellular alpha particle path length appears to allow specific target cell populations to be killed within bony stroma without excessive damage to nearby sensitive hematopoietic cells. 223Ra treatment in rodent models showed that this family of Ca ++ analogs delivers extremely high doses to stromal elements such as bone-resorbing osteoclasts and this selectivity may aid in decreasing SREs. Conclusions: We highlight the fact that some basic radiobiologic and cell compartment-specific stromal localization principles known to be effective in alpha particle radiopharmaceutical therapy may contribute to the very positive clinical outcomes observed while allowing subcellular damage accumulation to target cell groups.