Direct Correlation of Tumor Absorbed Dose with Overall Survival in Metastatic Castration-Resistant Prostate Cancer Treated with ¹⁷⁷Lu Prostate-Specific Membrane Antigen

Abstract

In systemic radiopharmaceutical therapy, a direct dosimetric correlation between the tumor absorbed dose and overall survival, that is, Grays to months, has never been explicitly defined. This dosimetric analysis expounds this relationship in the context of metastatic castration-resistant prostate cancer treated with ¹⁷⁷Lu prostate-specific membrane antigen (¹⁷⁷Lu-PSMA). Methods: The average tumor absorbed dose per unit of administered activity from the first to sixth treatments was extrapolated from population data. This was used to calculate the cumulative tumor absorbed doses above the response threshold for 2 empiric randomized ¹⁷⁷Lu-PSMA clinical trials (VISION and TheraP). This was correlated to the difference in overall survival between these 2 trials to derive the tumor absorbed dose–survival relationship. This result was used to calculate the overall survival for a hypothetical optimized first strike in the context of personalized predictive dosimetry. Results: The tumor absorbed dose–survival relationship is calculated to be approximately 1 mo of overall survival per 1 Gy above the response threshold. An optimized first strike can double the overall survival compared with empiric regimens, delivers a higher cumulative tumor absorbed dose in fewer treatments, and avoids futile whole-body irradiation. Overall survival is proportional to the area bounded by the tumor absorbed dose curve and the response threshold absorbed dose curve. This suggests that, in addition to an optimized first strike, overall survival may also be improved by the concurrent administration of other systemic agents that modify tumor radiobiology to lower the response threshold, such as radiosensitization. Conclusion: Dosimetric evidence advocates for personalized prescription based on predictive dosimetry to optimize overall survival by exploiting radiobiologic synergy between the first strike and tumor radiosensitization.