Targeted Alpha Therapy in mCRPC (Metastatic Castration-Resistant Prostate Cancer) Patients: Predictive Dosimetry and Toxicity Modeling of 225Ac-PSMA (Prostate-Specific Membrane Antigen)

Radioligand therapy is a type of internal radiotherapy combining a short-range radioisotope labeled to a carrier with a high affinity for a specific receptor expressed on tumor cells. Targeted alpha therapy (TAT) combines a high-linear energy transfer (LET) emitter (²²⁵Ac) with a prostate-specific membrane antigen (PSMA) carrier, specifically binding tumor cells in patients with metastatic castration-resistant prostate cancer. Although the antitumor activity of ²²⁵Ac-PSMA is well-documented, this treatment is nowadays only used as salvage therapy because the high incidence of xerostomia limits the therapeutic window. Thus, methods to reduce salivary toxicity and models able to describe xerostomia incidence are needed. We recently studied the efficacy of salivary gland protectors administered in combination with ¹⁷⁷Lu-PSMA therapy. Starting from these data, we performed a predictive dosimetric evaluation of ²²⁵Ac-PSMA to assess the impact of salivary gland protectors in TAT. ²²⁵Ac-PSMA predictive dosimetry was performed in 13 patients treated with ¹⁷⁷Lu-PSMA. Sequential whole-body planar images were acquired 0.5–1, 16–24, 36–48, and 120 h post-injection. ¹⁷⁷Lu time-activity curves were corrected for ²²⁵Ac physical decay and assumed in equilibrium for all daughters. The OLINDA/EXM spherical model was used for dose estimation of the parotid and submandibular glands. The dose for each daughter was calculated and summed for the total dose estimation. The biologically effective dose formalism was extended to high-LET emitters. For the total biologically effective dose formalism extended to high-LET emitters, including the contribution of all daughter isotopes, the brachytherapy formalism for a mixture of radionuclides was implemented. Equivalent doses in 2 Gy/fraction (EQD2) were then calculated and compared with the normal tissue complication probability model derived from external beam radiotherapy for grade ≥2 xerostomia induction. Median predictive doses were 0.86 Bd_RBE5/MBq for parotid glands and 1.05 Bd_RBE5/MBq for submandibular glands, with a 53% reduction compared with previously published data. The results show that the radiobiological model implemented is conservative, as it overestimates the complication rate with respect to the clinical data. Our data shows the possibility of reducing salivary gland uptake in TAT with the coadministration of organ protectors, but these results should be confirmed for TAT with ²²⁵Ac-PSMA by carrying out prospective trials with defined toxicity endpoints and dosimetry procedures.