Purpose <p>²²⁵Ac-Targeted alpha therapy is a potent and promising option for patients with metastatic castration-resistant prostate cancer (mCRPC) and failure of guideline-based therapies and ¹⁷⁷Lu-PSMA-radioligand therapy. Unfortunately, side effects associated with TAT can significantly affect quality of life. A combination treatment regimen adding ¹⁷⁷Lu and reducing ²²⁵Ac activities may mitigate side effects while preserving sufficient anti-tumour efficacy. We therefore evaluated different combinations [²²⁵Ac]Ac-/[¹⁷⁷Lu]Lu-PSMA-I&amp;T (ALCT) with regard to response and adverse events.</p> Methods <p>A total of 19 consecutive patients treated with ALCT on compassionate use basis at our department were evaluated. Patients were divided into two different subgroups, depending on the ²²⁵Ac/¹⁷⁷Lu-activity administered: group 1 (Gr1) received 4MBq and 4000MBq, group 2 (Gr2) 8 MBq and 1000MBq per therapy cycle, respectively. Laboratory (PSA, ALP, LDH, Hb, Lc, Tc, Crea) and imaging parameters on [¹⁸F]PSMA-1007-PET/CTs (TTV, SUVmax/mean) at baseline and after 2 cycles of therapy were evaluated for the total patient population as well as each therapy subgroup and statistically compared. Adverse events (xerostomia, anemia, leukopenia, thrombocytopenia, weight loss) were recorded. Response evaluation criteria in PSMA-PET/CT (RECIP 1.0) was used for response evaluation.</p> Results <p>According to the RECIP composite classification, 4 of 10 (40%) of patients from Gr1 and 5 of 9 (56%) from Gr2 showed a partial response, while 4/10 (40%) and 2/9 (22%) of patients from Gr1 and 2, respectively, showed progressive disease. After 2 cycles of ALCT the following adverse events newly developed or worsened by at least one grade: anemia in 2/10 (20%) patients from Gr1 and 3/9 (33%) patients from Gr2; thrombocytopenia in 1/10 (10%) patients from Gr1; leukopenia in 4/10 (40%) from Gr1 and 2/9 (22%) from Gr2; weight loss in 1/10 (10%) from Gr1 and 2/9 (22%) from Gr2 and xerostomia in 3/10 (30%) from Gr1 and 5/9 (56%) from Gr2. There was no significant difference between the two groups in respect to absolute values after therapy or pre- and post-therapy difference in any of the laboratory or imaging parameters evaluated.</p> Conclusion <p>Although no significant difference in response or adverse events could be found between the two treatment groups, ALCT with higher ²²⁵Ac-activities seems to favor a better outcome, albeit at the cost of a higher risk of xerostomia. ALCT with lower ²²⁵Ac activities may be a good choice when conserving salivary gland function and therefore quality of life is of higher concern, but renders more careful monitoring of blood values necessary.</p>