Optimizing the treatment regimen for targeted alpha therapy of mCRPC with Ac-PSMA-617

Aim: PSMA-targeting alpha-therapy (PSMA-TAT) of mCRPC with 225Ac-PSMA-617 (8 MBq, 3 cycles, 8 week intervals) already demonstrated promising anti-tumor activity, but also induced severe and often irreversible xerostomia (1,2). Our objective was to optimize the treatment protocol to improve tolerability. Methods: Patients with PSMA-positive mCRPC that were resistant against or ineligible for approved options and presented with progressive disease were treated with 225Ac-PSMA-617 under the conditions of the updated declaration of Helsinki, § 37 (Unproven interventions in clinical practice) and in accordance to the German Pharmaceuticals Law §13(2b) as a salvage therapy. In n=20 patients (concept A) only the first cycle was performed with a fixed dose of 8 MBq and in case of a >50% PSA-response at week-8, the treatment activity was reduced by 2 MBq for the next cycle, respectively. In n=20 patients (concept B), already at cycle-1 the treatment activity was reduced from 8 MBq to 6 MBq. Depending on PSA-response at week-8, treatment activity was escalated, de-escalated or kept constant. In n=5 patients (concept C, ongoing) 4 MBq 225Ac-PSMA-617 and 4 GBq 177Lu-PSMA-617, i.e. 50% of the respective single dose, were administered as a cocktail-regimen. Results: For concept A treatments were conducted with 8/8/6 MBq in 4 patients, 8/6/6 MBq in 13 patients, 8/6/4 MBq in 3 patients. PSA response rate was comparable to the already published (2) protocol because only favorable responders de-escalated dose; de-escalated patients did not discontinue due to dry mouth but this might include some psychological bias in awareness of the favorable response. For concept B 10 patients completed with 6/6/6 or further de-escalation, 5 had to escalate and 5 left therapy due to non-response. Tolerability of non-escalating patients was improved, but counteracted by the decreased anti-tumor activity. For concept C no patient discontinued due to dry mouth, yet. Until now 60% (3/5) demonstrated positive PSA-response. The observations for this group are currently ongoing. Conclusion: Dose de-escalation protocols or radionuclide combinations of low-dose 225Ac amended by beta-therapy, seem promising approaches to improve the tolerability of PSMA-TAT without losing too much anti-tumor activity.JRC.G.I.5-Advanced Nuclear Knowledg