Alpha Particle Therapy for PSMA-Targeting in Prostate Cancer
Actinium-225 (225Ac) is the primary alpha particle radioisotope currently in clinical trials for PSMA-targeted therapy in metastatic castration-resistant prostate cancer, most commonly conjugated as 225Ac-PSMA-617. 1, 2
Primary Alpha-Emitting Radiopharmaceuticals
225Ac-PSMA-617 represents the most extensively studied PSMA-targeted alpha therapy in current trials, demonstrating complete responses in advanced disease settings. 3 This agent delivers high-energy alpha radiation with a significantly shorter range and higher linear energy transfer compared to beta-emitters like Lutetium-177, potentially improving efficacy while reducing bystander toxicity. 2, 4
Additional alpha-emitting agents under investigation include:
- Thorium-227 (227Th) conjugates targeting PSMA are in development, though less extensively studied than actinium-based therapies. 2
- Radium-223 (223Ra) is FDA-approved but targets bone metastases through a different mechanism (bone-seeking properties rather than PSMA-targeting), making it distinct from PSMA-directed alpha therapies. 1
Clinical Evidence and Response Rates
The pooled PSA50 response rate (≥50% PSA reduction) for 225Ac-PSMA therapy across 18 studies involving 1,155 patients was 65% (95% CI, 57-72%). 5 Response rates varied significantly based on prior treatment exposure:
- No prior lines of therapy: 82% response rate (95% CI, 73-90%) 5
- One prior line: 72% response rate (95% CI, 56-85%) 5
- More than one prior line: 55% response rate (95% CI, 48-63%) 5
Progression-free survival ranged from 3 to 15 months, with overall survival ranging from 8 to 31 months across studies. 5
Treatment Sequencing Considerations
Prior exposure to 177Lu-PSMA therapy appears to reduce the efficacy of subsequent 225Ac-PSMA treatment. In patients previously treated with Lutetium-177, the pooled median PSA response was only 15.4% compared to 42.7% in treatment-naïve patients. 4 This suggests potential radioresistance development, though the underlying mechanisms remain unclear and require further investigation. 4
Safety Profile
Adverse events are predominantly mild (grades 1-2), with the most common severe toxicities (≥ grade 3) being:
- Anemia: 11% of patients 5
- Thrombocytopenia: 6% of patients 5
- Xerostomia (dry mouth): The most notable clinical side effect, though typically manageable 3
No significant hematologic toxicity was observed in early case reports of complete responders. 3
Current Clinical Trial Status
225Ac-PSMA-617 remains experimental and is primarily available through clinical trials for heavily pre-treated metastatic castration-resistant prostate cancer patients. 5, 6 The typical treatment protocol involves 100 kBq per kilogram of body weight administered bimonthly, with PSMA-positive disease confirmed by 68Ga-PSMA-11 PET/CT imaging. 3
Randomized controlled trials are needed to optimize treatment protocols and establish the role of PSMA-targeted alpha therapy in clinical practice. 5 Current investigations are exploring combination approaches with chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immunotherapy. 2