225Ac-PSMA-R2

225Ac-PSMA-R2 is an investigational radiopharmaceutical developed by Novartis for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC). It is a targeted alpha therapy (TAT) combining actinium-225 (²²⁵Ac), an alpha-emitting radionuclide, with PSMA-R2, a small-molecule ligand targeting prostate-specific membrane antigen (PSMA), a protein overexpressed in prostate cancer cells. The therapy delivers high-energy alpha radiation to induce DNA damage in cancer cells, leveraging the short tissue range of alpha particles to minimize damage to healthy tissues. As of May 2025, 225Ac-PSMA-R2 is in Phase I/II clinical trials and has not received regulatory approval.^[1][2]

225Ac-PSMA-R2 targets PSMA, a transmembrane protein highly expressed on prostate cancer cells, particularly in advanced mCRPC. The PSMA-R2 ligand binds PSMA with high affinity, delivering ²²⁵Ac to tumor sites. Actinium-225, with a 9.92-day half-life, emits four alpha particles in its decay chain, causing complex DNA double-strand breaks that lead to cancer cell death. The alpha particles' short penetration range (47–85 μm) enhances tumor selectivity compared to beta-emitting therapies like lutetium-177 (177Lu)-PSMA-617. A chelator in the PSMA-R2 molecule ensures stable ²²⁵Ac binding, optimizing tumor targeting and reducing off-target radiation.^[3][2][4]

The SatisfACtion trial (NCT04597411), a Phase I/II, open-label, multi-center study by Novartis, is evaluating 225Ac-PSMA-R2 in patients with mHSPC and mCRPC. The trial includes dose escalation and expansion phases to determine the maximum tolerated dose (MTD) or recommended dose for expansion (RDE). Patients must have PSMA-positive disease, confirmed by 68Ga-PSMA-11 PET/CT, and documented disease progression. The study includes cohorts with prior 177Lu-PSMA radioligand therapy, assessing safety, tolerability, and preliminary anti-tumor activity. As of March 2025, the trial is recruiting, with no published efficacy data.^[1][5]

Combination approaches, such as with androgen receptor inhibitors (e.g., darolutamide), are being explored to enhance outcomes. Challenges include the limited global supply of ²²⁵Ac, produced via thorium-229 decay or cyclotron methods, and the need for advanced imaging to monitor treatment response. Further trials are essential to establish 225Ac-PSMA-R2's clinical role and address supply constraints.^[1][6]

The safety profile of 225Ac-PSMA-R2 is under investigation, with preclinical and related ²²⁵Ac-PSMA therapies (e.g., 225Ac-PSMA-617) suggesting potential toxicities. Xerostomia (severe dry mouth) is a notable risk due to salivary gland uptake, often dose-limiting in ²²⁵Ac-based PSMA therapies. Other adverse effects may include myelosuppression (e.g., anemia, leukopenia, thrombocytopenia) and renal toxicity, though these are less common. The PSMA-R2 ligand incorporates improved linker technology to enhance tumor uptake and reduce off-target effects compared to earlier PSMA ligands like PSMA-617. The SatisfACtion trial is optimizing dosing to balance efficacy and toxicity.^[3][7]