225Ac-PSMA-617

225Ac-PSMA-617 is an investigational radiopharmaceutical used in targeted alpha therapy (TAT) for metastatic castration-resistant prostate cancer (mCRPC) and, more recently, for metastatic hormone-sensitive prostate cancer (mHSPC). Initially developed by the German Cancer Research Center and University Hospital Heidelberg, it combines actinium-225 (225Ac), an alpha-emitting radionuclide, with PSMA-617, a small-molecule ligand that targets 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 while leveraging the short tissue penetration of alpha particles to minimize damage to healthy tissues. As of May 2025, 225Ac-PSMA-617 remains in early-phase clinical trials and has not yet received regulatory approval.^[1][2]

Prostate cancer is a leading cause of cancer-related mortality in men, with mCRPC representing an advanced, incurable stage resistant to androgen deprivation therapy (ADT). PSMA, a transmembrane protein, is highly expressed in prostate cancer cells, making it an ideal target for radioligand therapy. While lutetium-177 (177Lu)-PSMA-617 (approved as Pluvicto) has shown efficacy in mCRPC, some patients are resistant or develop diffuse bone marrow infiltration, limiting beta-emitter use due to hematologic toxicity. 225Ac-PSMA-617, an alpha-emitter, emerged to address these challenges, offering higher energy and shorter tissue penetration for precise tumor targeting. Initial clinical use began in 2014 as a salvage therapy under compassionate use protocols.^[1][3]

The primary dose-limiting toxicity of 225Ac-PSMA-617 is xerostomia (severe dry mouth) due to salivary gland uptake, affecting up to 25% of patients and leading to treatment discontinuation in some cases. Hematologic toxicities, including anemia, leukopenia, and thrombocytopenia, occur in up to one-third of patients, particularly those with extensive bone metastases. Renal toxicity is less common but reported in patients with pre-existing kidney issues. De-escalated dosing (e.g., 4–8 MBq) and tandem regimens with 177Lu-PSMA-617 have reduced salivary gland toxicity. Ongoing trials aim to optimize dosing to minimize adverse effects while maintaining efficacy.^[4][5][6]

225Ac-PSMA-617 targets PSMA on prostate cancer cells via the PSMA-617 ligand, which binds with high affinity and induces rapid cellular internalization. Actinium-225, with a 9.92-day half-life, emits four alpha particles in its decay chain, delivering high linear energy transfer (LET) radiation (100 keV/μm) that causes complex DNA double-strand breaks, leading to cancer cell death. The alpha particles' short range (47–85 μm) minimizes damage to surrounding tissues compared to beta-emitters like 177Lu. The DOTA chelator in PSMA-617 ensures stable 225Ac binding, enhancing tumor retention and reducing off-target effects.^[7][1][8]

Clinical evaluation of 225Ac-PSMA-617 began with retrospective studies and compassionate use in mCRPC patients resistant to standard therapies. The AcTION trial (NCT04597411), a Phase I, open-label, dose-escalation study by Novartis, is assessing safety and tolerability in men with PSMA-positive mCRPC or mHSPC, with or without prior 177Lu-PSMA-617 exposure. Patients receive up to six cycles of 225Ac-PSMA-617 (100 kBq/kg) every 8 weeks, with 68Ga-PSMA-11 PET/CT confirming PSMA expression. Other trials, such as a Phase I study in China (2020–2021) and a Dutch trial with 225Ac-PSMA-I&T (NCT05902247), are exploring dosing and efficacy. As of May 2025, trials are ongoing, with no regulatory approvals.^{[2][4][9][10]}

Early clinical data suggest 225Ac-PSMA-617 has significant anti-tumor activity. A 2016 study reported complete responses in two mCRPC patients, with prostate-specific antigen (PSA) levels dropping below detectable limits.^[1] A 2020 prospective study of 28 mCRPC patients (54% post-177Lu-PSMA-617) showed a >50% PSA decline in 53.8–66.6% of patients, with median overall survival (OS) of 10–17 months.^[4] A South African pilot study in 17 chemotherapy-naïve patients reported a ≥90% PSA decline in 82%, with 41% in remission at 12 months.^[5] A 2022 meta-analysis found >80% of patients had some PSA decline, with 60% achieving >50% reduction.^[11] Tandem therapy with 177Lu-PSMA-617 has shown promise in enhancing efficacy while reducing toxicity.^[6]

The clinical adoption of 225Ac-PSMA-617 faces several hurdles. The global supply of 225Ac, primarily produced via thorium-229 decay or cyclotron methods, is limited, with annual production (e.g., 68 GBq from Karlsruhe, Oak Ridge, and Obninsk) supporting only thousands of doses.^[12] Small sample sizes, retrospective designs, and heterogeneity in prior treatments limit current trial data, necessitating larger, randomized controlled trials. Salivary gland toxicity remains a significant barrier, with ongoing research into protective strategies like sialendoscopy.^[11][9][13]

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