PSMAcTION: A Phase II/III, Open-label, International, Multicenter, Randomized Study of AAA817 Versus Standard of Care in the Treatment of Adult Participants With PSMA Positive Metastatic Castration-resistant Prostate Cancer Who Progressed on or After [177Lu]Lu-PSMA Targeted Therapy

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Overview

AAA817 (also known as [225Ac]Ac-PSMA-617) is an investigational, PSMA-targeted alpha‑emitting radioligand therapy being developed by Advanced Accelerator Applications (a Novartis company) for prostate cancer. Multiple single‑center and multicenter retrospective/prospective studies of 225Ac‑PSMA‑617 in metastatic castration‑resistant prostate cancer (mCRPC) have reported promising activity. Novartis is running randomized trials of AAA817, but no company‑sponsored efficacy results had been posted as of October 7, 2025. (novartis.com)

Mechanism of action

PSMA‑617 is a small‑molecule ligand for prostate‑specific membrane antigen (PSMA; FOLH1) that is rapidly internalized after binding. When labeled with actinium‑225 (half‑life ~10 days), it delivers short‑range, high‑LET alpha radiation that induces complex DNA double‑strand breaks and cell death, with limited cross‑fire to surrounding tissue compared with beta‑emitters. The DOTA chelator in PSMA‑617 secures the radionuclide and supports tumor retention. (jnm.snmjournals.org)

Clinical development

• Ongoing randomized studies:
• Phase III, open‑label study of AAA817 + ARPI vs standard of care in PSMA‑positive mCRPC, dosing 10 MBq ±10% up to 6 cycles; primary endpoint rPFS (NCT06855277). Results pending. (novartis.com)

• PSMAcTION Phase II/III randomized study of AAA817 vs standard of care in mCRPC after progression on [177Lu]Lu‑PSMA therapy (NCT06780670). Results pending. (novartis.com)

• Investigator‑initiated/early studies of 225Ac‑PSMA‑617 have established dose‑finding and feasibility (often ~100 kBq/kg every 8 weeks, with de‑escalation strategies). (jnm.snmjournals.org)

Efficacy

Across peer‑reviewed, predominantly single‑arm studies of 225Ac‑PSMA‑617 in heavily pretreated mCRPC:

• Systematic review/meta‑analysis (18 studies; n=1,155): pooled PSA50 response rate 65% (95% CI 57–72%); PFS 3–15 months; OS 8–31 months. (pubmed.ncbi.nlm.nih.gov)
• Retrospective series after [177Lu]Lu‑PSMA failure (n=26): PSA50 in 65% (17/26); median OS 7.7 months (95% CI 4.5–12.1). (pubmed.ncbi.nlm.nih.gov)
• Small cohorts (examples):
• Mixed pretreated population (n=13): PSA50 in 69%; ≥90% decline in 46%; radiologic partial response in 50% of evaluable; marked PET tumor volume reductions. (pubmed.ncbi.nlm.nih.gov)
• Chemotherapy‑naïve pilot: high PSA and imaging responses reported; de‑escalated dosing described. (link.springer.com)

Quality‑of‑life improvements (pain and other symptoms) have been observed in small series. (pubmed.ncbi.nlm.nih.gov)

Note: These data derive from nonrandomized or small studies; randomized AAA817 results are not yet available. (novartis.com)

Safety

The dominant toxicity is xerostomia from salivary‑gland uptake, which can be dose‑limiting:

• Post‑Lu‑177 failure series: all patients had grade 1–2 xerostomia; treatment discontinuation for xerostomia occurred in some patients. Grade 3/4 hematologic AEs (anemia 35%, leukopenia 27%, thrombocytopenia 19%). (pubmed.ncbi.nlm.nih.gov)
• Meta‑analysis: severe anemia 11% and thrombocytopenia 6% pooled; most AEs were grade 1–2. (pubmed.ncbi.nlm.nih.gov)
• Objective assessments show greater salivary‑gland impairment with alpha‑ or tandem alpha+beta regimens than with beta‑only therapy. (mdpi.com)
• De‑escalated dosing and supportive measures have been used to mitigate xerostomia; nephrotoxicity appears uncommon but reported in some series. (link.springer.com)

Overall, toxicity profiles vary with prior treatments, tumor burden (especially diffuse bone metastases), and dose/activity selection. Randomized trials are expected to better define benefit–risk. (pubmed.ncbi.nlm.nih.gov)

Further reading

• Kratochwil et al. First‑in‑human experience with 225Ac‑PSMA‑617 (J Nucl Med, 2016). (jnm.snmjournals.org)
• Kratochwil et al. Dosimetry and empirical dose finding for 225Ac‑PSMA‑617 (J Nucl Med, 2017). (jnm.snmjournals.org)
• Systematic review/meta‑analysis of PSMA‑targeted alpha therapy (Eur J Nucl Med Mol Imaging, 2025). (pubmed.ncbi.nlm.nih.gov)
• Outcomes after failure of [177Lu]Lu‑PSMA (Eur Urol Oncol, 2021). (pubmed.ncbi.nlm.nih.gov)
• QoL study with 225Ac‑PSMA‑617 (Indian J Nucl Med, 2020). (pubmed.ncbi.nlm.nih.gov)
• Novartis AAA817 randomized trials (NCT06855277; NCT06780670). (novartis.com)

Note: AAA817 remains investigational; efficacy and safety for labeled indications have not yet been established in randomized trials as of October 7, 2025. (novartis.com)

Last updated: Oct 2025

Inclusion Criteria: ∙

* adults ≥ 18 years of age.

* ECOG performance status of 0 to 2.

* histopathological and/or cytological confirmation of adenocarcinoma of the prostate.

* PSMA-positive disease as assessed by PSMA PET/CT scan using an approved PSMA imaging agent as protocol instructed,

* castrate level of serum/plasma testosterone (\< 50 ng/dL or \< 1.7 nmol/L).

* Prior treatments with an androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy, and progressed on or after \[177Lu\]Lu-PSMA targeted therapy.

* ≥ 1 metastatic lesion that is present on screening/baseline CT, MRI, or bone scan imaging obtained ≤ 28 days prior to randomization

* eGFR as requested by the sponsor

Exclusion Criteria:

* Any investigational agents within 28 days prior to the day of randomization.

* Any 225Ac-based investigational compound used prior to the day of randomization.

* Participants with a history of CNS metastases who are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity.

* Concurrent acute kidney injury (renal failure developed between 48 hours to 7 days) or chronic kidney disease (at least 3 months of ongoing renal injury)

* Baseline xerostomia ≥ Grade 2 by CTCAE v.5

* History of uncontrolled hypertension, myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to ICF signature and/or clinically active significant cardiac disease

* History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system within the past 5 years (except for basal cell carcinoma or actinic keratosis that have been treated with no evidence of recurrence in the past 3 months, non-invasive malignant colon polyps that have been removed).

Other protocol-defined inclusion/exclusion criteria may apply.