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

This is a Phase II/III study. Patient population is adult participants with PSMA-positive mCRPC who had treatments with androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy and progressed on or after \[177Lu\]Lu-PSMA targeted therapy. Treatment of interest: the investigational treatment is AAA817 regardless of subsequent anti-neoplastic treatment. The control treatment is investigator's choice of Standard of Care, regardless of subsequent anti-neoplastic treatment

More details:

Study CAAA817A12201 consists of 2 parts: a randomized, open-label, international, multicenter, phase II study (Phase II) to collect more information to support the proposed dose of AAA817 and a randomized, open-label, international, multicenter, 2- arm phase III study (Phase III) aimed to evaluate the efficacy and safety of proposed dose of AAA817 vs. investigator's choice of standard of care (SoC) in the treatment of adult participants with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who had treatments with ARPI and taxane-based chemotherapy, and progressed on or after \[177Lu\]Lu-PSMA targeted therapy. The purpose of the phase II part (Phase II) of this study is to collect additional information to support proposed phase III dose of AAA817.

Overview

AAA817 is Novartis/Advanced Accelerator Applications’ code name for 225Ac-PSMA-617, a prostate-specific membrane antigen (PSMA)–targeted alpha radioligand therapy being developed for PSMA-positive metastatic prostate cancer. Novartis is running a Phase I (AcTION; NCT04597411), a Phase II/III post–177Lu-PSMA study (PSMAcTION; NCT06780670), and a Phase III first post-ARPI study (AcTFirst; NCT06855277). As of September 2, 2025, these company-sponsored trials are recruiting and have not reported results. (novartis.com)

Mechanism of action

• Target: PSMA, highly expressed on prostate cancer cells. The small-molecule ligand PSMA‑617 binds PSMA and is internalized. (ncbi.nlm.nih.gov)
• Radionuclide: Actinium‑225 (t1/2 ≈ 9.92 days) emits multiple high‑LET alpha particles in its decay chain, producing dense DNA double‑strand breaks with a short tissue range (tens of micrometers), which can spare surrounding tissue relative to beta emitters. (ejnmmipharmchem.springeropen.com)
• Construct: PSMA‑617 linked to a DOTA chelator to complex 225Ac; while DOTA is widely used clinically, chelation stability and daughter recoil are known considerations for 225Ac conjugates. (ncbi.nlm.nih.gov)

Clinical development and dosing under study

• Phase I (AcTION; NCT04597411): dose‑escalation of up to six cycles of 225Ac‑PSMA‑617 in PSMA‑positive prostate cancer (with/without prior 177Lu‑PSMA). (novartis.com)
• Phase II/III (PSMAcTION; NCT06780670): AAA817 versus investigator’s choice in adults with PSMA‑positive mCRPC who progressed after ARPI, taxane chemotherapy, and 177Lu‑PSMA therapy. (novartis.com)
• Phase III (AcTFirst; NCT06855277): AAA817 (fixed 10 MBq ±10% per cycle, up to six cycles) plus ARPI versus standard of care in taxane‑naïve mCRPC after one ARPI. (novartis.com)

Efficacy (investigator‑initiated/retrospective clinical evidence with 225Ac‑PSMA‑617)

Although sponsor-run AAA817 trials have not yet read out, multiple peer‑reviewed, mostly retrospective series and meta‑analyses of 225Ac‑PSMA‑617 in mCRPC report high biochemical and imaging response rates:

• Post‑ADT setting (n=53): PSA decline ≥50% in 91%; PET negativity in 30/53; responders had markedly longer estimated PFS (22 vs. 4 months) and OS (not reached vs. 9 months at 55‑month follow‑up). (jnm.snmjournals.org)
• Systematic reviews/meta‑analyses: pooled “any PSA decline” ≈83–85% and PSA50 ≈59–65%; disease control and imaging responses frequent; outcomes generally observed in heavily pretreated mCRPC (often post‑177Lu‑PSMA). (pubmed.ncbi.nlm.nih.gov)
• Single‑center studies: PSA50 responses 69% with ≥90% declines in 46% (n=13); radiographic partial responses in 50% of evaluable patients. (pubmed.ncbi.nlm.nih.gov)
• Additional series reported median PFS ~12 months and median OS ~17 months in salvage settings. (pubmed.ncbi.nlm.nih.gov)
• Early experience in de novo mHSPC showed PSA50 in 86% (small cohort). (pmc.ncbi.nlm.nih.gov)

Important caveats: most reports are small, nonrandomized, and heterogeneous in dosing/schedules; prospective randomized data specific to AAA817 are pending. (pmc.ncbi.nlm.nih.gov)

Safety

Across published clinical series of 225Ac‑PSMA‑617, the most common toxicity is xerostomia (dry mouth), reflecting salivary gland PSMA expression; hematologic toxicity and renal effects occur less frequently but are reported:

• Meta‑analyses: xerostomia common (often Grade 1–2; ~60% in pooled data), with anemia, thrombocytopenia, and nephrotoxicity generally less frequent; overall toxicity acceptable but may exceed that seen with 177Lu‑PSMA. (pubmed.ncbi.nlm.nih.gov)
• Single‑center experiences: treatment discontinuation due to xerostomia occurred in about one‑third in one series; Grade 3–4 cytopenias occurred in a minority; renal insufficiency mostly Grade 1–2 but reported. (annalsofoncology.org)

Safety and dose‑intensity for AAA817 specifically will be defined by ongoing Phase I–III trials. (novartis.com)

Further reading

• Journal of Nuclear Medicine: Post‑ADT 225Ac‑PSMA‑617 outcomes (n=53). (jnm.snmjournals.org)
• 2024/2021 meta‑analyses of 225Ac‑PSMA therapies. (pubmed.ncbi.nlm.nih.gov)
• Salvage 225Ac‑PSMA‑617 series with PSA and imaging responses. (pubmed.ncbi.nlm.nih.gov, pmc.ncbi.nlm.nih.gov)
• Mechanistic/chemistry context for PSMA‑617, DOTA, and 225Ac. (ncbi.nlm.nih.gov, ejnmmipharmchem.springeropen.com)
• Novartis AAA817 trial listings: AcTION (Phase I), PSMAcTION (Phase II/III), AcTFirst (Phase III). (novartis.com)

Note: As of September 2, 2025, no efficacy or safety results have been publicly reported from Novartis-sponsored AAA817 randomized trials; available evidence comes predominantly from investigator‑initiated studies and meta‑analyses. (novartis.com)

Last updated: Sep 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.