225Ac-vipivotide tetraxetan (AAA817) / Novartis - LARVOL DELTA

ATNM-400, a first-in-class Actinium-225 antibody radioconjugate, demonstrates potent anti-tumor activity and overcomes resistance to enzalutamide and 177Lu-PSMA-617 in prostate cancer models (PCF 2025) - "We hypothesized that ATNM-400 would provide superior efficacy compared to current options and overcome resistance to AR inhibitors (enzalutamide) and PSMA-directed radioligands (177Lu-PSMA-617 or 225Ac-PSMA-617). ATNM-400 showed robust and durable anti-tumor efficacy and a favorable safety profile in preclinical PCa models. These findings support ATNM-400 as a next-generation Actinium-225 therapy - with potential as 1) Monotherapy in CRPC (pre-177Lu-PSMA-617), 2) Combination therapy with AR pathway inhibitors, or 3) Sequential therapy after ARPI or 177Lu-PSMA-617 failure. ATNM-400 holds promise to address critical gaps in mCRPC treatment landscape."

Preclinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • FOLH1

LUTACT: Comparison of 177Lu-PSMA-617 and 225Ac-PSMA-617 (clinicaltrials.gov) - P1 | N=45 | Recruiting | Sponsor: Thomas Hope | Not yet recruiting ➔ Recruiting

Enrollment open • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Radiotheranostics in Low- and Middle-Income Countries: Challenges, Practice, and Prospects. (PubMed, World J Nucl Med) - "Specifically, notable contributions have been made to the literature by groups from South Africa, India, and Türkiye on the safety and efficacy of 225Ac-PSMA-617 for therapy of advanced prostate cancer. Through the intervention of many international organizations, governments, and private sectors, there has been a steady improvement in the awareness, availability, access, and utilization of NM and radiotheranostics services in LMICs."

Journal • Review • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

PSMAcTION: Open-label Study Comparing AAA817 Versus Standard of Care in the Treatment of Previously Treated PSMA-positive mCRPC Adults Who Have Disease Progressed on or After [177Lu]Lu-PSMA Targeted Therapy (clinicaltrials.gov) - P2/3 | N=432 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Apr 2033 ➔ Jul 2033 | Trial primary completion date: Mar 2028 ➔ Jun 2028

Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

PSMAcTION trial-in-progress: a phase II/III randomized trial of [225Ac]Ac-PSMA-617 (225Ac-PSMA-617) versus standard of care in patients with PSMA-positive metastatic castration-resistant prostate cancer who progressed on or after [177Lu]Lu-PSMA therapy (ESMO 2025) - P2/3 | "Background Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) [ 177 Lu]Lu-PSMA-617 prolonged radiographic progression-free survival (rPFS) in patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) in the taxane-naive (PSMAfore) and post-taxane (VISION) settings...In phase 3, ∼420 patients will be randomized to 225 Ac-PSMA-617 for ≤ 6 cycles or investigator's choice of SoC (excluding PARP inhibitors and immunotherapy except sipuleucel-T)...Safety follow-up will occur at 56 and 30 days (+7) after the last dose of 225 Ac-PSMA-617 and SoC, respectively, with long-term follow-up for up to 5 years. As of April 2025, the first patient first visit occurred in the Asia-Pacific region."

Clinical • Metastases • P2/3 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Improving patient management in mCRPC: Combined in vitroalpha particle and x-ray radiotherapies with Enzalutamide (AACR-NCI-EORTC 2025) - "The first and only approved alpha particle emitter is Radium-223 dichloride, which targets the bone tumor microenvironment, but there is great academic and clinical interest in novel targeted alpha emitters in various stages of development and trial, many of which target the prostate-specific membrane antigen (PSMA)...High energy α-emitting radionuclides appended to short peptides or monoclonal antibodies establish the backbone of targeted alpha therapies—recent methods include 225Ac-PSMA-617, 213Bi-PSMA-617, 211At-PSMA-pentanedioic acid, and 227Th-PSMA-IgG1...AR inhibitors disrupt the DNA-repair function, and are under investigation for combined use with targeted radiotherapies. Our aim is to improve the therapeutic potential of alpha particle and combination radiotherapies in improving mCRPC patient management."

Preclinical • Castration-Resistant Prostate Cancer • Oncology • Osteosarcoma • Prostate Cancer • AR • FOLH1

Preclinical Evaluation of a PSMA-targeting Theranostic Candidate with Reduced Gland Uptake (EANM 2025) - "Radiochemistry: 64 Cu-REX003-DOTA, 64 Cu-PSMA617, 177 Lu-REX003-DOTA, 177 Lu-PSMA617, 225 Ac-REX003-DOTA, 225 Ac-PSMA617 were labeled according to the published generic radiochemical protocols by CROs: C-Ray, Huayi isotopes, InnoStar, or the First Affiliated Hospital of Soochow University. In parallel, investigator-initiated trials (IIT) are planned to characterize human dosimetry using multimodal imaging. With its optimized tumor targeting, reduced gland uptake, and superior compatibility with actinium-225, REX003 is well positioned for clinical translation and holds promise as a next-generation radioligand therapy for advanced prostate cancer."

Preclinical • Anesthesia • Castration-Resistant Prostate Cancer • Dental Disorders • Genito-urinary Cancer • Prostate Cancer • Solid Tumor • Xerostomia • FOLH1

Current status of radionuclide therapies in metastatic castration-resistant prostate cancer. (PubMed, Ther Adv Med Oncol) - "This article reviews recent advances and key clinical trials in various radionuclides and their combinations in the application for treating mCRPC. Further directions of this new treatment strategy are also discussed in this review."

Journal • Review • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Pain • Prostate Cancer • Solid Tumor

ANDROMEDA: Alpha-Emitting Radionuclide or Beta-Emitting Radionuclide With Metastasis-Directed Stereotactic Body Radiotherapy for the Treatment of Recurrent, Oligometastatic Prostate Adenocarcinoma (clinicaltrials.gov) - P2 | N=107 | Not yet recruiting | Sponsor: Jonsson Comprehensive Cancer Center

New P2 trial • Oncology • Prostate Adenocarcinoma • Prostate Cancer

Actinium-225-PSMA-617 treatment in a patient with advanced prostate cancer causes secondary myelofibrosis: a case report and literature review. (PubMed, Front Med (Lausanne)) - "Ac-225-PSMA-617 has demonstrated promising therapeutic efficacy in the management of advanced PCa; however, the potential risks associated with SMF necessitate careful consideration. Through comprehensive analysis of this clinical case and comparative evaluation with the existing literature, this study highlights the need to balance clinical benefit with increased vigilance for treatment-related adverse events."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hematological Disorders • Myelofibrosis • Oncology • Prostate Cancer • Solid Tumor

AcTFirst: Study Comparing AAA817+ARPI Versus Standard of Care in Adult Participants With PSMA-positive mCRPC (clinicaltrials.gov) - P3 | N=605 | Recruiting | Sponsor: Novartis Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

LUTACT: Comparison of 177Lu-PSMA-617 and 225Ac-PSMA-617 (clinicaltrials.gov) - P1 | N=45 | Not yet recruiting | Sponsor: Thomas Hope

New P1 trial • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Theranostic Pairs: Advancing Precision Medicine in Oncology (SNMMI 2025) - "Breast Cancer: [89Zr] Trastuzumab and [177Lu] Trastuzumab are being investigated as a theranostic pair targeting HER2-positive breast cancer...Alpha-emitting radionuclides, such as [225Ac]PSMA-617, are being explored for their high linear energy transfer, offering enhanced efficacy in treating resistant cancers while minimizing off-target effects... Theranostic pairs offer unparalleled precision in oncology, enabling real-time assessment of target expression and tailored therapeutic delivery. Established applications in NETs and prostate cancer underscore their clinical utility, while emerging agents promise to expand the scope of theranostics to other malignancies. Future research should focus on optimizing dosimetry, minimizing toxicity, and developing new radiopharmaceuticals to broaden the impact of theranostics in personalized medicine."

Breast Cancer • Endocrine Cancer • Fibrosis • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • HER-2 • SSTR

In Situ Vaccination for Castration Resistant Prostate Cancer (SNMMI 2025) - "Alternatively, treatment with 225Ac-PSMA-617 cured 1/9 treated mice at the same dose and was not well tolerated as was demonstrated by transient body weight loss after administration. We have evaluated our lead compound 177Lu-RIMS-2 in the immunocompetent RM1-PGLS mouse prostate cancer model which is the murine equivalent of human castration resistant prostate cancer as this model has a similar amount of PSMA expression, is heterogeneous and has similar drug internalization rates. Beta therapy in the RM1-PGLS mouse prostate cancer model with 177Lu-RIMS-2 demonstrated 4/9 animals cured and no tumor growth after rechallenging with RM1-PGLS cells which is indicative of a tumor specific immune response. Importantly, no long-term toxicities were observed in mice cured with 177Lu-RIMS-2, 125 days after treatment as was determined by a comprehensive metabolic panel, complete blood count analysis and H&E staining of radiosensitive organs such as the kidney, salivary gland..."

IO biomarker • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • FOLH1 • TLR7

Preclinical evaluation of [225Ac]Ac-PSMA-617 and in vivo effect comparison in combination with [177Lu]Lu-PSMA-617 for prostate cancer. (PubMed, Nucl Med Biol) - "This study shows that PSMA radioisotope therapy (RIT) and TAT combined therapy could improve patient management by delaying disease progression."

Journal • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Targeted Radionuclide Therapy in Diffuse Intrinsic Brainstem Gliomas: Exploring Options Beyond the Finish Line. (PubMed, Clin Nucl Med) - "We present a 12-year-old girl diagnosed with DIPG in July 2022, who received 60 Gy, 30 fractions of radical radiotherapy over 6 weeks, followed by temozolomide. With residual disease, the patient was referred to our department for the possibility of radiotheranostics. She underwent 68Ga PSMA PET/CT, which revealed tracer accumulation in the pontine mass and was subsequently given 2 cycles of Lu-177 PSMA 617 and 1 cycle of Ac-225 PSMA 617 therapy."

Journal • Brain Cancer • Glioma • Oncology • Pediatrics • Solid Tumor

Uncertainty Propagation from Projections to Region Counts in Tomographic Imaging: Application to Radiopharmaceutical Dosimetry. (PubMed, IEEE Trans Med Imaging) - "It is then applied to (i) Monte Carlo and (ii) multi-time point 177Lu-DOTATATE and 225Ac-PSMA-617 patient data for time integrated activity (TIA) uncertainty estimation. The outcomes of this work are two-fold: (i) the proposed uncertainty estimation algorithm is validated, and (ii) the propagation of VOI uncertainties to TIA uncertainty is validated with Monte Carlo data and applied to patient data. The proposed algorithm is made publicly available in the open-source image reconstruction library PyTomography and in the SPECT reconstruction extension of 3D Slicer."

Journal • Oncology

The efficacy and safety of 225Ac-PSMA-617 in metastatic castration-resistant prostate cancer. (PubMed, Front Oncol) - "Out of these patients, 11 had previously underwent 177 Lu-PSMA-617 radioligand therapy (RLT). In mCRPC, the results indicated that 225Ac-PSMA-617 demonstrated a favorable disease control rate and relatively minimal side effects. However, additional high-quality randomized controlled trials are required for future validation."

Journal • Castration-Resistant Prostate Cancer • Dental Disorders • Genito-urinary Cancer • Oncology • Pain • Prostate Cancer • Solid Tumor • Xerostomia

AcTFirst: Study Comparing AAA817+ARPI Versus Standard of Care in Adult Participants With PSMA-positive mCRPC (clinicaltrials.gov) - P3 | N=486 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals

New P3 trial • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Novartis’ first 225Ac nuclear medicine starts Phase III clinical trial [Google translation] (bydrug.pharmcube.com) - "On March 3rd local time, the official website of ClinicalTrials.gov showed that Novartis registered a Phase III clinical study (codename: AcTFirst) of 225Ac-PSMA-617 (AAA817) for the treatment of PSMA-positive metastatic castration-resistant prostate cancer (mCRPC)...AcTFirst is an open-label, multicenter Phase III clinical trial designed to evaluate the improvement of 225Ac-PSMA-617 combined with androgen receptor pathway inhibitors (ARPI) on radiological progression-free survival (rRFS) in PSMA-positive mCRPC patients compared with standard treatment (ARPI or chemotherapy)."

Trial status • Castration-Resistant Prostate Cancer

PSMAcTION: Open-label Study Comparing AAA817 Versus Standard of Care in the Treatment of Previously Treated PSMA-positive mCRPC Adults Who Have Disease Progressed on or After [177Lu]Lu-PSMA Targeted Therapy (clinicaltrials.gov) - P2/3 | N=432 | Recruiting | Sponsor: Novartis Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Just now, the blockbuster nuclear medicine IND was accepted! [Google translation] (bydrug.pharmcube.com) - "On February 6, according to the official website of CDE, Novartis' clinical trial application for [225Ac]Ac-PSMA-617 injection was accepted (acceptance number: JXHL2500015). [225Ac]Ac-PSMA-617 (AAA817) is a radionuclide-drug conjugate (RDC) targeting PSMA, and its indication is prostate cancer...Novartis has registered the Phase II/III clinical trial of Ac-PSMA-617 (AAA817) on the ClinicalTrials website...It is expected that 432 patients will be enrolled."

New P2/3 trial • Prostate Cancer

PSMAcTION: Open-label Study Comparing AAA817 Versus Standard of Care in the Treatment of Previously Treated PSMA-positive mCRPC Adults Who Have Disease Progressed on or After [177Lu]Lu-PSMA Targeted Therapy (clinicaltrials.gov) - P2/3 | N=432 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals

New P2/3 trial • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

225Ac-PSMA-617 Augmentation After Insufficient Response Under 177Lu-PSMA-617 Radioligand Therapy in mCRPC: Evaluation of Outcome and Safety From a Prospective Registry (REALITY Study). (PubMed, Clin Nucl Med) - "225Ac-PSMA-617 augmented 177Lu-PSMA-617 radioligand therapy seems to be an effective escalating treatment option in patients after failure of conventional 177Lu-PSMA-617 RLT and represents a promising approach balancing antitumor effect and tolerable side effects."

Journal • Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer

PSMA-617-100: Study of 225Ac-PSMA-617 in Men With PSMA-positive Prostate Cancer (clinicaltrials.gov) - P1 | N=99 | Recruiting | Sponsor: Endocyte | N=60 ➔ 99

Enrollment change • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor