AAA817 / Novartis - LARVOL DELTA

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 similr 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 where 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

Small Animal Total-Body Dynamic Imaging of Alpha-Emitter Radiopharmaceutical Therapy with the Upgraded Alpha-SPECT-Mini System (SNMMI 2025) - "[2] C. Kratochwil, et al, “225Ac-PSMA-617 for PSMA-targeted α-radiation therapy of metastatic castration-resistant prostate cancer,” Journal of Nuclear Medicine, 2016... The mouse imaging study with Ac-225 is shown in Fig. 2(A) where the mouse is imaged for 1 hour at 4-hour and 24-hour post-injection, respectively. The in-vivo Ra-223 mouse images at 10 min, 42min, 3h24min, 24h40min post injection are demonstrated in Fig."

Castration-Resistant Prostate Cancer • 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

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

Long-acting 225Ac-ART-101 for targeted alpha therapy of advanced CRPC (EANM 2024) - "The efficacy of therapeutic 225Ac-ART-101 was tested in groups of mice bearing PC3-PIP or LNCaP xenografts (n=5) receiving a single IV injection of saline, 225Ac-ART-101 20-80 kBq (~0.5-2 µCi), or 225Ac-PSMA-617 40-80 kBq (~1-2 µCi)... In conclusion, ART-101 showed significantly improved blood kinetics, enhanced tumor uptake, prolonged retention, and primarily hepatic clearance, translating into an improved therapeutic efficacy of 225Ac-ART-101 in murine models of mCRPC."

Metastases • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

225Ac-FL-020 is a novel PSMA-targeting radionuclide drug conjugate with promising in vivo anti-tumor activity (EANM 2024) - "Anti-tumor activity of 225Ac-FL-020 was evaluated in the LNCaP xenograft model and directly compared with 225Ac-PSMA-617. These results collectively demonstrate that 225Ac-FL-020 is a potent and selective PSMA-targeting RDC with superior anti-tumor activity and a favorable safety profile. A Phase 1 study will be started in 2024 to evaluate the safety, tolerability, and anti-tumor activity of 225Ac-FL-020 in patients with mCRPC."

Preclinical • Dental Disorders • Genito-urinary Cancer • Hematological Disorders • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • Xerostomia • FOLH1

Evaluation of the therapeutic efficacy of 225Ac-PSMA I&T in advanced prostate cancer: preliminary results (EANM 2024) - "The use of 225Ac-PSMA-617 to treat advanced prostate cancer has shown remarkable efficacy without significant side effects... Targeted α-therapy with the use of 225Ac-PSMA I&T is very promising and provides the possibility of effective treatment of advanced-stage prostate cancer patients progressing on existing treatment lines. Additional research involving a larger cohort of patients is necessary to evaluate the efficacy and safety of the treatment comprehensively."

Clinical • Metastases • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

Simple method for production and quality control of 225Ac- PSMA-617 for the targeted alpha therapy of castration-resistant prostate cancer. (EANM 2024) - "According to the results, the possibility of safety form synthesizing 225Ac-PSMA-617 has been confirmed. This protocol allows a routine production for the treatment of patients with metastatic prostate cancer."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

Development of 134Ce-PSMA-617 for Auger electron therapy and PET imaging of prostate cancer (SNMMI 2024) - "The in vitro assays for 134Ce-PSMA-617 demonstrated excellent binding affinity and cytotoxicity towards PC3-Pip cells over negative control PC3-Flu cells. As expected given the chemical similarity of the probes, 134Ce and 225Ac-PSMA-617 also demonstrated similar cell binding and internalization. The In vivo PET imaging and ex vivo biodistribution showed a high tumor uptake at 4 h post-injection."

Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

Deescalated 225Ac-PSMA-617 Versus 177Lu/225Ac-PSMA-617 Cocktail Therapy: A Single-Center Retrospective Analysis of 233 Patients. (PubMed, J Nucl Med) - "The objective parameters that could be derived from this evaluation are compared with previous literature about AcPSMA and 177Lu-PSMA-617 (LuPSMA). If adjusted for prognostic baseline characteristics, the efficacy of both regimens was not significantly different. Deescalated treatment activities of AcPSMA or AcPSMA and LuPSMA cocktail regimens present better tolerability with regard to xerostomia than previous regimens of at least 100 kBq/kg while retaining high antitumor activity in poor-prognosis prostate cancer patients."

Journal • Retrospective data • Dental Disorders • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • Xerostomia

225Ac-PSMA-617 Augmentation in High-Risk mCRPC Undergoing 177Lu-PSMA-617 Radioligand Therapy: Pilot Experience From a Prospective Registry. (PubMed, Clin Nucl Med) - P=N/A | "225Ac-PSMA-617 augmentation in high-risk mCRPC undergoing 177Lu-PSMA-617 RLT appears to be an effective treatment option with a favorable safety profile. The pretherapeutic values of alkaline phosphatase, lactate dehydrogenase, the Eastern European Oncology Group Performance Score, and the presence of visceral metastases may be appropriate biomarkers predicting survival outcome of this treatment regimen."

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

Bromodomain inhibition potentiates the therapeutic effect of 225Ac-PSMA in Castration-Resistant Prostate Cancer (SNMMI 2024) - "Still, a significant proportion (~40%) of 225Ac-PSMA-617 treated patients do not respond, and dose escalation is limited by severe xerostomia...In vivo, the combination of 225Ac-PSMA + JQ1 elicited a stronger tumor volume reduction compared to single treatment 225Ac-PSMA, JQ1, or control (Figure 1... Our results demonstrate that DDR disruption via BET inhibition is a promising strategy to sensitize PCa cells to 225Ac radiation. Importantly, blunting DNA DSBs repair via BET inhibition may allow for reducing the required 225Ac administered activity for a given radiobiological endpoint, thereby potentially reducing toxic side effects such as xerostomia. The therapeutic activity demonstrated by this novel combination merits further optimization and possible clinical exploration"

Castration-Resistant Prostate Cancer • Dental Disorders • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • Xerostomia • BRCA1 • BRCA2 • RAD51

225Ac-FL-020 is a novel PSMA-targeting radionuclide drug conjugate (RDC) with superior in vivo anti-tumor activity (AACR 2024) - "Lutetium-177 (177Lu)-PSMA-617 (PLUVICTOTM) was approved in 2022 for the treatment of progressive PSMA-positive mCRPC...In addition, anti-tumor activities of 225Ac-FL-020 were evaluated in the LNCaP xenograft model and directly compared to 225Ac-PSMA-617...A mechanistic study was also conducted in 225Ac-FL-020-treated LNCaP tumor samples where DNA double-strand breaks and tumor cell apoptosis were observed, confirming the MOA of alpha emitters. Taken together, these results collectively demonstrate that 225Ac-FL-020 is a potent and selective PSMA-targeting radioligand therapy candidate with superior anti-tumor activity and a favorable safety profile warranting further clinical development."

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

Current state of theranostics in metastatic castrate-resistant prostate cancer. (PubMed, J Med Imaging Radiat Oncol) - "Strontium-89, Samarium-153 EDTMP and Radium-223 have been trialled with mixed results...Furthermore, 225-Actinium-PSMA-617 also showed promise even in patients pre-treated with 177-Lutetium-PSMA-617. Hence, there has been an explosion of radiopharmaceutical treatment options for patients with prostate cancer. This review explores past and current theranostic capacities in the radiopharmaceutical treatment of metastatic castrate-resistant prostate cancer."

Journal • Metastases • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Musculoskeletal Pain • Oncology • Pain • Prostate Cancer • Solid Tumor

Study of 225Ac-PSMA-617 in Men With PSMA-positive Prostate Cancer (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Endocyte | Trial completion date: Mar 2026 ➔ Jan 2027 | Trial primary completion date: Mar 2026 ➔ Jan 2027

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

Automated radiolabeling and handling of Lu- and Ac-PSMA-617 using a robotic pipettor. (PubMed, J Labelled Comp Radiopharm) - "To demonstrate the feasibility of using the OpenTrons OT-2 robotic pipettor to perform automated radiosyntheses, we radiolabeled and formulated Lu-PSMA-617 and Ac-PSMA-617 on the system. The OT-2 was then used to help streamline the quality control process for both products, further minimizing manual handling by and exposure to the radiochemist."

Journal

Study of 225Ac-PSMA-617 in Men With PSMA-positive Prostate Cancer (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Endocyte | Trial completion date: Oct 2025 ➔ Jan 2026 | Trial primary completion date: Oct 2025 ➔ Jan 2026

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