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

Efficacy Enhancement of PSMA-Targeted a- and ß --TRT by DNA-PK Inhibition Enables Dose De-Escalation (ASTRO 2026) - "Although [Lu-177]Lu- and [Ac-225]Ac-PSMA-617 demonstrate promising results in metastatic castration-resistant prostate cancer, 20-30% of patients exhibit primary or acquired TRT-resistance despite adequate target expression...For proof-of-concept combination study, PSMA-TRT was paired with Nedisertib®, a second-generation DNA-PK inhibitor targeting the non-homologous end-joining DNA repair pathway... DNA-PK inhibition significantly enhances the therapeutic response to PSMA-TRT and enables dose de-escalation. The response even in PSMA-negative PC-3 cells highlights the potential of Ac-225-based combination strategies for overcoming radioresistance. These findings support further mechanistic studies and in vivo validation of PSMA-TRT/DNA-PK inhibitor combinations."

Clinical • 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

AcTION: Phase 1 study of [225Ac]Ac-PSMA-617 (225Ac-PSMA-617) in men with metastatic castration-resistant prostate cancer (mCRPC) with or without prior [177Lu]Lu-PSMA (177Lu-PSMA) radioligand therapy (RLT). (ASCO 2026) - P1, P2/3, P3 | "225Ac-PSMA-617 demonstrated an acceptable safety profile and promising anti-tumor activity up to 10 MBq in pts with mCRPC regardless of prior 177Lu-PSMA RLT. Two phase 3 trials, AcTFirst (NCT06855277) and PSMAcTION (NCT06780670), are currently recruiting."

Metastases • P1 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Xerostomia

AcTFirst: A phase 3 trial of 225Ac-PSMA-617 plus ARPI versus standard of care in adults with PSMA-positive metastatic castration-resistant prostate cancer. (ASCO 2026) - P3 | "Participants will be randomized to three treatment arms: 1) a combination of 225Ac-PSMA-617 (up to six cycles) plus ARPI change (enzalutamide or abiraterone); 2) 225Ac-PSMA-617 monotherapy (up to six cycles); or 3) investigator's choice of SoC (ARPI change, taxane chemotherapy or 177Lu-PSMA-617). Other outcomes of interest include safety, health-related quality of life and other patient-reported outcomes. As of January 2026, patient enrollment is ongoing."

Clinical • Metastases • P3 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • HRD

Alpha-emitting radionuclide or beta-emitting radionuclide combined with metastasis-directed stereotactic body radiotherapy for oligorecurrent prostate adenocarcinoma (ANDROMEDA): A phase II trial. (ASCO 2026) - P2 | "Clinical Trial Registration Number: NCT07150715 Background: The recent LUNAR study (NCT05496959) found that adding beta-emitting 177Lutetium-PNT2002 (177Lu-PSMA) to stereotactic body radiation therapy (SBRT) more than doubled median progression-free survival (PFS) compared to SBRT alone in oligorecurrent hormone-sensitive prostate cancer (orHSPC), hazard ratio (HR)=0.37. However, the relative efficacy compared to novel alpha-emitting 225Actinium-PSMA-617 (225Ac-PSMA) is unknown...Early stopping guidelines include monitoring site-specific grade 4-5 toxicity with a safety threshold of 20% from the time of the first enrolled patient, which would trigger halting the trial and safety consultation. ANDROMEDA is currently open for enrollment."

P2 data • Hormone Sensitive Prostate Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer

Tumor microenvironment-mediated hematologic toxicity of 225Ac-PSMA-617 in metastatic castration-resistant prostate cancer: mechanisms, risk stratification, and clinical management. (PubMed, World J Urol) - "A thorough understanding of the triple-hit mechanism and implementation of risk stratification management facilitate safer and more effective application of 225Ac-PSMA-617 in the treatment of mCRPC. Future efforts should focus on expanding the therapeutic window of this therapy through individualized dosing, optimization of combination therapies, and development of multidimensional biomarkers."

Biomarker • Journal • Review • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hematological Disorders • Hematological Malignancies • Oncology • Prostate Cancer • Solid Tumor

AAA817: Regulatory submission for post Lu mCRPC in 2028 (Novartis) - Q2 2026 Results: Regulatory submission for 1L mCRPC in 2029 or later

Filing • Castration-Resistant Prostate Cancer • Oncology

Radioligand therapy in combination with CAR T cells overcomes the heterogeneous immunosuppressive prostate tumor microenvironment. (PubMed, bioRxiv) - "In human xenograft and mouse syngeneic prostate cancer models with homogeneous or heterogeneous antigen expression, the sequential administration of Lu-177 RLT, cyclophosphamide (Cy), and PSCA-CAR T cells improves tumor control and prolongs survival compared to monotherapies...We additionally evaluated 225 Ac-PSMA-617 RLT as an emerging approach in combination with CAR T cells and observed anti-tumor responses, supporting its potential as an alternative RLT partner. These findings support RLT as an immune priming strategy to enhance CAR T cell therapy and provide a rationale for clinical translation of this combination in mCRPC. Combining 177 Lu-PSMA-617 radioligand therapy with PSCA-CAR T cells improves tumor control and survival in prostate cancer models by overcoming the antigen heterogeneity and reshaping the immunosuppressive tumor microenvironment."

Biomarker • Heterogeneity • Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hematological Disorders • Hematological Malignancies • Oncology • Prostate Cancer • Solid Tumor • PSCA

AAA817: Data readout from P3 AcTFirst trial (NCT06855277) for mCRPC in 2028 (Novartis) - Q2 2026: Data readout from P2/3 PSMAcTION trial (NCT06780670) for post Lu mCRPC in 2028

P2/3 data • P3 data • Castration-Resistant Prostate Cancer • Oncology

Prostate-specific membrane antigen based diagnostic and therapeutic integration for prostate cancer management. (PubMed, Discov Oncol) - "Randomized phase III trials have demonstrated that 177Lu-PSMA-617 confers survival benefits to patients with metastatic castration-resistant PCa. Meanwhile, emerging α-emitter therapies, such as 225Ac-PSMA-617, exert potent cytotoxic effects in resistant disease but are associated with xerostomia as a dose-limiting toxicity and production constraints...PSMA-based theragnostics are associated with challenges related to access, isotope supply, and standardized protocols. However, PSMA-based theragnostics represents a paradigm shift toward individualized, biology-driven cancer care, setting the benchmark for future theragnostic developments across oncology."

Journal • Review • Dental Disorders • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Xerostomia

ASCO 2026: AcTION: Phase 1 Study of 225Ac-PSMA-617 in Men with mCRPC with or Without Prior 177Lu-PSMA Radioligand Therapy (UroToday) - "This analysis includes all 101 treated patients as of November 13, 2025. Group A patients had a median of 3 prior systemic therapies and a median baseline PSA of 73.4 ng/mL (range 1-3,320 ng/mL). Group B patients had a median baseline PSA of 223.4 (range: 5-12,308) ng/mL, and Group C patients had 5 prior systemic therapies and a median baseline PSA of 85.5 (range: 5-1,760) ng/mL...Across all 3 groups, there were no dose-limiting toxicities, and a maximum tolerated dosage was not reached. No grade 4/5 treatment-related adverse events occurred, and no dosage-dependent safety signals were observed...In Group A, the PSA50 rate was 58.8% (95% CI 40.7, 75.4) and the PSA90 rate was 63.6% (95% CI 30.8, 89.1)....For Group B patients, the PSA50 rate was 100% (95% CI 71.5, 100) and PSA90 rate was 90.9% (95% CI 58.7, 99.8)."

P1 data • Castration-Resistant Prostate Cancer

Novartis also presented data for its actinium-based RLT, 225Ac-PSMA-617, from the Phase 1 AcTION trial (GlobeNewswire) - "These...data were presented as an oral presentation at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting....The data showed promising early antitumor activity with PSA declines and radiographic responses, as well as a manageable safety profile which supports further clinical development in patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC)."

P1 data • Castration-Resistant Prostate Cancer

Tumor-intrinsic STING signaling determines response to PSMA radioligand therapy (SNMMI 2026) - "Results both the VISION and the PSMAfore phase 3 clinical trials showed that ¹⁷⁷Lu-PSMA-617 improved survival and delayed disease progression; however, relapse occurs, emphasizing the need to enhance and sustain RLT efficacy. To enhance and prolong RLT efficacy, we investigated 225Ac-PSMA-617 and its combination with immune modulation targeting the STimulator of INterferon Genes (STING) pathway...To inhibit type I/III interferon signaling, mice were treated with the JAK1 inhibitor ruxolitinib (33 mg/kg, orally, twice daily) and IFNAR-blocking antibody (0.2 mg, i.p.)... Together, these findings showed that STING and interferon signaling is required for effective PSMA radioligand therapy. These results indicate that strategies consisting in STING activation enhancement could enhance RLT efficacy in cancer."

IO biomarker • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Immune Modulation • Immunology • Oncology • Prostate Cancer • Solid Tumor • CCL2 • CCR2 • CD8 • FOLH1 • IFNAR1 • STING

ATNM-400: A First-in-Class Actinium-225 Antibody Radioconjugate Demonstrating Potent PSMA-Independent Efficacy in Prostate Cancer Models (SNMMI 2026) - "ATNM-400 demonstrates robust, PSMA-independent antitumor activity across PCa models, including PSMA-low, PSMA-negative, and PSMA-targeted therapy-resistant disease. By targeting a non-PSMA antigen linked to aggressive biology and resistance, ATNM-400 overcomes a key limitation of current PSMA-directed radioligand therapies and delivers favorable tumor retention with rapid normal tissue clearance, supporting a strong therapeutic index. ATNM-400 consistently outperformed both 177Lu-PSMA-617 and 225Ac-PSMA-617 in vivo, including in PSMA-therapy-resistant models, positioning ATNM-400 as a next-generation 225Ac antibody radioconjugate with potential utility as monotherapy across all prostate cancer disease states (HSPC, CRPC, and mCRPC) and as a complementary option before or after PSMA-targeted radioligand therapy."

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

Tumor-intrinsic STING signaling determines response to PSMA radioligand therapy (SNMMI 2026) - "Results both the VISION and the PSMAfore phase 3 clinical trials showed that ¹⁷⁷Lu-PSMA-617 improved survival and delayed disease progression; however, relapse occurs, emphasizing the need to enhance and sustain RLT efficacy. To enhance and prolong RLT efficacy, we investigated 225Ac-PSMA-617 and its combination with immune modulation targeting the STimulator of INterferon Genes (STING) pathway...To inhibit type I/III interferon signaling, mice were treated with the JAK1 inhibitor ruxolitinib (33 mg/kg, orally, twice daily) and IFNAR-blocking antibody (0.2 mg, i.p.)... Together, these findings showed that STING and interferon signaling is required for effective PSMA radioligand therapy. These results indicate that strategies consisting in STING activation enhancement could enhance RLT efficacy in cancer."

IO biomarker • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Immune Modulation • Immunology • Oncology • Prostate Cancer • Solid Tumor • CCL2 • CCR2 • CD8 • FOLH1 • IFNAR1 • STING

ATNM-400: A First-in-Class Actinium-225 Antibody Radioconjugate Demonstrating Potent PSMA-Independent Efficacy in Prostate Cancer Models (SNMMI 2026) - "ATNM-400 demonstrates robust, PSMA-independent antitumor activity across PCa models, including PSMA-low, PSMA-negative, and PSMA-targeted therapy-resistant disease. By targeting a non-PSMA antigen linked to aggressive biology and resistance, ATNM-400 overcomes a key limitation of current PSMA-directed radioligand therapies and delivers favorable tumor retention with rapid normal tissue clearance, supporting a strong therapeutic index. ATNM-400 consistently outperformed both 177Lu-PSMA-617 and 225Ac-PSMA-617 in vivo, including in PSMA-therapy-resistant models, positioning ATNM-400 as a next-generation 225Ac antibody radioconjugate with potential utility as monotherapy across all prostate cancer disease states (HSPC, CRPC, and mCRPC) and as a complementary option before or after PSMA-targeted radioligand therapy."

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

Radiochemistry and Comparative In Vitro Evaluation of PSMA-617 Labeled with 212Pb, 225Ac, and 177Lu. (SNMMI 2026) - "212Pb-PSMA-617 showed similar or better in vitro uptake compared to 177Lu-PSMA-617 in PSMA-positive cell lines. While 225Ac-PSMA-617 also showed selective and specific uptake in the two PSMA-positive cell lines, the uptake levels were substantially lower, likely due to the low molar activities achievable for 225Ac-PSMA-617 compared to 212Pb-PSMA-617 or 177Lu-PSMA-617."

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

Radiochemistry and Comparative In Vitro Evaluation of PSMA-617 Labeled with 212Pb, 225Ac, and 177Lu. (SNMMI 2026) - "212Pb-PSMA-617 showed similar or better in vitro uptake compared to 177Lu-PSMA-617 in PSMA-positive cell lines. While 225Ac-PSMA-617 also showed selective and specific uptake in the two PSMA-positive cell lines, the uptake levels were substantially lower, likely due to the low molar activities achievable for 225Ac-PSMA-617 compared to 212Pb-PSMA-617 or 177Lu-PSMA-617."

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

ATNM-400: A First-in-Class Actinium-225 Antibody Radioconjugate Demonstrating Potent PSMA-Independent Efficacy in Prostate Cancer Models (SNMMI 2026) - "ATNM-400 demonstrates robust, PSMA-independent antitumor activity across PCa models, including PSMA-low, PSMA-negative, and PSMA-targeted therapy-resistant disease. By targeting a non-PSMA antigen linked to aggressive biology and resistance, ATNM-400 overcomes a key limitation of current PSMA-directed radioligand therapies and delivers favorable tumor retention with rapid normal tissue clearance, supporting a strong therapeutic index. ATNM-400 consistently outperformed both 177Lu-PSMA-617 and 225Ac-PSMA-617 in vivo, including in PSMA-therapy-resistant models, positioning ATNM-400 as a next-generation 225Ac antibody radioconjugate with potential utility as monotherapy across all prostate cancer disease states (HSPC, CRPC, and mCRPC) and as a complementary option before or after PSMA-targeted radioligand therapy."

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

Dosimetric Comparison of Alpha and Beta Emitting Radioemitters for Targeted Radiopharmaceutical Therapy: A Pilot Virtual Clinical Trial (SNMMI 2026) - "A cohort of 10 virtual patients (BMI range: 20.3-36.1) were treated with standard clinical doses of either beta-emitting (7.4 GBq 177Lu-PSMA-617) or alpha-emitting (8 MBq 225Ac-PSMA-617) radiation sources. This work demonstrates the feasibility of a virtual clinical trial framework to estimate tumor and organ doses from alpha- and beta-emitting radiopharmaceuticals using patient-specific computational dosimetry. The results highlight the value of virtual patient–based simulations for comparative evaluation of RPT agents and support their use in treatment optimization, agent selection, and future study design."

Clinical

Tumor-intrinsic STING signaling determines response to PSMA radioligand therapy (SNMMI 2026) - "Results both the VISION and the PSMAfore phase 3 clinical trials showed that ¹⁷⁷Lu-PSMA-617 improved survival and delayed disease progression; however, relapse occurs, emphasizing the need to enhance and sustain RLT efficacy. To enhance and prolong RLT efficacy, we investigated 225Ac-PSMA-617 and its combination with immune modulation targeting the STimulator of INterferon Genes (STING) pathway...To inhibit type I/III interferon signaling, mice were treated with the JAK1 inhibitor ruxolitinib (33 mg/kg, orally, twice daily) and IFNAR-blocking antibody (0.2 mg, i.p.)... Together, these findings showed that STING and interferon signaling is required for effective PSMA radioligand therapy. These results indicate that strategies consisting in STING activation enhancement could enhance RLT efficacy in cancer."

IO biomarker • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Immune Modulation • Immunology • Oncology • Prostate Cancer • Solid Tumor • CCL2 • CCR2 • CD8 • FOLH1 • IFNAR1 • STING

Radiochemistry and comparative in vitro assessment of PSMA-617 labeled with lead-212 (212Pb), actinium-225 (225Ac), and lutetium-177 (177Lu). (PubMed, EJNMMI Radiopharm Chem) - "[212Pb]Pb-PSMA-617 showed similar or better uptake in PSMA-positive cell lines compared to [177Lu]Lu-PSMA-617. While [225Ac]Ac-PSMA-617 also showed selective and specific uptake in the two PSMA-positive cell lines, the uptake levels were substantially lower, likely due to the low molar activities achievable for [225Ac]Ac-PSMA-617 compared to [212Pb]Pb-PSMA-617 or [177Lu]Lu-PSMA-617."

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

PSMA-617-100: Study of 225Ac-PSMA-617 in Men With PSMA-positive Prostate Cancer (clinicaltrials.gov) - P1 | N=101 | Active, not recruiting | Sponsor: Endocyte | Recruiting ➔ Active, not recruiting

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

Comparative evaluation of 225Ac-PSMA-Trillium with other 225Ac-PSMA-SMOL assets in a preclinical prostate cancer xenograft model (AACR 2026) - P1 | "Here, we compared 225Ac-PSMA-Trillium with three other 225Ac-PSMA-SMOLs, i.e., 225Ac-PSMA-617, 225Ac-PSMA-R2 and 225Ac-PSMA-I&T, which all utilize a DOTA chelator for complexing 225Ac...177Lu-PSMA-617 SPECT imaging was performed to evaluate tumor uptake...In summary, 225Ac-PSMA-Trillium showed the highest tumor uptake and the strongest tumor growth inhibition with a clear dose response compared with the other 225Ac-PSMA-SMOLs. These data support the clinical development of 225Ac-PSMA-Trillium (NCT06217822)."

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

First target disclosure for the preclinical development of ATNM-400, a first-in-class actinium-225 radioconjugate with pan-tumor efficacy in solid tumors (AACR 2026) - "In vivo, ATNM-400 demonstrated sustained tumor uptake with off-target exposure in normal tissues, driving potent anti-tumor activity in:• Prostate cancer: ATNM-400 outperformed androgen receptor (AR) pathway inhibitor enzalutamide, 177Lu-PSMA-617, and 225Ac-PSMA-617, producing durable regressions and complete responses in enzalutamide- and 225Ac-PSMA-617-resistant models.• EGFR-mutant lung cancer: ATNM-400 synergized with EGFR inhibitor osimertinib, achieving complete cures in animals, correlating with increased target expression in osimertinib-resistant models.• Breast cancer: ATNM-400 exhibited tumor regressions in HR+ breast cancer, TNBC and combination activity in estrogen receptor (ER) inhibitor tamoxifen- and HER2 antibody trastuzumab-resistant tumors, correlating with increased target expression. ATNM-400 exhibits robust pan-tumor activity, overcomes resistance to AR, EGFR, and HER2/ER-targeted therapies, and demonstrates a favorable safety profile. These..."

Pan tumor • Preclinical • Breast Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer