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Last updated: June 17, 2026
PSMA radioligand therapy is a small-molecule PSMA-binding ligand chemically attached to a radioactive isotope. PSMA (Prostate-Specific Membrane Antigen, formal name glutamate carboxypeptidase II or GCPII) is a transmembrane glycoprotein highly expressed on the surface of prostate cancer cells — especially in metastatic and castration-resistant disease — with much lower normal expression on salivary glands, lacrimal glands, kidneys, and small intestine. The radiolabeled ligand binds PSMA on the tumor cell surface, is internalized, and delivers targeted radiation directly to PSMA-expressing tumor cells while sparing PSMA-negative tissues from full radiation exposure.
Two main isotope classes are in clinical use or late-stage development:
Terbium-161 (161Tb) is an emerging third isotope class — a beta-emitter with additional Auger and conversion electrons that may improve micro-metastatic kill. Phase 1–2 agents include 161Tb-PSMA-I&T (NCT05521412, NCT07621692), 161Tb-SibuDAB (NCT06343038), Tb-PSMA-I&T as neoadjuvant therapy (NCT07208240), and 161Tb-LNC1011 (NCT07381582, not yet recruiting).
Imaging-required class. PSMA radioligand therapy is the prototypical theranostic class: eligibility for treatment is established by PSMA-PET imaging upfront, using FDA-approved tracers Pylarify (18F-DCFPyL / piflufolastat), Locametz / Illuccix (68Ga-PSMA-11), or others. Patients with PSMA-negative imaging or significant PSMA-low disease are typically not eligible for the approved Pluvicto setting; some trials specifically target PSMA-low patients with intensified or modified dosing (NCT06526299 LPS-Boost; NCT06145633 vorinostat + 177Lu-PSMA-617).
| Drug | Sponsor | Target / Isotope | FDA Status | Administration |
|---|---|---|---|---|
| Pluvicto (177Lu-PSMA-617, lutetium-177 vipivotide tetraxetan) | Novartis / Advanced Accelerator Applications (AAA) | PSMA / 177Lu (beta-emitter) | FDA approval March 23, 2022 (PSMA-positive mCRPC post-taxane + post-ARSI, on the VISION pivotal NCT03511664). Expanded by the PSMAfore trial (NCT04689828) to the pre-chemotherapy setting (post-ARSI, taxane-naive PSMA-positive mCRPC) — readers should consult the current FDA prescribing information for the most up-to-date label. | Intravenous infusion every 6 weeks; PSMA-PET required upfront to confirm PSMA expression; radiation safety precautions ~48–72h post-infusion |
| AAA817 (225Ac-PSMA-617) | Novartis / Advanced Accelerator Applications (AAA) | PSMA / 225Ac (alpha-emitter) | Not yet FDA-approved. Two Phase 3 trials open: NCT06855277 (AAA817 + ARPI vs SOC in 1L PSMA-positive mCRPC) and NCT06780670 (AAA817 vs SOC post-177Lu-PSMA progression) | Intravenous infusion; alpha-emitter requires different radiation-safety handling than 177Lu |
| AZD2265 / FPI-2265 (225Ac-PSMA-I&T) | AstraZeneca (via Fusion Pharmaceuticals acquisition) | PSMA / 225Ac (alpha-emitter); different chelator (PSMA-I&T) than AAA817 | Not yet FDA-approved. Phase 3 VECTRA-01 trial (NCT07611110): AZD2265 vs SOC in PSMA-positive mCRPC | Intravenous infusion |
| 177Lu-TLX591 (Telix Pharmaceuticals rosopatamab tetraxetan; antibody-based PSMA radioligand) | Telix Pharmaceuticals | PSMA / 177Lu (beta-emitter); antibody-based scaffold (rather than small-molecule ligand) | Not yet FDA-approved. Phase 3 ProstACT Global (NCT06520345): 177Lu-TLX591 + SOC vs SOC alone in mCRPC | Intravenous infusion |
| 225Ac-PSMA-Trillium (BAY 3563254) | Bayer | PSMA / 225Ac (alpha-emitter) | Not yet FDA-approved. First-in-human Phase 1 (NCT06217822) in advanced mCRPC | Intravenous infusion (Phase 1 dose-finding) |
| Other emerging agents | Multiple (sponsors per individual NCT) | PSMA / 225Ac or 161Tb (alpha- or beta-emitter); various chelator backbones | Not yet FDA-approved. Phase 1 to Phase 1/2: 225Ac-PSMA-XT, 225Ac-J591 (Cornell-derived antibody-based), 225Ac-AKY-2519, 161Tb-PSMA-I&T, 161Tb-SibuDAB, 161Tb-LNC1011, 177Lu-rhPSMA-10.1, 177Lu-PSMA-EB-01 | Intravenous infusion |
What about PNT2002 / SPLASH? PNT2002 (177Lu-PNT2002, Lantheus / POINT Biopharma) was tested in the SPLASH Phase 3 trial for pre-chemotherapy mCRPC. Public reporting indicated SPLASH did not meet its primary radiographic progression-free survival endpoint — we are not promising patients access to PNT2002 as an approved or pivotal-positive PSMA radioligand here. Patients interested in pre-chemo mCRPC PSMA options should focus on the FDA-approved Pluvicto label (PSMAfore expansion), the AAA817 Phase 3 (NCT06855277), or the VECTRA-01 Phase 3 (NCT07611110). Verify the latest PNT2002 development status before drawing conclusions.
What about Janssen JNJ-69086420? JNJ-69086420 (Convergent-derived actinium-PSMA, acquired into the Janssen pipeline) is in earlier-stage clinical development. We did not surface a recruiting JNJ-69086420 trial in the ClinTrialFinder corpus as of June 17, 2026; the agent is not included on this hub. If a recruiting JNJ-69086420 trial opens later, it will be added.
FDA initial approval March 23, 2022 for adults with PSMA-positive mCRPC who have been treated with at least one ARPI / ARSI and a taxane chemotherapy regimen, based on the VISION pivotal trial (NCT03511664). Label was expanded by the PSMAfore trial (NCT04689828) to the pre-chemotherapy setting (post-ARSI, taxane-naive PSMA-positive mCRPC). Intravenous infusion every 6 weeks. PSMA-PET imaging required upfront for eligibility. Distinctive xerostomia / dry-eye / cytopenia side-effect signal from on-target radiation on salivary glands, lacrimal glands, and bone marrow. ~30 Pluvicto-anchored recruiting trials in the ClinTrialFinder corpus — spanning the approved mCRPC setting, the 1L mCRPC + ARPI combination wave, the de novo mHSPC poor-PSA-responder setting (PEACE6), oligometastatic disease, biochemical recurrence, dose / schedule personalization (PRODIGY-2, FLEX-MRT, RECIPROCAL), re-treatment after prior Pluvicto, low-PSMA-expressing disease (LPS-Boost), and adjuvant treatment for high-risk localized prostate cancer.
The 225Ac (actinium-225, alpha-emitter) successor to Pluvicto using the same PSMA-617 chelator backbone. Two registrational Phase 3 trials open in the ClinTrialFinder corpus: NCT06855277 (AAA817 + ARPI vs SOC in PSMA-positive mCRPC, 1L setting) and NCT06780670 (AAA817 vs SOC in previously treated PSMA-positive mCRPC patients whose disease progressed on or after 177Lu-PSMA targeted therapy). The post-177Lu trial directly addresses the most clinically-pressing question: does alpha-emitter PSMA work after beta-emitter PSMA fails? — the single most important real-world sequencing decision for Pluvicto-experienced patients. Not yet FDA-approved.
The 225Ac alpha-emitter using a different chelator backbone (PSMA-I&T) than AAA817 (PSMA-617). Phase 3 VECTRA-01 (NCT07611110): AZD2265 vs SOC in PSMA-positive mCRPC. AstraZeneca acquired Fusion Pharmaceuticals to bring the program in-house. The chelator-design difference vs AAA817 is a real biological variable — PSMA-I&T has somewhat different binding kinetics and biodistribution than PSMA-617, which may translate into different efficacy / toxicity profiles. The two will not be directly randomized head-to-head; cross-trial efficacy comparisons absent randomized data are not reliable. Not yet FDA-approved.
An antibody-based PSMA radioligand — distinct from the small-molecule ligand chemistry of Pluvicto. Phase 3 ProstACT Global (NCT06520345): 177Lu-TLX591 + SOC vs SOC alone in mCRPC. The antibody-scaffold approach has potentially different biodistribution and dosing kinetics than the small-molecule Pluvicto. Not yet FDA-approved.
Multiple early-stage 225Ac-PSMA agents in development: 225Ac-PSMA-Trillium / BAY 3563254 (Bayer, NCT06217822), 225Ac-PSMA-XT (NCT07135102), 225Ac-J591 (Cornell-derived antibody-based, NCT04886986 with 177Lu-PSMA combination; NCT04946370 pembro + AR inhibitor; NCT07414940 ACTinium-RES-LUTE post-lutetium), 225Ac-AKY-2519 (NCT07581184). Plus terbium-161 (161Tb) agents: 161Tb-PSMA-I&T (NCT05521412, NCT07621692), 161Tb-SibuDAB (NCT06343038), Tb-PSMA-I&T neoadjuvant (NCT07208240), 161Tb-LNC1011 (NCT07381582, not yet). Other 177Lu agents: 177Lu-rhPSMA-10.1 (NCT05413850), 177Lu-PSMA-EB-01 (NCT05613738), 177Lu-PSMA-XT (NCT07096128).
The 55 recruiting PSMA radioligand therapy trials below are grouped by the clinical setting most patients and oncologists ask about first — disease stage + line of therapy + prior treatment context. Each NCT links to ClinicalTrials.gov for current eligibility and study-site details. The Phase 3 wave is concentrated in mCRPC; the earlier-disease setting (mHSPC, oligometastatic, biochemical recurrence, adjuvant) is moving rapidly via Phase 2–3 trials.
The defining PSMA radioligand Phase 3 wave — moving beyond Pluvicto's current label into earlier mCRPC lines and into the actinium-225 alpha-emitter modality:
The FDA-approved Pluvicto setting (post-ARSI ± post-taxane mCRPC) plus combination Phase 1–2 trials:
Patients whose PSMA-PET shows lower-than-typical expression are typically excluded from standard Pluvicto eligibility. Two trials test strategies to extend PSMA radioligand benefit to PSMA-low patients:
Pluvicto's standard 6-cycle every-6-weeks regimen is being tested against flexible / personalized / de-escalated schedules:
Patients who respond to a Pluvicto course and later progress: can re-treatment work?
Earlier-disease settings — patients with rising PSA after local therapy but limited metastatic burden:
Even earlier intervention — PSMA radioligand as adjuvant or in the high-risk localized / locally advanced setting:
Different chelator designs than the PSMA-617 used in Pluvicto — potentially different binding kinetics and biodistribution:
161Tb is a beta-emitter with additional Auger and conversion electrons that may improve micro-metastatic cell kill:
Mechanism-focused studies — understanding how patients respond and resist:
Showing approximately 55 recruiting + 9 not-yet-recruiting interventional PSMA-targeted radioligand therapy trials for prostate cancer in the ClinTrialFinder corpus as of June 17, 2026. Off-prostate PSMA radioligand trials (gliomas, hepatocellular carcinoma, kidney cancer, meningioma) are tracked separately and not included on this prostate-focused hub. PSMA-PET diagnostic-only trials (Pylarify, 68Ga-PSMA-11, 64Cu-bisPSMA, 18F-PSMA-1007, and PSMA PET-guided radiation / prostatectomy without radioligand therapy) are also out-of-scope. For the latest searches: Pluvicto, 177Lu-PSMA-617, 225Ac-PSMA, PSMA radioligand.
PSMA radioligand therapy is one of several systemic options for advanced prostate cancer. The four-class comparison below frames where PSMA fits relative to ARSI, taxane chemotherapy, and PARP inhibitors:
| Class | Approved Drugs | Distinctive Side Effects | Where it fits |
|---|---|---|---|
| PSMA Radioligand Therapy (this page) | Pluvicto (177Lu-PSMA-617) — FDA-approved 2022 | Xerostomia (dry mouth), lacrimal gland damage (dry eyes), cytopenias from on-target radiation on salivary, lacrimal, and bone-marrow tissues; modest renal toxicity; fatigue / nausea; short-term radiation safety precautions | PSMA-positive mCRPC after at least one ARPI (post-taxane in the original VISION label; pre-chemo via the PSMAfore expansion). PSMA-PET imaging required upfront. Emerging 1L mCRPC + ARPI combination (AAA817 Phase 3), mHSPC (PEACE6), oligometastatic (Phase 3 vs observation) |
| ARSI / ARPI (Androgen Receptor Signaling / Pathway Inhibitors) | Enzalutamide, abiraterone, apalutamide, darolutamide | Fatigue, hot flashes, hypertension, hyperglycemia (abiraterone), increased fracture risk, cardiovascular events | Standard mHSPC and mCRPC backbone — usually the first targeted-therapy class after ADT |
| Taxane Chemotherapy | Docetaxel, cabazitaxel | Neutropenia, alopecia, peripheral neuropathy, fatigue, nausea | mHSPC intensification (docetaxel + ADT + ARPI in high-volume disease); post-ARSI mCRPC (docetaxel first, cabazitaxel second); reasonable head-to-head comparator vs Pluvicto for taxane-naive mCRPC (NCT06738303) |
| PARP Inhibitors (HRR-mutated subset) | Olaparib (± abiraterone), niraparib (± abiraterone), talazoparib (± enzalutamide), rucaparib | Anemia, fatigue, nausea, thrombocytopenia; requires BRCA1/2 or other HRR mutation testing for targeted use | BRCA-mutated or HRR-positive mCRPC — either as monotherapy or combined with an ARPI in the first-line mCRPC setting |
How PSMA radioligand is positioned in practice. Pluvicto is most commonly used after a patient has progressed on at least one ARPI — it is a post-ARSI, non-chemotherapy option for patients with PSMA-positive imaging. For some patients, that means it can come before docetaxel chemotherapy (the PSMAfore pre-chemo setting); for others, after docetaxel (the original VISION post-taxane setting). The 1L mCRPC + ARPI combination Phase 3 trials (AAA817 NCT06855277) are testing whether PSMA radioligand should move all the way to the first mCRPC line as part of an upfront combination. The most important practical gate is the PSMA-PET scan upfront — patients without sufficient imaging-confirmed PSMA expression are not candidates today.
Cross-trial efficacy comparisons between PSMA radioligand therapy and ARSI / chemotherapy / PARP — or between 177Lu and 225Ac PSMA agents — have not been validated in most head-to-head randomized trials and should not be inferred from separate single-arm studies. The choice of treatment sequence is a discussion with the patient's medical oncologist, urologist, and (for radioligand therapy) nuclear medicine physician.
PSMA radioligand therapy carries a PSMA-specific signal reflecting where PSMA is normally expressed besides prostate cancer cells — this is what distinguishes the class from ARSI, chemotherapy, or PARP:
By contrast, ARSI carries fatigue / hot-flashes / cardiovascular signals; chemotherapy (docetaxel, cabazitaxel) carries neutropenia / alopecia / neuropathy; PARP inhibitors carry anemia / fatigue / nausea with a requirement for HRR-mutation testing upfront. The PSMA radioligand signal — xerostomia + dry eyes + cytopenias on a PSMA-PET-confirmed PSMA-positive patient — is class-distinctive, generally livable, and the trade-off most patients are willing to accept for a chemotherapy-free systemic option.
What is PSMA radioligand therapy and how does it work?
PSMA radioligand therapy is a small molecule that binds PSMA (Prostate-Specific Membrane Antigen, formal name glutamate carboxypeptidase II) on the surface of prostate cancer cells, chemically linked to a radioactive isotope that delivers targeted radiation. The most common isotope today is lutetium-177 (a beta-emitter with a ~2 mm range), used in Pluvicto (177Lu-PSMA-617) — the only FDA-approved PSMA radioligand. The next-generation wave uses actinium-225, an alpha-emitter with a much shorter range (~0.05 mm) that delivers higher-energy radiation in a smaller area, potentially overcoming tumors that didn't respond well to 177Lu. PSMA is highly expressed on prostate cancer cells, especially in metastatic castration-resistant prostate cancer (mCRPC), but is also expressed at lower levels on normal salivary glands, lacrimal glands, kidneys, and small intestine — which explains the distinctive side-effect profile.
Who is eligible for Pluvicto and why is PSMA-PET imaging required upfront?
Pluvicto (177Lu-PSMA-617) is FDA-approved for adults with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with at least one androgen receptor pathway inhibitor (ARPI / ARSI such as enzalutamide, abiraterone, apalutamide, or darolutamide). FDA approval was granted March 23, 2022 based on the VISION pivotal trial (NCT03511664) in the post-taxane setting, and was expanded by the PSMAfore trial (NCT04689828) to the pre-chemotherapy setting for patients who have progressed on an ARPI but have not yet received taxane chemotherapy. Eligibility for Pluvicto requires a positive PSMA-PET scan upfront — usually with the FDA-approved PSMA-PET tracers Pylarify (18F-DCFPyL / piflufolastat) or Locametz / Illuccix (68Ga-PSMA-11) — to confirm sufficient PSMA expression on tumor lesions for the radioligand to bind. Patients with PSMA-negative imaging or with significant PSMA-low disease (a small fraction of mCRPC) are typically not eligible. Readers should consult the current FDA prescribing information for the most up-to-date label.
What are the side effects to expect (xerostomia, dry eyes, cytopenias)?
The defining PSMA radioligand therapy side effects reflect where PSMA is normally expressed besides prostate cancer: salivary glands, lacrimal glands, kidneys, and small intestine. The most patient-noticeable signals are xerostomia (dry mouth) and lacrimal gland damage (dry eyes) from on-target radiation, both common after multiple cycles and ranging from mild to moderate; severe xerostomia can affect oral intake and dental health. Cytopenias (anemia, thrombocytopenia, neutropenia) are common because radiation also reaches bone marrow, and can be dose-limiting. Fatigue and nausea are common but generally manageable. Renal toxicity is usually modest because the radiolabeled ligand is cleared through the kidneys. Patients receive radiation safety counseling for the first ~48–72 hours after each infusion (limited close contact with infants and pregnant partners, careful bathroom hygiene). Actinium-225 alpha-emitter agents may have a different toxicity profile than lutetium-177 beta-emitters — alpha radiation has a shorter range, potentially lower salivary impact in some studies, but bone-marrow safety in late-line patients is still being characterized in Phase 1–3 trials.
What is the difference between 177Lu-PSMA and 225Ac-PSMA?
Both agents target the same molecule (PSMA) using the same chemistry to bind to prostate cancer cells, but they deliver different types of radiation. 177Lu (lutetium-177) is a beta-emitter with a path length of about 2 mm in tissue — it produces a moderate-energy electron that spreads radiation across multiple adjacent cell layers, which is well-suited to bulky tumors with strong PSMA expression. 225Ac (actinium-225) is an alpha-emitter with a much shorter range (~0.05 mm) that delivers higher linear energy deposition over just a few cell diameters, which may be more effective against micro-metastatic disease or tumors with heterogeneous PSMA expression and may overcome 177Lu resistance. Pluvicto (177Lu-PSMA-617) is the only FDA-approved agent today; all actinium-225 PSMA agents remain investigational, with three Phase 3 trials underway (AAA817 / 225Ac-PSMA-617 in NCT06855277 and NCT06780670; AZD2265 / FPI-2265 / 225Ac-PSMA-I&T in VECTRA-01 / NCT07611110). There is also one head-to-head Phase 1 comparison (NCT07054346). Cross-trial efficacy comparisons between 177Lu and 225Ac agents without head-to-head data are not reliable; the choice today defaults to 177Lu-PSMA-617 as the only approved option.
How do I find a PSMA radioligand therapy clinical trial?
Use ClinTrialFinder's AI-powered matching to surface PSMA radioligand trials based on your specific situation — disease stage (mHSPC, mCRPC, biochemical recurrence, oligometastatic), prior ARPI / ARSI exposure, prior taxane chemotherapy exposure, prior Pluvicto exposure (some trials are specifically for post-Pluvicto progression — NCT06780670 AAA817 post-177Lu-PSMA, NCT07623460 zanzalintinib post-Pluvicto, NCT07414940 ACTinium-RES-LUTE), PSMA-PET status if available, and BRCA / HRR status (relevant for combination Phase 1b NCT07090369 with olaparib). Use the patient-match button below to enter the prostate cancer matching wizard. For Pluvicto specifically, ask your oncologist for a PSMA-PET scan upfront — without imaging-confirmed PSMA expression, eligibility cannot be established. For the broader prostate cancer trial landscape (ARSI, chemotherapy, PARP, bispecifics, ADCs), see /trials/prostate-cancer.
Find Matching PSMA Radioligand Trials
Use ClinTrialFinder's AI-powered matching to find Pluvicto, AAA817, AZD2265, TLX591, and other PSMA radioligand trials based on your disease stage, prior ARPI / taxane / Pluvicto exposure, and PSMA-PET status.
Find Matching PSMA Radioligand TrialsThis page is for information only and is not medical advice. ClinTrialFinder helps you find clinical trials that may match your situation, but enrollment decisions and treatment choices should always be made with your medical oncologist, urologist, and (for radioligand therapy) nuclear medicine physician. Trial eligibility, recruitment status, and treatment details can change — verify directly with the trial sponsor or on ClinicalTrials.gov before acting on any information here. FDA approval dates and indications are summarized for context only; consult the current FDA prescribing information for each drug for authoritative regulatory status.