{"entity":{"id":"psma-theranostics-roadmap","kind":"roadmap","name":"PSMA theranostics roadmap: antigen discovery → PSMA PET → 177Lu-PSMA-617 → earlier lines and alpha","aka":[],"tldr":"Prostate-specific membrane antigen was found on prostate cancer cells in 1987. It took until 2020-2022 for scans and treatments that target it to reach approval, but once they did, PSMA PET and Pluvicto changed how metastatic prostate cancer is staged and treated, and the same target is now being tried earlier in the disease and with more powerful alpha particles.","summary":"Prostate-specific membrane antigen (PSMA) was first identified in 1987 when Horoszewicz and Murphy raised the monoclonal antibody 7E11-C5 against the LNCaP prostate cancer cell line; Heston and Fair's group at Memorial Sloan Kettering cloned the PSMA gene in 1993. The first PSMA-targeted imaging agent to reach approval, indium-111 capromab pendetide (ProstaScint), was approved by the FDA on 28 October 1996, but bound only an intracellular epitope and had limited clinical impact.\n\nThe modern era begins with small-molecule PSMA ligands: Eder and colleagues at the German Cancer Research Center (DKFZ) Heidelberg synthesised the gallium-68-labelled HBED-CC compound that became PSMA-11 in 2012, building on first-in-human work from 2011. It took until 1 December 2020 for the FDA to approve 68Ga-PSMA-11 (jointly, as separate applications from UCSF and UCLA), the first PSMA PET agent approved in the US, followed by the first commercially distributable PSMA PET agent, Pylarify (piflufolastat F 18), on 26 May 2021. On the therapy side, Kratochwil's Heidelberg group had already shown in 2016 that the corresponding alpha-emitting ligand, 225Ac-PSMA-617, could produce complete responses; the beta-emitting version, 177Lu-PSMA-617 (Pluvicto), was approved by the FDA on 23 March 2022 for post-chemotherapy mCRPC, based on the VISION trial (a 38% reduction in risk of death).\n\nThe label then moved earlier: on 28 March 2025 the FDA expanded Pluvicto's indication, based on the PSMAfore trial, to PSMA-positive mCRPC patients who have progressed on one androgen receptor pathway inhibitor and are considered appropriate to delay chemotherapy, removing the prior-taxane requirement and roughly tripling the eligible US population. The alpha-emitting analogue of Pluvicto, 225Ac-PSMA-617 (AAA817, Novartis), and a second alpha PSMA ligand, FPI-2265 (225Ac-PSMA-I&T, Fusion Pharmaceuticals), are both now in phase 3 programmes for patients whose disease has progressed on 177Lu-PSMA, the next planned step in the sequence.","asOf":"2026-09-22","links":[{"label":"FDA: Ga 68 PSMA-11 injection approval (UCSF/UCLA), December 2020","url":"https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212643Orig1s000Approv.pdf"},{"label":"Lantheus: FDA approval of Pylarify, May 2021","url":"https://investor.lantheus.com/news-releases/news-release-details/lantheus-receives-us-fda-approval-pylarifyr-piflufolastat-f-18"},{"label":"FDA: Pluvicto (lutetium Lu 177 vipivotide tetraxetan) approval summary, March 2022 (PMC)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10159870/"},{"label":"FDA: Pluvicto label expansion based on PSMAfore, March 2025","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication"}],"tags":[],"related":["f-18","ga-68","in-111","lu-177","ac-225"],"indications":["prostate","prostate-mcrpc"],"sections":[],"technologies":["psma-pet","lu177-radioligand-therapy","targeted-alpha-therapy"],"targets":["psma"],"drugs":["ga68-psma-11","pylarify","pluvicto","illuccix","locametz","lu177-psma-it","ac225-psma"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["vision","psmafore","alphabreak"],"people":["clemens-kratochwil","uwe-haberkorn","michael-morris","thomas-hope","hofman-michael"],"bottlenecks":[],"keyPapers":["paper-vision-nejm-2021","paper-propsma-hofman-lancet-2020"],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1987-1996","title":"PSMA discovered; first imaging agent approved","description":"Horoszewicz, Kawinski and Murphy raise the 7E11-C5 monoclonal antibody against PSMA in 1987; Heston and Fair's group at Memorial Sloan Kettering clone the PSMA gene in 1993. The FDA approves the first PSMA-targeted imaging agent, indium-111 capromab pendetide (ProstaScint, Cytogen), on 28 October 1996, though the antibody binds an intracellular epitope and offers limited sensitivity.","refs":["prostate"],"status":"historic"},{"era":"2011-2012","title":"Small-molecule PSMA ligands and first-in-human PET","description":"The Heidelberg group at the German Cancer Research Center (DKFZ) reports first-in-human imaging with a gallium-68-labelled small-molecule PSMA inhibitor in 2011; Eder and colleagues publish the synthesis of the HBED-CC-chelated compound that becomes PSMA-11 in 2012, replacing antibody-based imaging with fast, high-contrast small-molecule PET.","refs":["psma-pet","uwe-haberkorn"],"status":"historic"},{"era":"2016","title":"225Ac-PSMA-617: alpha therapy proof of concept","description":"Kratochwil, Bruchertseifer and colleagues report complete biochemical and imaging responses with 225Ac-PSMA-617 in two heavily pretreated patients with mCRPC (J Nucl Med, 2016), the first demonstration that a PSMA-targeted alpha emitter could produce deep responses where beta therapy and other options had failed.","refs":["clemens-kratochwil","ac225-psma"],"status":"historic"},{"era":"2020-2022","title":"PSMA PET and Pluvicto reach approval","description":"The FDA approves 68Ga-PSMA-11 on 1 December 2020 (UCSF and UCLA applications), the first PSMA PET agent approved in the US; Pylarify (piflufolastat F 18, Lantheus) follows on 26 May 2021 as the first commercially distributed PSMA PET agent. Pluvicto (177Lu-PSMA-617, Novartis) is approved 23 March 2022 for PSMA-positive mCRPC after androgen receptor pathway inhibition and taxane chemotherapy, based on VISION (38% reduction in risk of death), the first FDA-approved targeted radioligand therapy for prostate cancer.","refs":["ga68-psma-11","pylarify","pluvicto","vision","paper-vision-nejm-2021"],"status":"historic"},{"era":"2025","title":"Pluvicto moves to an earlier line","description":"The FDA expands the Pluvicto label on 28 March 2025, based on the PSMAfore trial, to adults with PSMA-positive mCRPC who have progressed on at least one androgen receptor pathway inhibitor and are considered appropriate to delay taxane chemotherapy, removing the prior-taxane requirement and roughly tripling the eligible US patient population.","refs":["psmafore","pluvicto"],"status":"current"},{"era":"2024-2028","title":"Alpha-emitting PSMA ligands after 177Lu-PSMA","description":"Two alpha-emitting PSMA ligands are in phase 2/3 development for patients progressing after 177Lu-PSMA therapy: FPI-2265 (225Ac-PSMA-I&T, Fusion Pharmaceuticals/AstraZeneca) in AlphaBreak, and AAA817 (225Ac-PSMA-617, Novartis) in a phase 3 programme including PSMAcTION (NCT06780670) and a combination trial with an androgen receptor pathway inhibitor (NCT06855277).","refs":["alphabreak","ac225-psma"],"status":"emerging"},{"era":"2028+","title":"Speculative: PSMA-directed therapy at diagnosis","description":"Ideas under discussion include PSMA-PET-guided metastasis-directed therapy as a curative strategy in oligorecurrent disease, alpha-emitting PSMA therapy at first metastatic diagnosis rather than after multiple prior lines, and using PSMA PET tumour volume as a formally qualified imaging biomarker for trials.","refs":["idea-psma-pet-guided-mdt","idea-alpha-first-mhspc","idea-tr2-psma-volume-qualification"],"status":"speculative"}],"watch":[{"item":"AAA817 + ARPI vs standard of care in PSMA-positive mCRPC, phase 3 primary completion","expected":"Primary Completion (Estimated): 2028-09-29","source":"https://clinicaltrials.gov/study/NCT06855277","refs":["novartis"]},{"item":"AAA817 vs standard of care after 177Lu-PSMA progression (PSMAcTION), primary completion","expected":"Primary completion date: Jun 27, 2028 (Anticipated)","source":"https://www.allclinicaltrials.com/study/NCT06780670","refs":["novartis"]},{"item":"AlphaBreak (FPI-2265) phase 2 primary completion","expected":"Estimated Completion: July 23, 2026","source":"https://www.ancora.ai/en/detailsradiopharm/NCT06402331","refs":["alphabreak","fusion-pharma"]}]},"route":"/roadmaps/psma-theranostics-roadmap/","neighbours":{"isotope":[{"id":"ac-225","kind":"isotope","name":"Actinium-225","route":"/isotopes/ac-225/"},{"id":"f-18","kind":"isotope","name":"Fluorine-18","route":"/isotopes/f-18/"},{"id":"ga-68","kind":"isotope","name":"Gallium-68","route":"/isotopes/ga-68/"},{"id":"in-111","kind":"isotope","name":"Indium-111","route":"/isotopes/in-111/"},{"id":"lu-177","kind":"isotope","name":"Lutetium-177","route":"/isotopes/lu-177/"}],"indication":[{"id":"prostate-mcrpc","kind":"indication","name":"Metastatic castration-resistant prostate cancer","route":"/indications/prostate-mcrpc/"},{"id":"prostate","kind":"indication","name":"Prostate cancer","route":"/indications/prostate/"}],"technology":[{"id":"lu177-radioligand-therapy","kind":"technology","name":"Lutetium-177 radioligand therapy","route":"/technologies/lu177-radioligand-therapy/"},{"id":"psma-pet","kind":"technology","name":"PSMA PET","route":"/technologies/psma-pet/"},{"id":"targeted-alpha-therapy","kind":"technology","name":"Targeted alpha therapy","route":"/technologies/targeted-alpha-therapy/"}],"target":[{"id":"psma","kind":"target","name":"PSMA","route":"/targets/psma/"}],"drug":[{"id":"lu177-psma-it","kind":"drug","name":"177Lu-PSMA-I&T","route":"/drugs/lu177-psma-it/"},{"id":"ac225-psma","kind":"drug","name":"Actinium-225 PSMA agents","route":"/drugs/ac225-psma/"},{"id":"ga68-psma-11","kind":"drug","name":"Gallium-68 gozetotide (PSMA-11)","route":"/drugs/ga68-psma-11/"},{"id":"illuccix","kind":"drug","name":"Illuccix (kit for Ga-68 gozetotide)","route":"/drugs/illuccix/"},{"id":"locametz","kind":"drug","name":"Locametz (kit for Ga-68 gozetotide)","route":"/drugs/locametz/"},{"id":"pluvicto","kind":"drug","name":"Lutetium-177 vipivotide tetraxetan","route":"/drugs/pluvicto/"},{"id":"pylarify","kind":"drug","name":"Piflufolastat F-18 / Pylarify TruVu","route":"/drugs/pylarify/"}],"trial":[{"id":"alphabreak","kind":"trial","name":"AlphaBreak (FPI-2265) & AcTION (225Ac-PSMA-617)","route":"/trials/alphabreak/"},{"id":"psmafore","kind":"trial","name":"PSMAfore","route":"/trials/psmafore/"},{"id":"vision","kind":"trial","name":"VISION","route":"/trials/vision/"}],"person":[{"id":"clemens-kratochwil","kind":"person","name":"Clemens Kratochwil","route":"/people/clemens-kratochwil/"},{"id":"hofman-michael","kind":"person","name":"Michael Hofman","route":"/people/hofman-michael/"},{"id":"michael-morris","kind":"person","name":"Michael J. Morris","route":"/people/michael-morris/"},{"id":"thomas-hope","kind":"person","name":"Thomas A. Hope","route":"/people/thomas-hope/"},{"id":"uwe-haberkorn","kind":"person","name":"Uwe Haberkorn","route":"/people/uwe-haberkorn/"}],"paper":[{"id":"paper-propsma-hofman-lancet-2020","kind":"paper","name":"proPSMA: PSMA PET-CT versus conventional imaging for staging high-risk prostate cancer","route":"/key-papers/paper-propsma-hofman-lancet-2020/"},{"id":"paper-vision-nejm-2021","kind":"paper","name":"VISION: lutetium-177 PSMA-617 radioligand therapy extends survival in advanced prostate cancer","route":"/key-papers/paper-vision-nejm-2021/"}],"idea":[{"id":"idea-alpha-first-mhspc","kind":"idea","name":"Alpha-emitting PSMA therapy at first metastatic diagnosis","route":"/ideas/idea-alpha-first-mhspc/"},{"id":"idea-psma-pet-guided-mdt","kind":"idea","name":"PSMA-PET-guided metastasis-directed therapy as a curative strategy in oligorecurrent prostate cancer","route":"/ideas/idea-psma-pet-guided-mdt/"},{"id":"idea-tr2-psma-volume-qualification","kind":"idea","name":"Qualify PSMA PET tumour volume as a validated imaging biomarker","route":"/ideas/idea-tr2-psma-volume-qualification/"}]}}