US Food and Drug Administration (FDA). FDA approves Pluvicto for metastatic castration-resistant prostate cancer. News release March 23, 2022. Accessed January 10, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer.

European Medicines Agency (EMA). Pluvicto: EPAR – medicine overview. European public assessment report December 21, 2022. Accessed January 18, 2023. https://www.ema.europa.eu/en/documents/overview/pluvicto-epar-medicine-overview_en.pdf.

Benešová M, Schäfer M, Bauder-Wüst U, Afshar-Oromieh A, Kratochwil C, Mier W, et al. Preclinical evaluation of a tailor-made DOTA-conjugated PSMA inhibitor with optimized linker moiety for imaging and endoradiotherapy of prostate cancer. J Nucl Med. 2015;56(6):914–20. https://doi.org/10.2967/jnumed.114.147413.

Article  PubMed  CAS  Google Scholar 

Su SL, Huang IP, Fair WR, Powell CT, Heston WD. Alternatively spliced variants of prostate-specific membrane antigen RNA: ratio of expression as a potential measurement of progression. Cancer Res. 1995;55(7):1441–3.

PubMed  CAS  Google Scholar 

Paschalis A, Sheehan B, Riisnaes R, Nava Rodrigues D, Gurel B, Bertan C, et al. Prostate-specific membrane antigen heterogeneity and DNA repair defects in prostate cancer. Eur Urol. 2019;76:469–78. https://doi.org/10.1016/j.eururo.2019.06.030.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Matthias J, Engelhardt J, Schäfer M, Bauder-Wüst U, Meyer PT, Haberkorn U, et al. Cytoplasmic localization of prostate-specific membrane antigen inhibitors may confer advantages for targeted cancer therapies. Cancer Res. 2021;81:2234–45. https://doi.org/10.1158/0008-5472.CAN-20-1624.

Article  CAS  Google Scholar 

Morris ZS, Wang AZ, Knox SJ. The radiobiology of radiopharmaceuticals. Semin Radiat Oncol. 2021;31(1):20–7. https://doi.org/10.1016/j.semradonc.2020.07.002.

Article  PubMed  PubMed Central  Google Scholar 

US Food and Drug Administration (FDA). Label for PLUVICTO™. Accessed January 11, 2023. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=215833.

Graf F, Fahrer J, Maus S, Morgenstern A, Bruchertseifer F, Venkatachalam S, et al. DNA Double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy. PLoS One. 2014;9(2):e88239. https://doi.org/10.1371/journal.pone.0088239.

Article  PubMed Central  CAS  Google Scholar 

Kassis AI. Therapeutic radionuclides: biophysical and radiobiologic principles. Semin Nucl Med. 2008;38(5):358–66. https://doi.org/10.1053/j.semnuclmed.2008.05.002.

Article  PubMed  PubMed Central  Google Scholar 

Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385:1091–103. https://doi.org/10.1056/NEJMoa2107322.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Kuo P, Hesterman J, Rahbar K, Kendi AT, Wei XX, Fang B, et al. [68Ga]Ga-PSMA-11 PET baseline imaging as a prognostic tool for clinical outcomes to [177Lu]Lu-PSMA-617 in patients with mCRPC: a VISION substudy. J Clin Oncol. 2022;40(16_suppl):5002–5002. https://doi.org/10.1200/JCO.2022.40.16_suppl.5002.

Hofman MS, Emmett L, Sandhu S, Iravani A, Joshua AM, Goh JC, et al. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397:797–804. https://doi.org/10.1016/S0140-6736(21)00237-3.

Article  PubMed  CAS  Google Scholar 

Ruigrok EAM, Tamborino G, de Blois E, Roobol SJ, Verkaik N, de Saint-Hubert M, et al. Correction to: In vitro dose effect relationships of actinium-225- and lutetium-177-labeled PSMA-I&T. Eur J Nucl Med Mol Imaging. 2022;49:3956–7. https://doi.org/10.1007/s00259-022-05845-2.

Article  PubMed  PubMed Central  Google Scholar 

Sathekge MM, Bruchertseifer F, Vorster M, Morgenstern A, Lawal IO. Global experience with PSMA-based alpha therapy in prostate cancer. Eur J Nucl Med Mol Imaging. 2021;49:30–46. https://doi.org/10.1007/s00259-021-05434-9.

Article  PubMed  PubMed Central  Google Scholar 

Zacherl MJ, Gildehaus FJ, Mittlmeier L, Böning G, Gosewisch A, Wenter V, et al. First Clinical results for PSMA-targeted α-therapy using 225Ac-PSMA-I&T in advanced-mCRPC patients. J Nucl Med. 2021;62:669–674. https://doi.org/10.2967/jnumed.120.251017. Provides response assessment after alpha therapy distinguishing between patients with and without history of prior [177Lu]Lu-PSMA RLT.

Sathekge M, Bruchertseifer F, Vorster M, Lawal IO, Knoesen O, Mahapane J, et al. Predictors of overall and disease-free survival in metastatic castration-resistant prostate cancer patients receiving 225Ac-PSMA-617 radioligand therapy. J Nucl Med. 2020;61:62–69. https://doi.org/10.2967/jnumed.119.229229. Compares differences in PFS and OS after alpha therapy between patients with and without history of prior [177Lu]Lu-PSMA RLT.

Yadav MP, Ballal S, Sahoo RK, Tripathi M, Seth A, Bal C. Efficacy and safety of 225Ac-PSMA-617 targeted alpha therapy in metastatic castration-resistant prostate cancer patients. Theranostics. 2020;10(20):9364–9377. https://doi.org/10.7150/thno.48107. Provides a comprehensive analysis of response and survival outcomes following alpha therapy in two balanced groups of patients with and without history of prior [177Lu]Lu-PSMA RLT.

Feuerecker B, Tauber R, Knorr K, Heck M, Beheshti A, Seidl C, et al. Activity and adverse events of actinium-225-PSMA-617 in advanced metastatic castration-resistant prostate cancer after failure of lutetium-177-PSMA. Eur Urol. 2021;79:343–350. https://doi.org/10.1016/j.eururo.2020.11.013. Analyses response and survival outcomes after alpha therapy of patients refractory to [177Lu]Lu-PSMA RLT and distinguishes between prior responders and non-responders to RLT.

Khreish F, Ebert N, Ries M, Maus S, Rosar F, Bohnenberger H, et al. 225Ac-PSMA-617/177Lu-PSMA-617 tandem therapy of metastatic castration-resistant prostate cancer: pilot experience. Eur J Nucl Med Mol Imaging. 2020;47:721–728. https://doi.org/10.1007/s00259-019-04612-0. Compares response and survival outcomes after [225Ac]Ac-PSMA/[177Lu]Lu-PSMA tandem therapy of [177Lu]Lu-PSMA RLT-refractory patients distinguishing between prior responders and non-responders to RLT.

Rosar F, Hau F, Bartholomä M, Maus S, Stemler T, Linxweiler J, et al. Molecular imaging and biochemical response assessment after a single cycle of [225Ac]Ac-PSMA-617/[177Lu]Lu-PSMA-617 tandem therapy in mCRPC patients who have progressed on [177Lu]Lu-PSMA-617 monotherapy. Theranostics. 2021;11(9):4050–4060. https://doi.org/10.7150/thno.56211. Reports response and survival outcomes after [225Ac]Ac-PSMA/[177Lu]Lu-PSMA tandem therapy of [177Lu]Lu-PSMA RLT-refractory patients in a more challenging cohort than in 20.

Kulkarni H, Zhang J, Langbein T, Schuchardt C, Singh A, Mueller D, et al. Radioligand therapy using combination of Ac-225 and Lu-177 labelled PSMA ligands for progressive end-stage metastatic prostate cancer: effective trade-off between response and toxicity. J Nucl Med. 2019;60(supplement 1):464. [abstract]

Rosar F, Krause J, Bartholomä M, Maus S, Stemler T, Hierlmeier I, et al. Efficacy and safety of [225Ac]Ac-PSMA-617 augmented [177Lu]Lu-PSMA-617 radioligand therapy in patients with highly advanced mCRPC with poor prognosis. Pharmaceutics. 2021;13:722. https://doi.org/10.3390/pharmaceutics13050722.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Rahbar K, Ahmadzadehfar H, Kratochwil C, Haberkorn U, Schäfers M, Essler M, et al. German multicenter study investigating 177Lu-PSMA-617 radioligand therapy in advanced prostate cancer patients. J Nucl Med. 2017;58:85–90. https://doi.org/10.2967/jnumed.116.183194.

Article  PubMed  CAS  Google Scholar 

Buteau JP, Martin AJ, Emmett L, Iravani A, Sandhu S, Joshua AM, et al. PSMA and FDG-PET as predictive and prognostic biomarkers in patients given [177Lu]Lu-PSMA-617 versus cabazitaxel for metastatic castration-resistant prostate cancer (TheraP): a biomarker analysis from a randomised, open-label, phase 2 trial. Lancet Oncol. 2022;23(11):1389–97. https://doi.org/10.1016/S1470-2045(22)00605-2.

Article  PubMed  CAS  Google Scholar 

Watt F, Martorana A, Brookes DE, Ho T, Kingsley E, O’Keefe DS, et al. A tissue-specific enhancer of the prostate-specific membrane antigen gene, FOLH1. Genomics. 2001;73(3):243–54. https://doi.org/10.1006/geno.2000.6446.

Article  PubMed  CAS  Google Scholar 

Wright GL Jr, Grob BM, Haley C, Grossman K, Newhall K, Petrylak D, et al. Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy. Urology. 1996;48:326–34. https://doi.org/10.1016/s0090-4295(96)00184-7.

Article  PubMed  Google Scholar 

Kranzbühler B, Salemi S, Umbricht CA, Müller C, Burger IA, Sulser T, et al. Pharmacological upregulation of prostate-specific membrane antigen (PSMA) expression in prostate cancer cells. Prostate. 2018;78:758–65. https://doi.org/10.1002/pros.23522.

Article  PubMed  CAS  Google Scholar 

Lückerath K, Wei L, Fendler WP, Evans-Axelsson S, Stuparu AD, Slavik R, et al. Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer. EJNMMI Res. 2018;8:96. https://doi.org/10.1186/s13550-018-0451-z.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Staniszewska M, Fragoso Costa P, Eiber M, Klose JM, Wosniack J, Reis H, et al. Enzalutamide enhances PSMA expression of PSMA-low prostate cancer. Int J Mol Sci. 2021;22:7431. https://doi.org/10.3390/ijms22147431.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Emmett L, Yin C, Crumbaker M, Hruby G, Kneebone A, Epstein R, et al. Rapid modulation of PSMA expression by androgen deprivation: serial 68Ga-PSMA-11 PET in men with hormone-sensitive and castrate-resistant prostate cancer commencing androgen blockade. J Nucl Med. 2019;60:950–4. https://doi.org/10.2967/jnumed.118.223099.

Article  PubMed  CAS  Google Scholar 

Rosar F, Dewes S, Ries M, Schäfer A, Khreish F, Maus S, et al. New insights in the paradigm of upregulation of tumoral PSMA expression by androgen receptor blockade: enzalutamide induces PSMA upregulation in castration-resistant prostate cancer even in patients having previously progressed on enzalutamide. Eur J Nucl Med Mol Imaging. 2020;47(3):687–94. https://doi.org/10.1007/s00259-019-04674-0.

Article  PubMed  CAS  Google Scholar 

Rosar F, Neher R, Burgard C, Linxweiler J, Schreckenberger M, Hoffmann MA, et al. Upregulation of PSMA expression by enzalutamide in patients with advanced mCRPC. Cancers. 2022;14:1696. https://doi.org/10.3390/cancers14071696.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Rosar F, Bader H, Bartholomä M, Maus S, Burgard C, Linxweiler J, et al. Addition of standard enzalutamide medication shows synergistic effects on response to [177Lu]Lu-PSMA-617 radioligand therapy in mCRPC patients with imminent treatment failure-preliminary evidence of pilot experience. Cancers (Basel). 2022;14(11):2691. https://doi.org/10.3390/cancers14112691. Shows that it is possible to rescue the efficacy of [177Lu]Lu-PSMA-617 in refractory patients by adding enzalutamide to the treatment regimen.

Emmett L, Subramaniam S, Joshua AM, Crumbaker M, Martin A, Zhang AY, et al. ENZA-p trial protocol: a randomized phase II trial using prostate-specific membrane antigen as a therapeutic target and prognostic indicator in men with metastatic castration-resistant prostate cancer treated with enzalutamide (ANZUP 1901). BJU Int. 2021;128(5):642–51. https://doi.org/10.1111/bju.15491.

Article  PubMed  CAS  Google Scholar 

Suman S, Parghane RV, Joshi A, Prabhash K, Talole S, Basu S. Combined 177Lu-PSMA-617 PRLT and abiraterone acetate versus 177Lu-PSMA-617 PRLT monotherapy in metastatic castration-resistant prostate cancer: an observational study comparing the response and durability. The Prostate. 2021;81:1225–1234. https://doi.org/10.1002/pros.24219. Reports an improvement of PFS and OS with combined [177Lu]Lu-PSMA-617 and abiraterone acetate, albeit in [177Lu]PSMA RLT-naïve patients only.

Müller C, de Prado LM, Dominietto MD, Umbricht CA, Safai S, Perrin RL, et al. Combination of proton therapy and radionuclide therapy in mice: preclinical pilot study at the Paul Scherrer Institute. Pharmaceutics. 2019;11:450. https://doi.org/10.3390/pharmaceutics11090450.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Sheehan B, Neeb A, Buroni L, Paschalis A, Riisnaes R, Gurel B, et al. Prostate-specific membrane antigen expression and response to DNA damaging agents in prostate cancer. Clin Cancer Res. 2022;28:3104–15. https://doi.org/10.1158/1078-0432.CCR-21-4531.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Wei X, Schlenkhoff C, Schwarz B, Essler M, Ahmadzadehfar H. Combination of 177Lu-PSMA-617 and external radiotherapy for the treatment of cerebral metastases in patients with castration-resistant metastatic prostate cancer. Clin Nucl Med. 2017;42(9):704–6. https://doi.org/10.1097/RLU.0000000000001763.