Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Emerging evidence for sequencing and combining PSMA-based therapies in prostate cancer

Nature Reviews Urology (2025)Cite this article

Subjects

Abstract

Prostate-specific membrane antigen (PSMA) is upregulated in prostate cancer cells relative to other cells. The increased expression and enzymatic activity of PSMA in high-stage disease confers a selective advantage on such cells, contributing to their increased proliferation, the tendency to metastasize and the development of a castration-resistant phenotype. The decades of radiobiochemical advances in the development of PSMA targeting radiolabelled ligands has led to the subsequent FDA approval of a number of radiotracers and radiotherapeutics for clinical use. Novel developments in therapeutic advances using PSMA-based combinatorial approaches include PSMA-targeted antibody–drug conjugates and PSMA-targeted radionuclide payloads. Combining and sequencing some of these strategies with standard therapy options such as surgery, radiotherapy and androgen receptor pathway inhibitors could improve patient outcomes. Immunotherapy and chimeric antigen receptor T cell therapy are relevant to PSMA-based therapies as PSMA can serve as a specific target antigen for these treatments, enabling precise tumour recognition and enhanced efficacy of prostate cancer therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: ADC.
Fig. 2: PSMA–CD3 coupling.

Similar content being viewed by others

References

  1. European Association of Urology. Epidemiology and aetiology. EAU https://uroweb.org/guidelines/prostate-cancer/chapter/epidemiology-and-aetiology (2023).

  2. World Health Organization. Cancer today. IARC https://gco.iarc.fr/today/en/dataviz/tables?mode=population&types=1&cancers=27&group_populations=0&multiple_populations=1&sexes=1 (2022).

  3. Rönningås, U., Holm, M., Fransson, P., Beckman, L. & Wennman-Larsen, A. Symptoms and quality of life among men starting treatment for metastatic castration-resistant prostate cancer — a prospective multicenter study. BMC Palliat. Care 23, 80 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Jain, R. et al. Patient, caregiver experiences in metastatic castration-resistant prostate cancer: insights from a multi-national survey. Future Oncol. 21, 2053–2066 (2025).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Rajasekaran, A. K., Anilkumar, G. & Christiansen, J. J. Is prostate-specific membrane antigen a multifunctional protein? Am. J. Physiol. Cell Physiol. 288, 975 (2005).

    Article  Google Scholar 

  6. Bravaccini, S. et al. PSMA expression: a potential ally for the pathologist in prostate cancer diagnosis. Sci. Rep. 8, 4254 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bakht, M. K. et al. Neuroendocrine differentiation of prostate cancer leads to PSMA suppression. Endocr. Relat. Cancer 26, 131–146 (2018).

    Article  PubMed  Google Scholar 

  8. Hupe, M. C. et al. Expression of Prostate-Specific Membrane Antigen (PSMA) on biopsies is an independent risk stratifier of prostate cancer patients at time of initial diagnosis. Front. Oncol. 8, 623 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  9. [No authors listed] FDA approves first PSMA-targeted PET drug. J. Nucl. Med. 62, 11N (2021).

  10. US Food and Drug Administration. FDA approves second PSMA-targeted PET imaging drug for men with prostate cancer. FDA https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-second-psma-targeted-pet-imaging-drug-men-prostate-cancer (2021).

  11. ASCO Post Staff. FDA approves flotufolastat fluorine-18 injection, first radiohybrid PSMA-targeted PET imaging agent for prostate cancer. ASCO Post https://ascopost.com/news/may-2023/fda-approves-flotufolastat-fluorine-18-injection-first-radiohybrid-psma-targeted-pet-imaging-agent-for-prostate-cancer (2023).

  12. Wurzer, A. et al. Radiohybrid ligands: a novel tracer concept exemplified by 18F- or 68Ga-labeled rhPSMA inhibitors. J. Nucl. Med. 61, 735–742 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Rauscher, I. et al. Detection efficacy of 18F-rhPSMA-7.3 PET/CT and impact on patient management in patients with biochemical recurrence of prostate cancer after radical prostatectomy and prior to potential salvage treatment. J. Nucl. Med. 62, 1719–1726 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Wang, Q. et al. Diagnostic efficacy of [99mTc]Tc-PSMA SPECT/CT for prostate cancer: a meta-analysis. BMC Cancer 24, 982 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. de Barros, H. A. et al. Robot-assisted prostate-specific membrane antigen-radioguided salvage surgery in recurrent prostate cancer using a DROP-IN gamma probe: the first prospective feasibility study. Eur. Urol. 82, 97–105 (2022).

    Article  PubMed  Google Scholar 

  16. Medicines and Healthcare products Regulatory Agency. World first as MHRA approves trofolastat for diagnostic imaging of prostate cancer in men. MHRA https://www.gov.uk/government/news/world-first-as-mhra-approves-trofolastat-for-diagnostic-imaging-of-prostate-cancer-in-men (2025).

  17. Pant, V., Vinjamuri, S., Zanial, A. Z. & Naeem, F. Lessons from a 3-year review of PSMA PET-CT in a tertiary setting: can we fine tune referral criteria by identifying factors predicting positivity and negativity? Diagnostics 13, 2542 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Udovicich, C. et al. Evolving paradigms in prostate cancer: the integral role of prostate-specific membrane antigen positron emission tomography/computed tomography in primary staging and therapeutic decision-making. Int. J. Radiat. Oncol. Biol. Phys. 121, 307–316 (2025).

    Article  PubMed  Google Scholar 

  19. Donswijk, M. L. et al. The accuracy and intra- and interobserver variability of PSMA PET/CT for the local staging of primary prostate cancer. Eur. J. Nucl. Med. Mol. Imaging 51, 1741–1752 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. National Center for Biotechnology Information. Molecular Imaging and Contrast Agent Database (MICAD) (NCBI, 2013).

  21. Chang, S. S. Overview of prostate-specific membrane antigen. Rev. Urol. 6, S13–S18 (2004).

    PubMed  PubMed Central  Google Scholar 

  22. Sengupta, S., Asha Krishnan, M., Chattopadhyay, S. & Chelvam, V. Comparison of prostate-specific membrane antigen ligands in clinical translation research for diagnosis of prostate cancer. Cancer Rep. 2, e1169 (2019).

    Google Scholar 

  23. Stein, M. N. et al. Preliminary results from a phase 1/2 study of co-stimulatory bispecific PSMAxCD28 antibody REGN5678 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 41, 154 (2023).

    Article  Google Scholar 

  24. Kelly, W. et al. A phase 1/2 study of REGN4336, a PSMAxCD3 bispecific antibody, alone and in combination with cemiplimab in patients with metastatic castration-resistant prostate cancer. J. Clin. Oncol. 41, TPS284 (2023).

    Article  Google Scholar 

  25. Hummel, H.-D. et al. Pasotuxizumab, a BiTE immune therapy for castration-resistant prostate cancer: phase I, dose-escalation study findings. Immunotherapy 13, 125–141 (2021).

    Article  PubMed  CAS  Google Scholar 

  26. Vaishampayan, U. N. et al. Phase II trial of pembrolizumab and anti-CD3 x anti-HER2 bispecific antibody-armed activated T cells in metastatic castration-resistant prostate cancer. Clin. Cancer Res. 29, 122–133 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Milowsky, M. I. et al. Phase 1/2 multiple ascending dose trial of the prostate-specific membrane antigen-targeted antibody drug conjugate MLN2704 in metastatic castration-resistant prostate cancer. Urol. Oncol. 34, 530.e15–530.e21 (2016).

    Article  PubMed  CAS  Google Scholar 

  28. Paschalis, A. et al. Prostate-specific membrane antigen heterogeneity and DNA repair defects in prostate cancer. Eur. Urol. 76, 469–478 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Narayan, V. et al. PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat. Med. 28, 724–734 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Alpen, E. L. in Radiation Biophysics 2nd edn 1–10 (Academic, 1998).

  31. Kassis, A. I. Therapeutic radionuclides: biophysical and radiobiologic principles. Semin. Nucl. Med. 38, 358–366 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kim, Y.-S. & Brechbiel, M. W. An overview of targeted alpha therapy. Tumor Biol. 33, 573–590 (2012).

    Article  CAS  Google Scholar 

  33. Graf, F. 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 9, e88239 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Batra, J. S. et al. Phase I trial of docetaxel plus lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 (177Lu-J591) for metastatic castration-resistant prostate cancer. Urol. Oncol. 38, 848.e9–848.e16 (2020).

    Article  PubMed  CAS  Google Scholar 

  35. Czerwińska, M., Bilewicz, A., Kruszewski, M., Wegierek-Ciuk, A. & Lankoff, A. Targeted radionuclide therapy of prostate cancer-from basic research to clinical perspectives. Molecules 25, 1743 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  36. de Kruijff, R., Wolterbeek, H. & Denkova, A. A critical review of alpha radionuclide therapy — how to deal with recoiling daughters? Pharmaceuticals 8, 321–336 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Eychenne, R., Chérel, M., Haddad, F., Guérard, F. & Gestin, J.-F. Overview of the most promising radionuclides for targeted alpha therapy: the “Hopeful Eight”. Pharmaceutics 13, 906 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Golan, S. et al. Neoadjuvant 177Lu-PSMA-I&T radionuclide treatment in patients with high-risk prostate cancer before radical prostatectomy: a single-arm phase 1 trial. Eur. Urol. Oncol. 6, 151–159 (2023).

    Article  PubMed  Google Scholar 

  39. Griffiths, M. R. et al. First-in-human 212Pb-PSMA-targeted α-therapy SPECT/CT imaging in a patient with metastatic castration-resistant prostate cancer. J. Nucl. Med. 65, 664 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  40. ARTBIO. FogPharma and ARTBIO announce collaboration to co-develop multiple Helicon-enabled alpha-particle radioligand therapies for the treatment of cancer. ARTBIO https://artbio.com/fogpharma-and-artbio-announce-collaboration-to-co-develop-multiple-helicon-enabled-alpha-particle-radioligand-therapies-for-the-treatment-of-cancer (2024).

  41. Saidi, A., Stallons, T. A., Wong, A. G. & Torgue, J. J. Preclinical investigation of [212Pb]Pb-DOTAM-GRPR1 for peptide receptor radionuclide therapy in a prostate tumor model. J. Nucl. Med. 65, 1769–1775 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Oranomed. A diverse pipeline of 212Pb-labeled compounds. Oranomed https://www.oranomed.com/en/pipeline (2025).

  43. Tagawa, S. T. et al. Prostate-specific membrane antigen-targeting alpha emitter via antibody delivery for metastatic castration-resistant prostate cancer: a phase I dose-escalation study of 225Ac-J591. J. Clin. Oncol. 42, 842–851 (2024).

    Article  PubMed  CAS  Google Scholar 

  44. Nauseef, J. T. et al. A phase I/II dose-escalation study of fractionated 225Ac-J591 for progressive metastatic castration-resistant prostate cancer (mCRPC) in patients with prior treatment with 177Lu-PSMA. J. Clin. Oncol. 41, TPS288 (2023).

    Article  Google Scholar 

  45. Clarke, A. FDA clears IND for 225Ac-J591 in advanced prostate cancer. Urology Times https://www.urologytimes.com/view/fda-clears-ind-for-225ac-j591-in-advanced-prostate-cancer (2024).

  46. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04946370 (2025).

  47. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04597411 (2025).

  48. Sun, M. P. et al. Phase I results of a phase I/II study of pembrolizumab and AR signaling inhibitor (ARSI) with 225Ac-J591. J. Clin. Oncol. 41, 181–181 (2023).

    Article  Google Scholar 

  49. Ling, S. W. et al. Evaluation of the tolerability and safety of [225Ac]Ac-PSMA-I&T in patients with metastatic prostate cancer: a phase I dose escalation study. BMC Cancer 24, 146 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Full-Life Technologies. Full-life technologies granted FDA fast track designation for 225Ac-FL-020 for the treatment of metastatic castration-resistant prostate cancer. Full-Life Technologies https://www.full-life.com/media/press-releases/27 (2024).

  51. Hammer, S. et al. Preclinical efficacy of a PSMA-targeted thorium-227 conjugate (PSMA-TTC), a targeted alpha therapy for prostate cancer. Clin. Cancer Res. 26, 1985–1996 (2020).

    Article  PubMed  CAS  Google Scholar 

  52. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03724747 (2024).

  53. Delpassand, I. S. et al. Preliminary efficacy and safety results from the TATCIST trial: a PSMA-directed targeted alpha therapy with FPI-2265 (225Ac-PSMA-I&T) for the treatment of metastatic castration-resistant prostate cancer. Presented at the American Association for Cancer Research Annual Meeting (2024).

  54. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05983198 (2025).

  55. Saleh, R. et al. ACCEL: [Ac-225]-PSMA-62 phase Ia/Ib/II clinical trial to characterize efficacy, safety, tolerability, and dosimetry in oligometastatic hormone-sensitive and metastatic castration-resistant prostate cancer. J. Clin. Oncol. 43, 842–851 (2025).

    Article  Google Scholar 

  56. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06881823 (2025).

  57. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06855277 (2025).

  58. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06402331 (2025).

  59. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06780670 (2025).

  60. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04225910 (2020).

  61. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05902247 (2023).

  62. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06217822 (2025).

  63. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06052306 (2025).

  64. Klaassen, Z. PSMA and beyond 2025: overview of clinical trials of PSMA RLT in 2025. UroToday https://www.urotoday.com/conference-highlights/2025-ucsf-ucla-psma-conference/159332-psma-and-beyond-2025-overview-of-clinical-trials-of-psma-rlt-in-2025.html (2025).

  65. Sgouros, G., Bodei, L., McDevitt, M. R. & Nedrow, J. R. Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat. Rev. Drug Discov. 19, 589–608 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. US Food and Drug Administration. FDA approves Pluvicto for metastatic castration-resistant prostate cancer. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer (2022).

  67. Hennrich, U. & Eder, M. [177Lu]Lu-PSMA-617 (Pluvicto): the first FDA-approved radiotherapeutical for treatment of prostate cancer. Pharmaceuticals 15, 1292 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Tagawa, S. T. et al. Randomized, double-blinded phase II study of ketoconazole (keto), hydrocortisone (HC), and anti-PSMA antibody J591 labeled with 177Lu or 111In in patients (pts) with high-risk non-metastatic (met) castration-resistant prostate cancer (M0 CRPC). J. Clin. Oncol. 41, LBA21 (2023).

    Article  Google Scholar 

  69. Tagawa, S. T. et al. Phase 1/2 study of fractionated dose lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 (177 Lu-J591) for metastatic castration-resistant prostate cancer. Cancer 125, 2561–2569 (2019).

    Article  PubMed  CAS  Google Scholar 

  70. Bander, N. H. et al. Phase I trial of 177lutetium-labeled J591, a monoclonal antibody to prostate-specific membrane antigen, in patients with androgen-independent prostate cancer. J. Clin. Oncol. 23, 4591–4601 (2005).

    Article  PubMed  CAS  Google Scholar 

  71. Tagawa, S. T. et al. Anti-prostate specific membrane antigen-based radioimmunotherapy for prostate. Cancer 116, 1075–1083 (2010).

    Article  PubMed  CAS  Google Scholar 

  72. Liu, H. et al. Monoclonal antibodies to the extracellular domain of prostate-specific membrane antigen also react with tumor vascular endothelium. Cancer Res. 57, 3629–3634 (1997).

    PubMed  CAS  Google Scholar 

  73. Fung, E. K. et al. Targeting of radiolabeled J591 antibody to PSMA-expressing tumors: optimization of imaging and therapy based on non-linear compartmental modeling. EJNMMI Res. 6, 7 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Tagawa, S. T. et al. Phase II study of lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer. Clin. Cancer Res. 19, 5182–5191 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. National Cancer Institute. Lutetium Lu 177 rsopatamab tetraxetan. NCI https://www.cancer.gov/publications/dictionaries/cancer-drug/def/lutetium-lu-177-rosopatamab-tetraxetan (2023).

  76. Telix Pharmaceuticals. First patient dosed in phase III ProstACT GLOBAL study of antibody-based prostate cancer therapy candidate, TLX591. TelixPharmaceuticals https://telixpharma.com/news-views/first-patient-dosed-in-phase-iii-prostact-global-study-of-antibody-based-prostate-cancer-therapy-candidate-tlx591 (2023).

  77. Telix Pharmaceuticals. Telix announces positive rPFS data from ProstACT SELECT trial of TLX591 rADC therapy candidate in prostate cancer. PR Newswire https://www.prnewswire.com/apac/news-releases/telix-announces-positive-rpfs-data-from-prostact-select-trial-of-tlx591-radc-therapy-candidate-in-prostate-cancer-302160140.html (2024).

  78. Kassis, A. I. Cancer therapy with Auger electrons: are we almost there? J. Nucl. Med. 44, 1479–1481 (2003).

    PubMed  CAS  Google Scholar 

  79. Bodei, L., Kassis, A. I., Adelstein, S. J. & Mariani, G. Radionuclide therapy with iodine-125 and other auger-electron-emitting radionuclides: experimental models and clinical applications. Cancer Biother. Radiopharm. 18, 861–877 (2003).

    PubMed  CAS  Google Scholar 

  80. Müller, C. et al. Terbium-161 for PSMA-targeted radionuclide therapy of prostate cancer. Eur. J. Nucl. Med. Mol. Imaging 46, 1919–1930 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Buteau, J. P. et al. First-in-human results of terbium-161 [161Tb]Tb-PSMA-I&T dual beta–Auger radioligand therapy in patients with metastatic castration-resistant prostate cancer (VIOLET): a single-centre, single-arm, phase 1/2 study. Lancet Oncol. 26, 1009–1017 (2025).

    Article  PubMed  CAS  Google Scholar 

  82. Chirindel, A. et al. First-in-human administration of [161Tb]Tb-SibuDAB and comparative dosimetry with standard [177Lu]Lu-PSMA-I&T as part of the PROGNOSTICS phase Ia study. Eur. J. Nucl. Med. Mol. Imaging 52, 1628–1630 (2025).

    Article  PubMed  CAS  Google Scholar 

  83. Fu, Z., Li, S., Han, S., Shi, C. & Zhang, Y. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal. Transduct. Target. Ther. 7, 1–25 (2022).

    Google Scholar 

  84. de Bono, J. S. et al. Phase I study of MEDI3726: a prostate-specific membrane antigen-targeted antibody–drug conjugate, in patients with mCRPC after failure of abiraterone or enzalutamide. Clin. Cancer Res. 27, 3602–3609 (2021).

    Article  PubMed  Google Scholar 

  85. Shen, J. et al. 1804P APEX-01: first-in-human phase I/II study of ARX517 an anti- prostate-specific membrane antigen (PSMA) antibody-drug conjugate (ADC) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Ann. Oncol. 34, S974–S975 (2023).

    Article  Google Scholar 

  86. Chu, Y., Zhou, X. & Wang, X. Antibody-drug conjugates for the treatment of lymphoma: clinical advances and latest progress. J. Hematol. Oncol. 14, 88 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Li, F. et al. Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models. Cancer Res. 76, 2710–2719 (2016).

    Article  PubMed  CAS  Google Scholar 

  88. Modi, S. et al. Trastuzumab deruxtecan in previously treated HER2-Positive breast cancer. N. Engl. J. Med. 382, 610–621 (2020).

    Article  PubMed  CAS  Google Scholar 

  89. Hurvitz, S. A. et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet 401, 105–117 (2023).

    Article  PubMed  CAS  Google Scholar 

  90. US Food and Drug Administraton. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2-positive-breast-cancer (2019).

  91. Daiichi-Sankyo. ENHERTU approved in the US as first tumor agnostic HER2 directed therapy for previously treated patients with metastatic HER2 positive solid tumors. Daiichi-Sankyo https://daiichisankyo.us/press-releases/-/article/enhertu-approved-in-the-u-s-as-first-tumor-agnostic-her2-directed-therapy-for-previously-treated-patients-with-metastatic-her2-positive-solid-tumors (2024).

  92. ecancer. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. ecancer https://ecancer.org/en/news/17123-fda-approves-new-treatment-option-for-patients-with-her2-positive-breast-cancer-who-have-progressed-on-available-therapies (2020).

  93. Cho, S. et al. Antitumor activity of MEDI3726 (ADCT-401), a pyrrolobenzodiazepine antibody–drug conjugate targeting PSMA, in preclinical models of prostate cancer. Mol. Cancer Ther. 17, 2176–2186 (2018).

    Article  PubMed  CAS  Google Scholar 

  94. Petrylak, D. P. et al. Phase 1 study of PSMA ADC, an antibody-drug conjugate targeting prostate-specific membrane antigen, in chemotherapy-refractory prostate cancer. Prostate 79, 604–613 (2019).

    Article  PubMed  CAS  Google Scholar 

  95. Petrylak, D. P. et al. PSMA ADC monotherapy in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide: efficacy and safety in open-label single-arm phase 2 study. Prostate 80, 99–108 (2020).

    Article  PubMed  CAS  Google Scholar 

  96. Colombo, R. & Rich, J. R. The therapeutic window of antibody drug conjugates: a dogma in need of revision. Cancer Cell 40, 1255–1263 (2022).

    Article  PubMed  CAS  Google Scholar 

  97. Skidmore, L. et al. Preclinical characterization of ARX517, a next-generation anti-PSMA antibody drug conjugate for the treatment of metastatic castration-resistant prostate cancer [abstract 3997]. Cancer Res. 83, 3997 (2023).

    Article  Google Scholar 

  98. Ambrx Biopharma. FDA grants fast track designation for Ambrx’s ARX517 for the treatment of metastatic castration-resistant prostate cancer. GlobeNewswire https://www.globenewswire.com/news-release/2023/07/19/2707358/0/en/FDA-Grants-Fast-Track-Designation-for-Ambrx-s-ARX517-for-the-Treatment-of-Metastatic-Castration-Resistant-Prostate-Cancer.html (2023).

  99. Klaassen, Z. APEX-01: first-in-human phase 1/2 study of ARX517, an anti-PSMA ADC, in patients with mCRPC. UroToday https://www.urotoday.com/conference-highlights/esmo-2023/esmo-2023-prostate-cancer/147612-esmo-2023-apex-01-first-in-human-phase-1-2-study-of-arx517-an-anti-psma-adc-in-patients-with-mcrpc.html (2023).

  100. Skidmore, L. K. et al. Preclinical characterization of ARX517, a site-specific stable PSMA-targeted antibody-drug conjugate for the treatment of metastatic castration-resistant prostate cancer. Mol. Cancer Ther. 23, 1842–1853 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Huehls, A. M., Coupet, T. A. & Sentman, C. L. Bispecific T-cell engagers for cancer immunotherapy. Immunol. Cell Biol. 93, 290–296 (2015).

    Article  PubMed  CAS  Google Scholar 

  102. Haber, L. et al. Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning. Sci. Rep. 11, 14397 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Tian, Z., Liu, M., Zhang, Y. & Wang, X. Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies. J. Hematol. Oncol. 14, 75 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. US Food and Drug Administration. FDA grants accelerated approval to elranatamab-bcmm for multiple myeloma. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-elranatamab-bcmm-multiple-myeloma (2023).

  105. US Food and Drug Administration. FDA grants regular approval to blinatumomab and expands indication to include Philadelphia chromosome-positive B cell. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-blinatumomab-and-expands-indication-include-philadelphia-chromosome (2017).

  106. US Food and Drug Administration. FDA granted accelerated approval to blinatumomab (Blincyto, Amgen Inc.) for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-granted-accelerated-approval-blinatumomab-blincyto-amgen-inc-treatment-adult-and-pediatric (2018).

  107. US Food and Drug Administration. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer (2024).

  108. Ahn, M.-J. et al. Tarlatamab for patients with previously treated small-cell lung cancer. N. Engl. J. Med. 389, 2063–2075 (2023).

    Article  PubMed  CAS  Google Scholar 

  109. Deegen, P. et al. The PSMA-targeting half-life extended BiTE therapy AMG 160 has potent antitumor activity in preclinical models of metastatic castration-resistant prostate cancer. Clin. Cancer Res. 27, 2928–2937 (2021).

    Article  PubMed  CAS  Google Scholar 

  110. Tran, B. et al. Results from a phase I study of AMG 160, a half-life-extended (HLE), PSMA-targeted, bispecific T-cell engager (BiTE) immune therapy for metastatic castration-resistant prostate cancer (mCRPC) [abstract 609O]. Ann. Oncol. 31, S507 (2020).

  111. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04631601 (2025).

  112. Dorff, T. et al. A phase I study of acapatamab, a half-life extended, PSMA-targeting bispecific T-cell engager for metastatic castration-resistant prostate cancer. Clin. Cancer Res. 30, 1488–1500 (2024).

    Article  Google Scholar 

  113. Dang, K. et al. Attenuating CD3 affinity in a PSMAxCD3 bispecific antibody enables killing of prostate tumor cells with reduced cytokine release. J. Immunother. Cancer 9, e002488 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Falchook, G. S. et al. Phase 1 clinical trial of AMG 340, a prostate-specific membrane antigen (PSMA)-targeted T-cell engager with a novel low-affinity CD3 binding domain designed to mitigate toxicity for the treatment of metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 42, e14587 (2024).

    Article  Google Scholar 

  115. Machulkin, A. E. et al. Synthesis, characterization, and preclinical evaluation of a small-molecule prostate-specific membrane antigen-targeted monomethyl auristatin E conjugate. J. Med. Chem. 64, 17123–17145 (2021).

    Article  PubMed  CAS  Google Scholar 

  116. Stein, M. N. et al. Pasritamig, a first-in-class, bispecific T-Cell engager targeting human kallikrein 2, in metastatic castration-resistant prostate cancer: a phase 1 study. J. Clin. Oncol. 43, 2515–2526 (2025).

    Article  PubMed  Google Scholar 

  117. Markowski, M. et al. Phase I study of CCW702, a bispecific small molecule-antibody conjugate targeting PSMA and CD3 in patients with metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 39, TPS5094 (2021).

    Article  Google Scholar 

  118. Austin, R. J. et al. TriTACs, a novel class of T-cell–engaging protein constructs designed for the treatment of solid tumors. Mol. Cancer Ther. 20, 109–120 (2021).

    Article  PubMed  CAS  Google Scholar 

  119. Molloy, M. E. et al. HPN328, a trispecific T cell–activating protein construct targeting DLL3-expressing solid tumors. Mol. Cancer Ther. 23, 1294–1304 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Bendell, J. C. et al. First-in-human phase I study of HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager in patients with metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 38, 5552–5552 (2020).

    Article  Google Scholar 

  121. De, B. J. S. et al. Results of an ongoing phase 1/2a dose escalation study of HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager, in patients with metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 39, 5013 (2021).

    Article  Google Scholar 

  122. Taylor, N. P. Regeneron rethinks CD28 bispecific R&D plan after 2 patients die. Fierce Biotech https://www.fiercebiotech.com/biotech/regeneron-rethinks-cd28-bispecific-rd-plan-after-2-patients-die (2023).

  123. Amgen. Teneobio acquisition adds talent and new types of antibodies to Amgen. Amgen https://www.amgen.com/stories/2022/01/teneobio-acquisition-adds-talent-and-new-types-of-antibodies-to-amgen (2022).

  124. US Food and Drug Administration. FDA approves tisagenlecleucel for relapsed or refractory follicular lymphoma. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-relapsed-or-refractory-follicular-lymphoma (2022).

  125. US Food and Drug Administration. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-b-cell-all-and-tocilizumab-cytokine-release-syndrome (2017).

  126. US Food and Drug Administration. YESCARTA. FDA https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yescarta (2025).

  127. US Food and Drug Administration. TECARTUS. FDA https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/tecartus (2025).

  128. US Food and Drug Administration. FDA approves lisocabtagene maraleucel for relapsed or refractory mantle cell lymphoma. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lisocabtagene-maraleucel-relapsed-or-refractory-mantle-cell-lymphoma (2024).

  129. US Food and Drug Administration. FDA approves idecabtagene vicleucel for multiple myeloma. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-idecabtagene-vicleucel-multiple-myeloma (2021).

  130. US Food and Drug Administration. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ciltacabtagene-autoleucel-relapsed-or-refractory-multiple-myeloma (2022).

  131. Gade, T. P. F. et al. Targeted elimination of prostate cancer by genetically directed human T lymphocytes. Cancer Res. 65, 9080–9088 (2005).

    Article  PubMed  CAS  Google Scholar 

  132. Maher, J., Brentjens, R. J., Gunset, G., Rivière, I. & Sadelain, M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor. Nat. Biotechnol. 20, 70–75 (2002).

    Article  PubMed  CAS  Google Scholar 

  133. Junghans, R. P. et al. Phase I trial of anti-PSMA designer CAR-T cells in prostate cancer: possible role for interacting interleukin 2-T cell pharmacodynamics as a determinant of clinical response. Prostate 76, 1257–1270 (2016).

    Article  PubMed  CAS  Google Scholar 

  134. Slovin, S. F. et al. Phase 1 study of P-PSMA-101 CAR-T cells in patients with metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 40, 98 (2022).

    Article  Google Scholar 

  135. Rosa, K. FDA halts phase 1 trial with P-PSMA-101 in mCRPC following patient death. OncLive https://www.onclive.com/view/fda-halts-phase-1-trial-with-p-psma-01-in-mcrpc-following-patient-death (2020).

  136. Yakoub-Agha, I. et al. Management of adults and children undergoing CAR T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica 105, 297–316 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  137. eviQ. Cytokine-release syndrome (CRS). eviQ https://www.eviq.org.au/clinical-resources/oncological-emergencies/3500-cytokine-release-syndrome-associated-with-car#background (2025).

  138. Saxena, A. et al. Prevalence of adverse events following T-cell engaging bispecific antibodies (bsAbs) and chimeric antigen receptor (CAR) T-cell therapy in patients with metastatic castrate-resistant prostate cancer (mCRPC): a meta-analysis. J. Clin. Oncol. 43, 128–128 (2025).

    Article  Google Scholar 

  139. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT0308 (2025).

  140. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04227275 (2023).

  141. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04768608 (2023).

  142. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05732948 (2023).

  143. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04633148 (2024).

  144. Kfoury, Y. et al. Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment. Cancer Cell 39, 1464–1478.e8 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-Cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Roddie, C. et al. Obecabtagene autoleucel in adults with B-cell acute lymphoblastic leukemia. N. Engl. J. Med. 391, 2219–2230 (2024).

    Article  PubMed  CAS  Google Scholar 

  147. Sartor, O. et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N. Engl. J. Med. 385, 1091–1103 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Abdel-Aty, H. et al. The STAMPEDE2 trial: a site survey of current patterns of care, access to imaging and treatment of metastatic prostate cancer. Clin. Oncol. 35, e628–e635 (2023).

    Article  CAS  Google Scholar 

  149. STAMPEDE2. STAMPEDE2: a randomised controlled platform trial testing treatments in metastatic hormone sensitive prostate cancer. STAMPEDE2 https://www.stampede2trial.org (2025).

  150. Davis, I. D. et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N. Engl. J. Med. 381, 121–131 (2019).

    Article  PubMed  CAS  Google Scholar 

  151. Armstrong, A. J. et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J. Clin. Oncol. 37, 2974–2986 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Smith, M. R. et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N. Engl. J. Med. 378, 1408–1418 (2018).

    Article  PubMed  CAS  Google Scholar 

  153. Hussain, M. et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N. Engl. J. Med. 378, 2465–2474 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Sternberg, C. N. et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N. Engl. J. Med. 382, 2197–2206 (2020).

    Article  PubMed  CAS  Google Scholar 

  155. Rice, M. A., Malhotra, S. V. & Stoyanova, T. Second-generation antiandrogens: from discovery to standard of care in castration resistant prostate cancer. Front. Oncol. 9, 801 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Chen, Y., Zhou, Q., Hankey, W., Fang, X. & Yuan, F. Second generation androgen receptor antagonists and challenges in prostate cancer treatment. Cell Death Dis. 13, 632 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Emmett, L. et al. [177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 25, 563–571 (2024).

    Article  PubMed  CAS  Google Scholar 

  158. Yazdanpanah, O. et al. Efficacy of 177Lu-PSMA-617 with or without ARPIs for the treatment of mCRPC: VISION secondary analysis. J. Clin. Oncol. 43, 121–121 (2025).

    Article  Google Scholar 

  159. Muniz, M. et al. Outcomes for 177Lu-PSMA-617 with and without concurrent use of ARPIs in patients with mCRPC. J. Clin. Oncol. 43, 112–112 (2025).

    Article  Google Scholar 

  160. Morales, J. C. et al. Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Crit. Rev. Eukaryot. Gene Expr. 24, 15–28 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Mateo, J. et al. DNA-repair defects and olaparib in metastatic prostate cancer. N. Engl. J. Med. 373, 1697–1708 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Sandhu, S., Guo, C. & Hofman, M. S. Radionuclide therapy in prostate cancer: from standalone to combination PSMA theranostics. J. Nucl. Med. 62, 1660–1668 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Fenor de la Maza, M. D., Pérez Gracia, J. L., Miñana, B. & Castro, E. PARP inhibitors alone or in combination for prostate cancer. Ther. Adv. Urol. 16, 17562872241272928 (2024).

    Article  Google Scholar 

  164. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03874884 (2025).

  165. Sandhu, S. et al. LuPARP: phase 1 trial of 177Lu-PSMA-617 and olaparib in patients with metastatic castration resistant prostate cancer (mCRPC). J. Clin. Oncol. 41, 5005 (2023).

    Article  Google Scholar 

  166. Ruigrok, E. A. M. et al. Preclinical assessment of the combination of PSMA-targeting radionuclide therapy with PARP inhibitors for prostate cancer treatment. Int. J. Mol. Sci. 23, 8037 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Connell-Crowley, L., Harper, J. W. & Goodrich, D. W. Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation. Mol. Biol. Cell 8, 287–301 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Franco, R., Cao, J. Q., Yassa, M. & Hijal, T. Safety of CDK4/6 inhibitors combined with radiotherapy in patients with metastatic breast cancer: a review of the literature. Curr. Oncol. 30, 5485–5496 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Kubeczko, M. et al. Safety and feasibility of radiation therapy combined with CDK 4/6 inhibitors in the management of advanced breast cancer. Cancers 15, 690 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. O’Leary, B., Finn, R. S. & Turner, N. C. Treating cancer with selective CDK4/6 inhibitors. Nat. Rev. Clin. Oncol. 13, 417–430 (2016).

    Article  PubMed  Google Scholar 

  171. Von Hoff, D. D. et al. Phase I study of PSMA-targeted docetaxel-containing nanoparticle BIND-014 in patients with advanced solid tumors. Clin. Cancer Res. 22, 3157–3163 (2016).

    Article  Google Scholar 

  172. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05113537 (2025).

  173. Pienta, K. J. Preclinical mechanisms of action of docetaxel and docetaxel combinations in prostate cancer. Semin. Oncol. 28, 3–7 (2001).

    Article  PubMed  CAS  Google Scholar 

  174. Puente, J. et al. Docetaxel in prostate cancer: a familiar face as the new standard in a hormone-sensitive setting. Ther. Adv. Med. Oncol. 9, 307–318 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Dhiantravan, N. et al. UpFrontPSMA: a randomized phase 2 study of sequential 177Lu-PSMA-617 and docetaxel vs docetaxel in metastatic hormone-naïve prostate cancer (clinical trial protocol). BJU Int. 128, 331–342 (2021).

    Article  PubMed  CAS  Google Scholar 

  176. Azad, A. A. et al. Sequential [177Lu]Lu-PSMA-617 and docetaxel versus docetaxel in patients with metastatic hormone-sensitive prostate cancer (UpFrontPSMA): a multicentre, open-label, randomised, phase 2 study. Lancet Oncol. 25, 1267–1276 (2024).

    Article  PubMed  CAS  Google Scholar 

  177. 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. 42, 704–706 (2017).

    Article  PubMed  Google Scholar 

  178. Waldman, A. D., Fritz, J. M. & Lenardo, M. J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat. Rev. Immunol. 20, 651–668 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Drake, C. G., Lipson, E. J. & Brahmer, J. R. Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer. Nat. Rev. Clin. Oncol. 11, 24–37 (2014).

    Article  PubMed  CAS  Google Scholar 

  180. Haffner, M. C. et al. Genomic and phenotypic heterogeneity in prostate cancer. Nat. Rev. Urol. 18, 79–92 (2021).

    Article  PubMed  Google Scholar 

  181. Vareki, S. M. High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors. J. Immunother. Cancer 6, 157 (2018).

    Article  Google Scholar 

  182. Verma, S., Turkbey, B. & Muradyan, N. Overview of dynamic contrast-enhanced MRI in prostate cancer diagnosis and management. AJR Am. J. Roentgenol. 198, 1277 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).

    Article  PubMed  CAS  Google Scholar 

  184. Sharma, P. & Allison, J. P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Antonarakis, E. S. et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study. J. Clin. Oncol. 38, 395–405 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Powles, T. et al. Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Nat. Med. 28, 144–153 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Petrylak, D. P. et al. Pembrolizumab plus docetaxel versus docetaxel for previously treated metastatic castration-resistant prostate cancer: the randomized, double-blind, phase III KEYNOTE-921 trial. J. Clin. Oncol. 43, 1638–1649 (2025).

    Article  PubMed  CAS  Google Scholar 

  188. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05806814 (2025).

  189. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05568550 (2025).

  190. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05077098 (2025).

  191. Cheema, A. K. et al. Radiotherapy induces innate immune responses in patients treated for prostate cancers. Clin. Cancer Res. 29, 921–929 (2023).

    Article  PubMed  CAS  Google Scholar 

  192. Eapen, R. S. et al. Neoadjuvant lutetium PSMA, the TIME and immune response in high-risk localized prostate cancer. Nat. Rev. Urol. 21, 676–686 (2024).

    Article  PubMed  Google Scholar 

  193. Lunj, S. et al. Immune effects of α and β radionuclides in metastatic prostate cancer. Nat. Rev. Urol. 21, 651–661 (2024).

    Article  PubMed  CAS  Google Scholar 

  194. Colciago, R. R. et al. Overview of the synergistic use of radiotherapy and immunotherapy in cancer treatment: current challenges and scopes of improvement. Expert Rev. Anticancer Ther. 23, 135–145 (2023).

    Article  PubMed  CAS  Google Scholar 

  195. Mole, R. H. Whole body irradiation; radiobiology or medicine? Br. J. Radiol. 26, 234–241 (1953).

    Article  PubMed  CAS  Google Scholar 

  196. Demaria, S. et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int. J. Radiat. Oncol. Biol. Phys. 58, 862–870 (2004).

    Article  PubMed  Google Scholar 

  197. Sandhu, S. et al. Evolution: phase II study of radionuclide 177Lu-PSMA-617 therapy versus 177Lu-PSMA-617 in combination with ipilimumab and nivolumab for men with metastatic castration-resistant prostate cancer (mCRPC; ANZUP 2001). J. Clin. Oncol. 41, TPS271 (2023).

    Article  Google Scholar 

  198. Sandhu, S. et al. PRINCE: phase I trial of 177 Lu-PSMA-617 in combination with pembrolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 40, 5017 (2022).

    Article  Google Scholar 

  199. Aggarwal, R. et al. Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial. Lancet Oncol. 24, 1266–1276 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  200. Sayyid, R. The current state of treatment implementation for mCRPC in North America. UroToday https://www.urotoday.com/library-resources/advanced-prostate-cancer/147780-the-current-state-of-treatment-implementation-for-mcrpc-in-north-america.html (2023).

  201. Pilepich, M. V. et al. Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int. J. Radiat. Oncol. Biol. Phys. 50, 1243–1252 (2001).

    Article  PubMed  CAS  Google Scholar 

  202. Roach, M. et al. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J. Clin. Oncol. 26, 585–591 (2008).

    Article  PubMed  Google Scholar 

  203. Denham, J. W. et al. Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial. Lancet Oncol. 6, 841–850 (2005).

    Article  PubMed  CAS  Google Scholar 

  204. Dhiantravan, N. et al. Clinical trial protocol for LuTectomy: a single-arm study of the dosimetry, safety, and potential benefit of 177Lu-PSMA-617 prior to prostatectomy. Eur. Urol. Focus 7, 234–237 (2021).

    Article  PubMed  Google Scholar 

  205. Jones, C. U. et al. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N. Engl. J. Med. 365, 107–118 (2011).

    Article  PubMed  CAS  Google Scholar 

  206. National Institute for Health and Care Excellence. Locally Advanced Prostate Cancer (NICE, 2019).

  207. European Association of Urology. Prostace cancer — treatment. EAU https://uroweb.org/guidelines/prostate-cancer/chapter/treatment (2025).

  208. Klaassen, Z. EAU 2023: LuTectomy: a prospective study of dosimetry, safety and potential benefit of upfront 177Lu-PSMA-617 radioligand therapy prior to radical prostatectomy in men with high-risk localized prostate cancer. UroToday https://www.urotoday.com/conference-highlights/eau-annual-congress-2023/eau-2023-prostate-cancer/143074-eau-2023-lutectomy-a-prospective-study-of-dosimetry-safety-and-potential-benefit-of-upfront-177lu-psma-617-radioligand-therapy-prior-to-radical-prostatectomy-in-men-with-high-risk-localized-prostate-cancer.html (2023).

  209. Eapen, R. S. et al. Administering [177Lu]Lu-PSMA-617 prior to radical prostatectomy in men with high-risk localised prostate cancer (LuTectomy): a single-centre, single-arm, phase 1/2 study. Eur. Urol. 85, 217–226 (2024).

    Article  PubMed  CAS  Google Scholar 

  210. Adeleke, S., Haroon, A. & Kasivisvanathan, V. Re: [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Eur. Urol. 80, 118–119 (2021).

    Article  PubMed  CAS  Google Scholar 

  211. Bao, X. & Xie, L. Targeting purinergic pathway to enhance radiotherapy-induced immunogenic cancer cell death. J. Exp. Clin. Cancer Res. 41, 222 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  212. Chen, C., Liu, Y. & Cui, B. Effect of radiotherapy on T cell and PD-1 / PD-L1 blocking therapy in tumor microenvironment. Hum. Vaccin. Immunother. 17, 1555–1567 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  213. Krafft, U. et al. A randomized phase I/II study of neoadjuvant treatment with 177-Lutetium-PSMA-617 with or without ipilimumab in patients with very high-risk prostate cancer who are candidates for radical prostatectomy (NEPI trial). J. Clin. Oncol. 42, TPS352 (2024).

    Article  Google Scholar 

  214. Chen, J. et al. Synergistic effects of immunotherapy and adjunctive therapies in prostate cancer management. Crit. Rev. Oncol. Hematol. 207, 104604 (2025).

    Article  PubMed  Google Scholar 

  215. Pisansky, T. M., Thompson, I. M., Valicenti, R. K., D’Amico, A. V. & Selvarajah, S. Adjuvant and salvage radiotherapy after prostatectomy: ASTRO/AUA guideline amendment 2018–2019. J. Urol. 202, 533–538 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  216. George, G. et al. Long-term adherence to GnRH agonists in men with prostate cancer: a nation-wide population-based study in prostate cancer data base Sweden. Scand. J. Urol. 54, 20–26 (2020).

    Article  PubMed  CAS  Google Scholar 

  217. von Eyben, F. E. et al. 177Lu-PSMA-617 radioligand therapy for a patient with lymph node metastatic prostate cancer. Oncotarget 8, 66112–66116 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  218. Arham, A. B. et al. Updated follow up of a randomized, double-blinded phase II study of ketoconazole (keto), hydrocortisone (HC), and anti-PSMA antibody J591 labeled with 177Lu or 111In in patients (pts) with high-risk non-metastatic (met) castration-resistant prostate cancer (M0 CRPC). J. Clin. Oncol. 43, 172–172 (2025).

    Article  Google Scholar 

  219. Sartor, A. et al. PSMAddition: a phase 3 trial to compare treatment with 177Lu-PSMA-617 plus standard of care (SOC) versus SOC alone in patients with metastatic hormone-sensitive prostate cancer. J. Clin. Oncol. 40, TPS210 (2022).

    Article  Google Scholar 

  220. Petrelli, F. et al. Better survival of patients with oligo- compared with polymetastatic cancers: a systematic review and meta-analysis of 173 studies. F1000Res. 10, 423 (2021).

    Article  PubMed  CAS  Google Scholar 

  221. Palma, D. A. et al. Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial. J. Clin. Oncol. 38, 2830–2838 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  222. Wang, Y. et al. The future of PSMA PET and WB MRI as next-generation imaging tools in prostate cancer. Nat. Rev. Urol. 19, 475–493 (2022).

    Article  PubMed  CAS  Google Scholar 

  223. Ost, P. et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial. J. Clin. Oncol. 36, 446–453 (2018).

    Article  PubMed  CAS  Google Scholar 

  224. Nguyen, P. L. et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur. Urol. 67, 825–836 (2015).

    Article  PubMed  CAS  Google Scholar 

  225. Cao, B., Kim, M., Reizine, N. M. & Moreira, D. M. Adverse events and androgen receptor signaling inhibitors in the treatment of prostate cancer: a systematic review and multivariate network meta-analysis. Eur. Urol. Oncol. 6, 237–250 (2023).

    Article  PubMed  Google Scholar 

  226. Ma, T. M. et al. LUNAR: a randomized phase 2 study of 177Lutetium-PSMA neoadjuvant to ablative radiotherapy for oligorecurrent prostate cancer (clinical trial protocol). BJU Int. 132, 65–74 (2023).

    Article  PubMed  CAS  Google Scholar 

  227. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05079698 (2025).

  228. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05560659 (2025).

  229. Privé, B. M. et al. Lutetium-177-PSMA-617 in low-volume hormone-sensitive metastatic prostate cancer: a prospective pilot study. Clin. Cancer Res. 27, 3595–3601 (2021).

    Article  PubMed  Google Scholar 

  230. Telix Pharmaceuticals. ProstACT update: TARGET study ethics approval. Telix Pharmaceuticals https://telixpharma.com/news-views/prostact-update-target-study-ethics-approval (2022).

  231. Privé, B. M. et al. Lutetium-177-PSMA-I&T as metastases directed therapy in oligometastatic hormone sensitive prostate cancer, a randomized controlled trial. BMC Cancer 20, 884 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  232. Satapathy, S. et al. Short-course 177Lu-PSMA-617 radioligand therapy in high-volume metastatic hormone-sensitive prostate cancer: time to take the leap? Eur. Urol. 80, 390–392 (2021).

    Article  PubMed  Google Scholar 

  233. Pfannkuchen, N., Bausbacher, N., Pektor, S., Miederer, M. & Rosch, F. In vivo evaluation of [225Ac]Ac-DOTAZOL for α-Therapy of bone metastases. Curr. Radiopharm. 11, 223–230 (2018).

    Article  PubMed  CAS  Google Scholar 

  234. Chi, K. N. et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N. Engl. J. Med. 381, 13–24 (2019).

    Article  PubMed  CAS  Google Scholar 

  235. Fizazi, K. et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 20, 686–700 (2019).

    Article  PubMed  CAS  Google Scholar 

  236. Hofman, M. S. 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 397, 797–804 (2021).

    Article  PubMed  CAS  Google Scholar 

  237. Kostos, L. et al. AlphaBet: combination of Radium-223 and [177Lu]Lu-PSMA-I&T in men with metastatic castration-resistant prostate cancer (clinical trial protocol). Front. Med. 9, 1059122 (2022).

    Article  Google Scholar 

  238. Morris, M. J. et al. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet 404, 1227–1239 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  239. US Food and Drug Administration. FDA expands Pluvicto’s metastatic castration-resistant prostate cancer indication. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication (2025).

  240. Gafita, A. et al. Predictors and real-world use of prostate-specific radioligand therapy: PSMA and beyond. Am. Soc. Clin. Oncol. Educ. Book 42, 1–17 (2022).

    PubMed  Google Scholar 

  241. Roberts, M. J. et al. Using PSMA imaging for prognostication in localized and advanced prostate cancer. Nat. Rev. Urol. 20, 23–47 (2023).

    Article  PubMed  Google Scholar 

  242. Gafita, A. et al. Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study. Lancet Oncol. 22, 1115–1125 (2021).

    Article  PubMed  CAS  Google Scholar 

  243. Herrmann, K. et al. Multivariable models of outcomes with [177Lu]Lu-PSMA-617: analysis of the phase 3 VISION trial. EClinicalMedicine 77, 102862 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  244. Gafita, A. et al. Early experience of rechallenge 177Lu-PSMA radioligand therapy after an initial good response in patients with advanced prostate cancer. J. Nucl. Med. 60, 644–648 (2019).

    Article  PubMed  CAS  Google Scholar 

  245. Seifert, R. et al. Safety and efficacy of extended therapy with [177Lu]Lu-PSMA: a German multicenter study. J. Nucl. Med. 65, 909–916 (2024).

    Article  PubMed  CAS  Google Scholar 

  246. Lawal, I. O. et al. Hematologic toxicity profile and efficacy of [225Ac]Ac-PSMA-617 α-radioligand therapy of patients with extensive skeletal metastases of castration-resistant prostate cancer. Eur. J. Nucl. Med. Mol. Imaging 49, 3581–3592 (2022).

    Article  PubMed  CAS  Google Scholar 

  247. Khawar, A. et al. Preliminary results of biodistribution and dosimetric analysis of [68Ga]Ga-DOTAZOL: a new zoledronate-based bisphosphonate for PET/CT diagnosis of bone diseases. Ann. Nucl. Med. 33, 404–413 (2019).

    Article  PubMed  CAS  Google Scholar 

  248. Mazzucato, G. et al. Robot-assisted PSMA-radioguided salvage surgery for oligorecurrent prostate cancer using the novel SENSEI drop-in gamma probe: correlation of intraoperative measurements to preoperative imaging and final histology. Cancers 17, 93 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  249. Gandaglia, G. et al. Prostate-specific membrane antigen radioguided surgery to detect nodal metastases in primary prostate cancer patients undergoing robot-assisted radical prostatectomy and extended pelvic lymph node dissection: results of a planned interim analysis of a prospective phase 2 study. Eur. Urol. 82, 411–418 (2022).

    Article  PubMed  Google Scholar 

  250. Oderda, M. et al. Robot-assisted PSMA-radioguided surgery to assess surgical margins and nodal metastases in prostate cancer patients: report on three cases using an intraoperative PET-CT specimen imager. Urology 182, e257–e261 (2023).

    Article  PubMed  Google Scholar 

  251. Di Giorgio, A. et al. Long-term outcomes of PSMA PET/CT-guided radiotherapy in biochemical failure patients post-radical prostatectomy: a 5-year follow-up analysis. Eur. J. Nucl. Med. Mol. Imaging 52, 3720–3729 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  252. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05555017 (2023).

  253. Zilli, T. et al. The multicenter, randomized, phase 2 PEACE V-STORM trial: defining the best salvage treatment for oligorecurrent nodal prostate cancer metastases. Eur. Urol. Focus 7, 241–244 (2021).

    Article  PubMed  Google Scholar 

  254. Knipper, S. et al. Cohort study of oligorecurrent prostate cancer patients: oncological outcomes of patients treated with salvage lymph node dissection via prostate-specific membrane antigen–radioguided surgery. Eur. Urol. 83, 62–69 (2023).

    Article  PubMed  CAS  Google Scholar 

  255. Autio, K. A. et al. Safety and efficacy of BIND-014, a docetaxel nanoparticle targeting prostate-specific membrane antigen for patients with metastatic castration-resistant prostate cancer: a phase 2 clinical trial. JAMA Oncol. 4, 1344–1351 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  256. Michalska, M. et al. In vitro and in vivo effects of a recombinant anti-PSMA immunotoxin in combination with docetaxel against prostate cancer. Oncotarget 7, 22531–22542 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  257. Machulkin, A. E. et al. PSMA-targeted small-molecule docetaxel conjugate: synthesis and preclinical evaluation. Eur. J. Med. Chem. 227, 113936 (2022).

    Article  PubMed  CAS  Google Scholar 

  258. Alzubi, J. et al. PSMA-Directed CAR T cells combined with low-dose docetaxel treatment induce tumor regression in a prostate cancer xenograft model. Mol. Ther. Oncolytics 18, 226–235 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  259. Lim, E. A. et al. Phase 1 study of safety and preliminary clinical activity of JNJ-63898081, a PSMA and CD3 bispecific antibody, for metastatic castration-resistant prostate cancer. Clin. Genitourin. Cancer 21, 366–375 (2023).

    Article  PubMed  Google Scholar 

  260. Burnell, S. E. A. et al. STEAP2 knockdown reduces the invasive potential of prostate cancer cells. Sci. Rep. 8, 6252 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  261. Lillard, J. W., Moses, K. A., Mahal, B. A. & George, D. J. Racial disparities in Black men with prostate cancer: a literature review. Cancer 128, 3787–3795 (2022).

    Article  PubMed  Google Scholar 

  262. Roehrborn, C. G. & Black, L. K. The economic burden of prostate cancer. BJU Int. 108, 806–813 (2011).

    Article  PubMed  Google Scholar 

  263. Alonso, J. et al. Economic evaluations of radioembolization with yttrium-90 microspheres in liver metastases of colorectal cancer: a systematic review. BMC Gastroenterol. 23, 181 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  264. Shinto, A., Kamaleshwaran, K., Shibu, D., Vyshak, K. & Antony, J. Empiric therapy with low-dose I-131 in differentiated cancer thyroid: what is the magic number? World J. Nucl. Med. 12, 61–64 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  265. Olsen, T. A., Filson, C. P., Richards, T. B., Ekwueme, D. U. & Howard, D. H. The cost of metastatic prostate cancer in the United States. Urol. Pract. 10, 41–47 (2023).

    Article  PubMed  Google Scholar 

  266. Rathke, H. et al. Dosimetry estimate and initial clinical experience with 90Y-PSMA-617. J. Nucl. Med. 60, 806–811 (2019).

    Article  PubMed  CAS  Google Scholar 

  267. International Atomic Energy Agency. Therapeutic Radionuclide Generators: 90Sr/90Yand 188W/188Re Generators (IAEA, 2009).

  268. Kurth, J., Krause, B. J., Hakenberg, O., Schwarzenboeck, S. & Heuschkel, M. [90Y]Y-PSMA-617 for the treatment of metastatic castration-resistant prostate cancer — post-therapeutic kidney and bone marrow dosimetry for individualized therapy. J. Nucl. Med. 61, 190 (2020).

    Google Scholar 

  269. Sobral, M. C., Mota, S. I., Oliveira, P. J., Urbano, A. M. & Paulo, A. Two targets, one mission: heterobivalent metal-based radiopharmaceuticals for prostate cancer imaging and therapy. ChemMedChem 20, e202500128 (2025).

    Article  PubMed  CAS  Google Scholar 

  270. de Klerk, J. M. H. et al. Dose escalation study of rhenium-186 hydroxyethylidene diphosphonate in patients with metastatic prostate cancer. Eur. J. Nucl. Med. 21, 1114–1120 (1994).

    Article  PubMed  Google Scholar 

  271. Liepe, K., Kropp, J., Runge, R. & Kotzerke, J. Therapeutic efficiency of rhenium-188-HEDP in human prostate cancer skeletal metastases. Br. J. Cancer 89, 625–629 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  272. Evans-Axelsson, S., Timmermand, O. V., Bjartell, A., Strand, S.-E. & Elgqvist, J. Radioimmunotherapy for prostate cancer — current status and future possibilities. Semin. Nucl. Med. 46, 165–179 (2016).

    Article  PubMed  Google Scholar 

  273. Lepareur, N. et al. Rhenium-188 labeled radiopharmaceuticals: current clinical applications in oncology and promising perspectives. Front. Med. 6, 132 (2019).

    Article  Google Scholar 

  274. Cardinale, J. et al. PSMA-GCK01: a generator-based 99mTc/188Re theranostic ligand for the prostate-specific membrane antigen. J. Nucl. Med. 64, 1069–1075 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  275. Trujillo, B., Wu, A., Wetterskog, D. & Attard, G. Blood-based liquid biopsies for prostate cancer: clinical opportunities and challenges. Br. J. Cancer 127, 1394–1402 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  276. Danila, D. C. et al. Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin. Cancer Res. 13, 7053–7058 (2007).

    Article  PubMed  CAS  Google Scholar 

  277. Liu, H., Gao, Y., Vafaei, S., Gu, X. & Zhong, X. The prognostic value of plasma cell-free DNA concentration in the prostate cancer: a systematic review and meta-analysis. Front. Oncol. 11, 599602 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  278. Vandekerkhove, G. et al. Circulating tumor DNA abundance and potential utility in de novo metastatic prostate cancer. Eur. Urol. 75, 667–675 (2019).

    Article  PubMed  CAS  Google Scholar 

  279. De Giorgi, U. et al. Circulating androgen receptor gene amplification and resistance to 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer: results of a Phase 2 trial. Br. J. Cancer 125, 1226–1232 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  280. Nimir, M. et al. Detection of AR-V7 in liquid biopsies of castrate resistant prostate cancer patients: a comparison of AR-V7 analysis in circulating tumor cells, circulating tumor RNA and exosomes. Cells 8, 688 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  281. Quist, S. W., Paulissen, J. H. J., Wyndaele, D. N. J., Nagarajah, J. & Freriks, R. D. Costs of radium-223 and the pharmacy preparation 177Lu-PSMA-I&T for metastatic castration-resistant prostate cancer in Dutch hospitals. J. Med. Econ. 26, 366–375 (2023).

    Article  PubMed  CAS  Google Scholar 

  282. Mehrens, D. et al. Cost-effectiveness analysis of 177Lu-PSMA-617 radioligand therapy in metastatic castration-resistant prostate cancer. J. Natl Compr. Cancer Netw. 21, 43–50.e2 (2023).

    Article  CAS  Google Scholar 

  283. Vogel, W. V., van der Marck, S. C. & Versleijen, M. W. J. Challenges and future options for the production of lutetium-177. Eur. J. Nucl. Med. Mol. Imaging 48, 2329–2335 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  284. Fanti, S. et al. EAU-EANM consensus statements on the role of prostate-specific membrane antigen positron emission tomography/computed tomography in patients with prostate cancer and with respect to [177Lu]Lu-PSMA radioligand therapy. Eur. Urol. Oncol. 5, 530–536 (2022).

    Article  PubMed  Google Scholar 

  285. Song, R., Jeet, V., Sharma, R., Hoyle, M. & Parkinson, B. Cost-effectiveness analysis of Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography/Computed Tomography (PET/CT) for the primary staging of prostate cancer in Australia. Pharmacoeconomics 40, 807–821 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  286. Ostuni, E. & Taylor, M. R. G. Commercial and business aspects of alpha radioligand therapeutics. Front. Med. 9, 1070497 (2022).

    Article  Google Scholar 

  287. National Institute for Health and Care Excellence. Lutetium-177 Vipivotide Tetraxetan for Treating PSMA-Positive Hormone-Relapsed Metastatic Prostate Cancer after 2 or More Treatments (NICE, 2023).

  288. Thevenot, L. I. & Jacobson, G. M. ASTRO Letter to FDA re Pluvicto 3 14 2023__signed (ASTRO, 2023).

  289. Novartis. Novartis expands production of Pluvicto with addition of its largest and most advanced radioligand therapy manufacturing facility in Indianapolis. Novartis https://www.novartis.com/news/media-releases/novartis-expands-production-pluvictotm-addition-its-largest-and-most-advanced-radioligand-therapy-manufacturing-facility-indianapolis (2024).

  290. Bessette, Z. FDA approves Lutetium-177-PSMA-617 production at New Jersey facility. GU Oncology Now https://www.guoncologynow.com/post/fda-approves-lutetium-177-psma-617-production-at-new-jersey-facility (2023).

  291. Flegar, L. et al. Adoption of Lutetium-177 PSMA radioligand therapy for metastatic castration resistant prostate cancer: a total population analysis in Germany from 2016 to 2020. Eur. J. Nucl. Med. Mol. Imaging 50, 2188–2195 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  292. Genesiscare. PSMA PET-CT scan. Genesiscare https://www.genesiscare.com/uk/diagnostics/imaging-scans/pet-ct-scan/68gallium-psma-pet-ct-scan.%20Accessed%207th%20June,%202025 (2024).

  293. Africa Infoline. PET CT scan cost in African cities. Africa Infoline https://africainfoline.com/listing/scans/africa/pet-ct-scan-cost-in-african-cities-find-best-hospital-and-book-appointment (2025).

  294. Pramesh, C. S. et al. Priorities for cancer research in low- and middle-income countries: a global perspective. Nat. Med. 28, 649–657 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  295. Di, M. et al. Costs of care during chimeric antigen receptor T-cell therapy in relapsed or refractory B-cell lymphomas. JNCI Cancer Spectr. 8, pkae059 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  296. Wang, J. et al. Pretherapeutic 68Ga-PSMA-617 PET may indicate the dosimetry of 177Lu-PSMA-617 and 177Lu-EB-PSMA-617 in main organs and tumor lesions. Clin. Nucl. Med. 44, 431–438 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  297. Yadav, M. P. et al. Post-therapeutic dosimetry of 177Lu-DKFZ-PSMA-617 in the treatment of patients with metastatic castration-resistant prostate cancer. Nucl. Med. Commun. 38, 91–98 (2017).

    Article  PubMed  Google Scholar 

  298. Rosar, F. et al. Comparison of different methods for post-therapeutic dosimetry in [177Lu]Lu-PSMA-617 radioligand therapy. EJNMMI Phys. 8, 40 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  299. Society of Nuclear Medicine and Molecular Imaging. 177Lu PSMA-617 therapy (Pluvicto). SNMMI https://snmmi.org/AM/Patients/Procedures/177Lu-PSMA-617-Therapy-Pluvicto.aspx (2022).

  300. Muniz, M. et al. Salivary toxicity from PSMA-targeted radiopharmaceuticals: what we have learned and where we are going. Cancer Treat. Rev. 127, 102748 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  301. Emmett, L. 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. 128, 642–651 (2021).

    Article  PubMed  CAS  Google Scholar 

  302. Herrmann, K. et al. Dosimetry of 177Lu-PSMA-617 for the treatment of metastatic castration-resistant prostate cancer: results from the VISION trial sub-study. J. Clin. Oncol. 40, 97–97 (2022).

    Article  Google Scholar 

  303. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03454750 (2025).

  304. Maffey-Steffan, J. et al. The 68Ga/177Lu-theragnostic concept in PSMA-targeting of metastatic castration–resistant prostate cancer: impact of post-therapeutic whole-body scintigraphy in the follow-up. Eur. J. Nucl. Med. Mol. Imaging 47, 695–712 (2020).

    Article  PubMed  CAS  Google Scholar 

  305. Alsadi, R., Djekidel, M., Bouhali, O. & Doherty, J. O. Towards routine clinical use of dosimetry in [177Lu]Lu-PSMA prostate cancer radionuclide therapy: current efforts and future perspectives. Front. Phys. 10, 940677 (2022).

    Article  Google Scholar 

Download references

Author information

Author notes

  1. These authors contributed equally: Sola Adeleke, Joao R. Galante.

Authors and Affiliations

  1. School of Biomedical Engineering and Imaging Sciences (BMEIS), King’s College London, London, UK

    Sola Adeleke & Gary J. R. Cook

  2. Royal Marsden Hospital NHS Foundation Trust, London, UK

    Joao R. Galante

  3. Royal Free London NHS Foundation Trust, London, UK

    Yishen Wang

  4. Guy’s & St Thomas’ NHS Foundation Trust, London, UK

    Gurdip Azad

  5. Institute of Nuclear Medicine, University College London, London, UK

    Simon Wan & Jamshed Bomanji

  6. St Bartholomew’s Hospital NHS Foundation Trust, London, UK

    Athar Haroon

  7. Kent Oncology Centre, Maidstone & Tunbridge Wells Hospitals, Kent, UK

    Diletta Bianchini

  8. Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Centre Melbourne, Melbourne, Victoria, Australia

    Michael S. Hofman

  9. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia

    Michael S. Hofman

  10. California Institute for Biomedical Research (CALIBR), Scripps Research, La Jolla, CA, USA

    Travis S. Young

Authors
  1. Sola Adeleke
    View author publications

    Search author on:PubMed Google Scholar

  2. Joao R. Galante
    View author publications

    Search author on:PubMed Google Scholar

  3. Yishen Wang
    View author publications

    Search author on:PubMed Google Scholar

  4. Gurdip Azad
    View author publications

    Search author on:PubMed Google Scholar

  5. Simon Wan
    View author publications

    Search author on:PubMed Google Scholar

  6. Athar Haroon
    View author publications

    Search author on:PubMed Google Scholar

  7. Diletta Bianchini
    View author publications

    Search author on:PubMed Google Scholar

  8. Jamshed Bomanji
    View author publications

    Search author on:PubMed Google Scholar

  9. Michael S. Hofman
    View author publications

    Search author on:PubMed Google Scholar

  10. Travis S. Young
    View author publications

    Search author on:PubMed Google Scholar

  11. Gary J. R. Cook
    View author publications

    Search author on:PubMed Google Scholar

Contributions

S.A., J.R.G. and Y.W. researched data for the article. All authors substantially to discussion of the content. S.A., J.R.G., Y.W., S.W., A.H., T.S.Y. and G.J.R.C. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Sola Adeleke.

Ethics declarations

Competing interests

M.S.H. acknowledges philanthropic/government grant support from the Prostate Cancer Foundation (PCF), including CANICA Oslo Norway, Peter MacCallum Foundation and NHMRC Investigator Grant; other funding in the past 10 years from Movember/Medical Research Future Fund (MRFF), US Department of Defense and the Prostate Cancer Foundation of Australia (PCFA); research grant support (to Peter MacCallum Cancer Centre) from Novartis, ANSTO, Bayer, Isotopia and MIM; and consulting fees for lectures or advisory boards from Janssen and MSD in the past 2 years and AstraZeneca, Astellas and Mundipharma in the past 5 years. T.S.Y. receives research funding support from AbbVie. G.J.R.C. receives research support from Theragnostics, NanoMab Technology (UK) and Siemens Healthineers; provides consultancy and advisory board support to Serac Healthcare, Amgen, Telix Pharmaceuticals, Blue Earth Diagnostics, NanoMab Technology (UK), GE Healthcare and Full Life Technology; and receives lecture fees from Telix Pharmaceuticals and Curium. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Urology thanks Fransesco Ceci, Tobias Maurer, Mike Sathekge, Ken Herrmann and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Adeleke, S., Galante, J.R., Wang, Y. et al. Emerging evidence for sequencing and combining PSMA-based therapies in prostate cancer. Nat Rev Urol (2025). https://doi.org/10.1038/s41585-025-01107-6

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41585-025-01107-6

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer