Towards Improving the Efficacy of PSMA-Targeting Radionuclide Therapy for Late-Stage Prostate Cancer-Combination Strategies

Overview

Journal Curr Oncol Rep

Publisher Current Science

Specialty Oncology

Date 2023 Oct 20

PMID 37861915

Authors

Daria Arbuznikova

Matthias Eder

Anca-Ligia Grosu

Philipp T Meyer

Christian Gratzke

Constantinos Zamboglou

Ann-Christin Eder

Affiliations

Soon will be listed here.

Abstract

Purpose Of Review: [Lu]Lu-PSMA-617 is a radiopharmaceutical that emits beta-minus radiation and targets prostate-specific membrane antigen (PSMA)-positive prostate cancer. Despite its clinical success, there are still patients not showing sufficient response rates. This review compiles latest studies aiming at therapy improvement in [Lu]Lu-PSMA-617-naïve and -resistant patients by alternative or combination treatments.

Recent Findings: A variety of agents to combine with [Lu]Lu-PSMA-617 are currently under investigation including alpha radiation-emitting pharmaceuticals, radiosensitizers, taxane chemotherapeutics, androgen receptor pathway inhibitors, immune checkpoint inhibitors, and external beam radiation. Actinium-225 (Ac)-labeled PSMA-targeting inhibitors are the most studied pharmaceuticals for combination therapy or as an alternative for treatment after progression under [Lu]Lu-PSMA-617 therapy. Alpha emitters seem to have a potential of achieving a response to PSMA-targeting radionuclide therapy in both initial non-responders or responders to [Lu]Lu-PSMA-617 later developing treatment resistance. Emerging evidence for immunostimulatory effects of radiopharmaceuticals and first prospective studies support the combination of [Lu]Lu-PSMA-617 and immune checkpoint inhibition for late-stage prostate cancer.

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References

Watt F, Martorana A, Brookes D, Ho T, Kingsley E, OKeefe D . A tissue-specific enhancer of the prostate-specific membrane antigen gene, FOLH1. Genomics. 2001; 73(3):243-54. DOI: 10.1006/geno.2000.6446. View

Sathekge M, Bruchertseifer F, Vorster M, Lawal I, Knoesen O, Mahapane J . Predictors of Overall and Disease-Free Survival in Metastatic Castration-Resistant Prostate Cancer Patients Receiving Ac-PSMA-617 Radioligand Therapy. J Nucl Med. 2019; 61(1):62-69. DOI: 10.2967/jnumed.119.229229. View

Paschalis A, Sheehan B, Riisnaes R, Nava Rodrigues D, Gurel B, Bertan C . Prostate-specific Membrane Antigen Heterogeneity and DNA Repair Defects in Prostate Cancer. Eur Urol. 2019; 76(4):469-478. PMC: 6853166. DOI: 10.1016/j.eururo.2019.06.030. View

Staniszewska M, Fragoso Costa P, Eiber M, Klose J, Wosniack J, Reis H . Enzalutamide Enhances PSMA Expression of PSMA-Low Prostate Cancer. Int J Mol Sci. 2021; 22(14). PMC: 8304389. DOI: 10.3390/ijms22147431. View

Sathekge M, Bruchertseifer F, Vorster M, Morgenstern A, Lawal I . Global experience with PSMA-based alpha therapy in prostate cancer. Eur J Nucl Med Mol Imaging. 2021; 49(1):30-46. PMC: 8712297. DOI: 10.1007/s00259-021-05434-9. View

Khreish F, Ebert N, Ries M, Maus S, Rosar F, Bohnenberger H . Ac-PSMA-617/Lu-PSMA-617 tandem therapy of metastatic castration-resistant prostate cancer: pilot experience. Eur J Nucl Med Mol Imaging. 2019; 47(3):721-728. DOI: 10.1007/s00259-019-04612-0. View

Kassis A . Therapeutic radionuclides: biophysical and radiobiologic principles. Semin Nucl Med. 2008; 38(5):358-66. PMC: 2584872. DOI: 10.1053/j.semnuclmed.2008.05.002. View

Suman S, Parghane R, Joshi A, Prabhash K, Talole S, Basu S . Combined Lu-PSMA-617 PRLT and abiraterone acetate versus Lu-PSMA-617 PRLT monotherapy in metastatic castration-resistant prostate cancer: An observational study comparing the response and durability. Prostate. 2021; 81(15):1225-1234. DOI: 10.1002/pros.24219. View

Wright Jr G, Grob B, Haley C, Grossman K, Newhall K, Petrylak D . Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy. Urology. 1996; 48(2):326-34. DOI: 10.1016/s0090-4295(96)00184-7. View

10.

Patel R, Hernandez R, Carlson P, Grudzinski J, Bates A, Jagodinsky J . Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade. Sci Transl Med. 2021; 13(602). PMC: 8449934. DOI: 10.1126/scitranslmed.abb3631. View

11.

Emmett L, Yin C, Crumbaker M, Hruby G, Kneebone A, Epstein R . Rapid Modulation of PSMA Expression by Androgen Deprivation: Serial Ga-PSMA-11 PET in Men with Hormone-Sensitive and Castrate-Resistant Prostate Cancer Commencing Androgen Blockade. J Nucl Med. 2018; 60(7):950-954. DOI: 10.2967/jnumed.118.223099. View

12.

Batra J, Niaz M, Whang Y, Sheikh A, Thomas C, Christos P . Phase I trial of docetaxel plus lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 (Lu-J591) for metastatic castration-resistant prostate cancer. Urol Oncol. 2020; 38(11):848.e9-848.e16. DOI: 10.1016/j.urolonc.2020.05.028. View

13.

Rosar F, Krause J, Bartholoma M, Maus S, Stemler T, Hierlmeier I . Efficacy and Safety of [Ac]Ac-PSMA-617 Augmented [Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Highly Advanced mCRPC with Poor Prognosis. Pharmaceutics. 2021; 13(5). PMC: 8156464. DOI: 10.3390/pharmaceutics13050722. View

14.

Antonarakis E, Piulats J, Gross-Goupil M, Goh J, Ojamaa K, Hoimes C . Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. J Clin Oncol. 2019; 38(5):395-405. PMC: 7186583. DOI: 10.1200/JCO.19.01638. View

15.

Rosar F, Neher R, Burgard C, Linxweiler J, Schreckenberger M, Hoffmann M . Upregulation of PSMA Expression by Enzalutamide in Patients with Advanced mCRPC. Cancers (Basel). 2022; 14(7). PMC: 8997007. DOI: 10.3390/cancers14071696. View

16.

Rosar F, Dewes S, Ries M, Schaefer A, Khreish F, Maus S . 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):687-694. DOI: 10.1007/s00259-019-04674-0. View

17.

Czernin J, Current K, Mona C, Nyiranshuti L, Hikmat F, Radu C . Immune-Checkpoint Blockade Enhances Ac-PSMA617 Efficacy in a Mouse Model of Prostate Cancer. J Nucl Med. 2020; 62(2):228-231. DOI: 10.2967/jnumed.120.246041. View

18.

Sartor O, de Bono J, Chi K, Fizazi K, Herrmann K, Rahbar K . Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021; 385(12):1091-1103. PMC: 8446332. DOI: 10.1056/NEJMoa2107322. View

19.

Feuerecker B, Tauber R, Knorr K, Heck M, Beheshti A, Seidl C . Activity and Adverse Events of Actinium-225-PSMA-617 in Advanced Metastatic Castration-resistant Prostate Cancer After Failure of Lutetium-177-PSMA. Eur Urol. 2020; 79(3):343-350. DOI: 10.1016/j.eururo.2020.11.013. View

20.

Maharaj M, Heslop L, Govender T, Korowlay N, Singh A, Choudhary P . The Outcome and Safety of Re-challenge Lutetium-177 PSMA (Lu-PSMA) Therapy with Low-Dose Docetaxel as a Radiosensitizer-a Promising Combination in Metastatic Castrate-Resistant Prostate Cancer (mCRPC): a Case Report. Nucl Med Mol Imaging. 2021; 55(3):136-140. PMC: 8139998. DOI: 10.1007/s13139-021-00696-5. View