Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Nov;25(11):1363-1374.
doi: 10.1007/s11912-023-01458-6. Epub 2023 Oct 20.

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

Daria Arbuznikova  1   2   3 , Matthias Eder  4   5 , Anca-Ligia Grosu  3 , Philipp T Meyer  1 , Christian Gratzke  6 , Constantinos Zamboglou  3 , Ann-Christin Eder  1   2
Affiliations
Review

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

Daria Arbuznikova et al. Curr Oncol Rep. 2023 Nov.

Abstract

Purpose of review: [177Lu]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 [177Lu]Lu-PSMA-617-naïve and -resistant patients by alternative or combination treatments.

Recent findings: A variety of agents to combine with [177Lu]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 (225Ac)-labeled PSMA-targeting inhibitors are the most studied pharmaceuticals for combination therapy or as an alternative for treatment after progression under [177Lu]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 [177Lu]Lu-PSMA-617 later developing treatment resistance. Emerging evidence for immunostimulatory effects of radiopharmaceuticals and first prospective studies support the combination of [177Lu]Lu-PSMA-617 and immune checkpoint inhibition for late-stage prostate cancer.

Keywords: Combination therapy; Lutetium-177-PSMA-617; Metastatic castration-resistant prostate cancer; Prostate-specific membrane antigen; Radioligand therapy.

PubMed Disclaimer

Conflict of interest statement

Matthias Eder and Ann-Christin Eder hold patent rights on PSMA inhibitors. Daria Arbuznikova, Anca-Ligia Grosu, Philipp T. Meyer, Christian Gratzke, and Constantinos Zamboglou declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Modes of action of therapeutic agents for late-stage prostate cancer that are under evaluation for a combination therapy with [177Lu]Lu-PSMA-617. [225Ac]Ac-PSMA RLT is one of the most promising options for mCRPC patients that experienced [177Lu]Lu-PSMA RLT failure. Alpha particles exhibit a higher LET than β− particles, thus, causing denser DNA damage in the form of DSBs. For [177Lu]Lu-PSMA RLT-naïve patients, immunotherapy with pembrolizumab emerges as a therapeutic modality with high potential in the combination with the radiopharmaceutical. Pembrolizumab binds to PD-1 receptors on T cells and abrogates the immunosuppressive interaction between immune checkpoint proteins on T cells and tumor cells. This leads to an immune attack on the tumor cells in response to recognition of neoantigens presented on major histocompatibility complexes (MHC). The genistein-derivative idronoxil facilitates cell death and led to a longer OS in combination with [177Lu]Lu-PSMA-617 as compared to the monotherapy with the latter. Other potentially radiosensitizing candidates are the taxane chemotherapeutic cabazitaxel and PARP inhibitor olaparib that are investigated in clinical trials. Taxanes interfere with microtubule dynamics, thereby, preventing the normal process of mitosis. PARP inhibitors suppress the sensing and repair of DNA SSBs which leads to the formation of DSBs. It remains to be investigated whether ARPI-induced PSMA upregulation, and thus increased binding capacity for [177Lu]Lu-PSMA-617, can translate into a higher efficacy of the radiopharmaceutical therapy. Another question is whether patients that are already receiving ARPIs can benefit from the approach. Created with BioRender.com
See this image and copyright information in PMC

References

    1. 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-appro....
    1. 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-o....
    1. 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):914–920. doi: 10.2967/jnumed.114.147413. - DOI - PubMed
    1. 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):1441–1443. - PubMed
    1. 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;76:469–478. doi: 10.1016/j.eururo.2019.06.030. - DOI - PMC - PubMed

Publication types

MeSH terms