[ 177 Lu]-PSMA-617 for targeted prostate cancer treatment: a magic bullet?

Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed in aggressive variants of prostate cancer, which is associated with poor prognostic factors such as high tumour grade, resulting in higher Gleason and Epstein scores. 1 Bravaccini S Puccetti M Bocchini M et al. PSMA expression: a potential ally for the pathologist in prostate cancer diagnosis. Sci Rep. 2018; 8: 4254 Crossref PubMed Scopus (93) Google Scholar PSMA is further upregulated by androgen-deprivation therapy and second-generation antiandrogens such as enzalutamide or abiraterone. 2 Bakht MK Oh SW Youn H Cheon GJ Kwak C Kang KW Influence of androgen deprivation therapy on the uptake of PSMA-targeted agents: emerging opportunities and challenges. Nucl Med Mol Imaging. 2017; 51: 202-211 Crossref PubMed Scopus (34) Google Scholar , 3 Murga JD1 Moorji SM Han AQ Magargal WW DiPippo VA Olson WC Synergistic co-targeting of prostate-specific membrane antigen and androgen receptor in prostate cancer. Prostate. 2015; 75: 242-254 Crossref PubMed Scopus (61) Google Scholar These characteristics have led to the development of diagnostic and therapeutic strategies using radioconjugated PSMA antagonists for treatments such as [68Ga]-PSMA-HBED for PET imaging and lutetium-177 [177Lu]-PSMA-617. 4 Fendler WP Rahbar K Herrmann K Kratochwil C Eiber M 177Lu-PSMA Radioligand therapy for prostate cancer. J Nucl Med. 2017; 58: 1196-1200 Crossref PubMed Scopus (109) Google Scholar Once bound to the cell membrane, the PSMA ligands are internalised and the emission of beta particles exerts a toxic effect on tumour DNA. Even more interesting is the use of alpha particles such as actinium-225 PSMA to establish the break of the double helix of DNA. 5 Kratochwil C Bruchertseifer F Rathke H et al. Targeted α-therapy of metastatic castration-resistant prostate cancer with 225Ac-PSMA-617: dosimetry estimate and empiric dose finding. J Nucl Med. 2017; 58: 1624-1631 Crossref PubMed Scopus (278) Google Scholar Several studies have focused on the use of PSMA-radioligand therapy with palliative intent for patients with metastatic castration-resistant prostate cancer. 6 von Eyben FE Roviello G Kiljunen T et al. Third-line treatment and 177Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review. Eur J Nucl Med Mol Imaging. 2018; 45: 496-508 Crossref PubMed Scopus (123) Google Scholar However, most of these studies are retrospective and more prospective data are needed to clarify some issues relating to PSMA-radioligand therapy including the best treatment protocol, patient selection and stratification, and use of concomitant drugs. 6 von Eyben FE Roviello G Kiljunen T et al. Third-line treatment and 177Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review. Eur J Nucl Med Mol Imaging. 2018; 45: 496-508 Crossref PubMed Scopus (123) Google Scholar [177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 studyOur findings show that radionuclide treatment with [177Lu]-PSMA-617 has high response rates, low toxic effects, and reduction of pain in men with metastatic castration-resistant prostate cancer who have progressed after conventional treatments. This evidence supports the need for randomised controlled trials to further assess efficacy compared with current standards of care. Full-Text PDF