Radionuclide Therapy in Prostate Cancer: From Standalone to Combination PSMA Theranostics

Abstract

Despite significant advances in therapeutic developments for prostate cancer over the last 2 decades, metastatic prostate cancer remains a lethal disease. Prostate-specific membrane antigen (PSMA), which is markedly overexpressed in prostate cancer cells and metastatic sites but has low normal-tissue expression, has emerged as an important theranostic target for this disease. Both b-emitting and a-emitting PSMA-targeted radionuclide therapy (RNT) are in clinical development. Several of these agents have already shown promising activity; however, a subset of patients have primary resistant disease, and secondary resistance invariably occurs. Further, the effect of these therapies on healthy organs limits their therapeutic window. Elucidating the biology of PSMA and characterizing the pharmacokinetic and pharmacodynamic properties of PSMA-targeted RNT and mechanisms of resistance will facilitate therapeutic approaches aimed at improving efficacy and safety. In this review, we provide an overview of existing PSMA-targeting RNT and novel RNT combinatorial approaches, such as those with novel hormonal agents, poly-[adenosine diphosphate-ribose]-polymerase inhibitors and immunotherapy, currently under investigation.

Biomarkers to personalize treatment with 177Lu-PSMA-617 in men with metastatic castration-resistant prostate cancer - a state of the art review

“…Currently, 177Lu-PSMA-617 therapy is investigated even in earlier stage of disease (locally advanced, primary metastatic), prior to chemotherapy and/or ARSI as well as in combination with PARP inhibitors (olaparib), hormonal therapy (enzalutamide) or immunotherapy (pembrolizumab) (reviewed in Sandhu et al 16 ).…”

Quantification of biochemical PSA dynamics after radioligand therapy with [177Lu]Lu-PSMA-I&T using a population pharmacokinetic/pharmacodynamic model

“…The mechanism of action of [ 177 Lu]Lu-PSMA is the result of a cytotoxic radiation dose due to β minus particle (β − ) emission, which modifies the tumor microenvironment and induces DNA damage followed by cell death [ 12 ]. Theoretically, a higher (homogeneous) cumulative absorbed dose (i.e.…”

Prognostic role of early prostate specific antigen changes after [177Lu]Lu‐PSMA radioligand therapy of metastasized prostate cancer: A meta‐analysis

“…14 Positron emission tomography with radiolabeled PSMA have been approved and are currently used to stage newly diagnosed high-risk prostate cancer, to assess patients with biochemical recurrence and to evaluate the response to treatment of advanced cancers, respectively. [15][16][17] Notably, the subsequent introduction of several [ 177 Lu]Lu-targeted PSMA ligands such as [ 177 Lu] Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T, PSMA-based radioligand therapy (RLT) has gained prominence for the treatment of metastasized mCRPC 18,19 and has been approved by the Food and Drug Administration and the European Medicines Agency 20,21 after the results of the phase III VISION trial demonstrated that the Lu-PSMA-617 treatment prolongs progression free survival (PFS) and OS in mCRPCP heavily pretreated PSMA positive mCRPC. 22 Moreover, the phase II TheraP trial has show great efficacy of Lu-PSMA-617 in improving PFS compared to cabazitaxel treatment, but failed to demonstrate OS improvements.…”