Theranostics for Advanced Prostate Cancer: Current Indications and Future Developments

Abstract

Context

Advanced prostate cancer (PCa) is a prominent cause of cancer death in men; positron emission tomography (PET) imaging may play a relevant role in detecting metastases and thus allowing a more tailored therapy in these patients. Radioligand therapy (RLT) may also gain relevance as a treatment strategy in advanced disease.

Objective

The aim of this review is to highlight how the recently developed theranostic processes may become a part of both the available diagnostic and the therapy arsenal in advanced PCa patients.

Evidence acquisition

An expert panel of nuclear medicine physicians and a urologist, highly experienced in the fields of radionuclide imaging and RLT in advanced PCa, performed a nonsystematic review of the current indications, performance, limitations, and potential future developments of the currently available options in PCa theranostics.

Evidence synthesis

Among PET radiotracers, prostate-specific membrane antigen (PSMA)-based compounds in advanced PCa are the focus of a continuously growing interest, mostly due to their potential relevance as theranostic agents. The impact of PSMA-based PET/computed tomography imaging on treatment strategies and prognosis is promising, but still not unquestionably clear. Potential applications may include a role as a gatekeeper to PSMA-directed RLT, as well as monitoring the spread of systemic disease. Currently, initial results seem to substantiate the role of PSMA-directed RLT in terms of feasibility and efficacy.

Conclusions

PSMA is a promising molecule for both imaging and therapy in advanced PCa patients; nevertheless, further studies are needed to investigate its role and to determine the impact of its side effects and its overall strategy outcome.

Patient summary

Prostate-specific membrane antigen (PSMA), a protein, is highly expressed on prostate cancer cells. The possibility to perform diagnostic imaging and subsequently administer therapies by the means of the same molecule is called “theranostics”. In patients with advanced prostate cancer, PSMA might have a role in detecting disease spread through both positron emission tomography and single-photon emission computed tomography imaging, while treating prostate cancer systemic localizations with radioligand therapy. Further studies are needed to better determine patients’ risks and benefits of these therapeutic approaches.

Introduction

The word “theranostic” derives from Greek words therapeia (therapy) and gnosis (knowledge) and refers to the possibility of combining a diagnostic biomarker with a therapeutic agent [1].

This concept has been known since the end of the 20th century, with various applications currently available. Its first nuclear medical application dates back to 1946, when radioiodine therapy was first used to treat metastases of thyroid adenocarcinoma [2]. More recently, increased interest in theranostics led to the implementation of this combined approach to other clinical settings, including neuroendocrine tumors and advanced prostate cancer (PCa).

PCa is a leading cause of cancer mortality in men worldwide due to the development of metastatic disease [3]. Most patients with advanced disease initially respond to androgen deprivation therapy (ADT), but they develop invariably fatal castration-resistant PCa (CRPC) within 1–3 yr [4]. In 2004, two pivotal phase 3 studies demonstrated that docetaxel-based regimens improved overall survival (OS) in patients with CRPC [5], [6]. Since 2010, six new therapeutic agents with diverse mechanisms of action have been added to the available therapy arsenal, five of which (sipuleucel-T [7], cabazitaxel [8], abiraterone [9], enzalutamide [10], and radium-223 [11]) have been approved for the treatment of CRPC based on OS and progression-free survival (PFS) benefits. While these new treatments provided therapy tailoring options based on patient characteristics, none resulted in durable clinical responses, as the survival benefit was generally limited to <6 mo [10], [12]. Therefore, there is an unmet need for the development of new treatments.

During the last few years, prostate-specific membrane antigen (PSMA) ligands for positron emission tomography (PET) imaging have drawn the attention of the medical community. To date, the only Food and Drug Administration (FDA)-approved agent is the ¹¹¹In-capromab pendetide (ProstaScint) for single-photon emission computed tomography (SPECT) imaging (1996), directed against an intracellular domain of PSMA [13], while the first human PSMA-PET study was performed in 2012 [14]. PSMA is a type II, carboxypeptidase-associated transmembranous glycoprotein with folate hydrolase activity [15]. It has been demonstrated that PSMA is overexpressed in PCa cells [16], and over the last few years, several radiolabeled PSMA ligands have been investigated in both PET and SPECT imaging. Additionally, current evidence suggests that a PSMA-targeting combined approach may provide not only a more accurate diagnosis, but also a realistic option to treat CRPC patients, for example, by employing ligands such as β-emitting isotopes, Auger emitters [17], or α-emitting isotopes.