The field of "theranostics" (i.e., the combination of a diagnostic radiopharmaceutical for patient selection with a therapeutic radioligand therapy to treat appropriate patients [1] has existed since the dawn of nuclear medicine due to Saul Hertz’s seminal contributions to thyroid therapy [2]. In recent years, the concept has had a resurgence, with pivotal clinical trials demonstrating the efficacy of a variety of small molecules and peptides for oncologic applications including mid-gut neuroendocrine tumors [3], metastatic pheochromocytoma/paraganglioma [4], and metastatic, castration-resistant prostate cancer [5].

However, even as such agents have gained regulatory approval, those approvals are often highly constrained to the somewhat arbitrary conditions that were utilized in the registration clinical trials. For example, at the time of this writing, the United States Food & Drug Administration (FDA) approval for the prostate cancer (PCa) prostate-specific membrane antigen (PSMA)-targeted theranostic 177Lu-PSMA-617 mandates that it be used in the castration-resistant setting either pre- or post-chemotherapy. Emerging data can call those restrictive indications into doubt [6], although the regulatory aspects of changing labeled indications can be challenging.

Within that broader context, the field of theranostics is radically changing tack in a manner that will hopefully have an impact on the regulatory landscape. Newer theranostic targets are increasingly viewed as "pan-cancer". A key example would be the class of agents that target the fibroblast activation protein (FAP) that is found on cancer-associated fibroblasts [7]. Those agents emphasize the importance of identifying target expression with a positron emission tomography (PET) diagnostic radiotracer, while also appropriately treating patients with target expression, independent of the cell of origin (Fig. 1) [8].

As such, we are becoming "agnostic" to the cell of origin, in order to define patients that might benefit from radioligand therapy. In looking back at the recent history of nuclear medicine, there has been a push-and-pull between whether we should call the overall field "theranostics" [1] or "theragnostics" [9]. Herein, we suggest that, although the field should be referred to as "theranostics", we should still come to consider ourselves as ther-"agnostic" to the cell of origin, so long as the appropriate level of target expression can be established with targeted PET.

The purpose of this review was to discuss the evolution within the field of theranostics by which we will become less focused in the use of individual therapeutic agents in specific disease states and will instead focus on the broad use of such agents in patients with appropriate target expression.