Alternatives to tissue biopsy have long been sought for patients with advanced metastatic disease. The need for liquid biopsy stems, in part, from logistical challenges associated with traditional tissue biopsies. For example, we may not want to sequence tissue from prostatectomies that were performed years ago. In other cases, we may want to test a specimen but do not have access to it. With bone-only metastases, biopsy is invasive and may be technically challenging, and it does not always result in a good sample. 

Multiple studies have shown that circulating tumor cells carry strong, independent, prognostic information; however, this approach was never incorporated into clinical practice because no prospective study was done in which results from a circulating tumor cell assay were used to make treatment decisions. 

With the advent of ctDNA, which has been very exciting, we have an opportunity to obtain an early indication of how well a patient is responding to treatment. Additionally, ctDNA has the potential to provide more information about the biology of the cancer, including which clones are becoming dominant. It becomes a bit more complex when profiling noninvasively using ctDNA to select patients for treatment with poly (ADP-ribose) polymerase inhibitors. Liquid biopsies are certainly desirable in metastatic castration-resistant prostate cancer, but there are gaps in our understanding of the most appropriate diagnostic testing method to identify those who would quality for and benefit from treatment with poly (ADP-ribose) polymerase inhibitors. Most of the clinical trials have actually required tissue-based DNA sequencing, or germline testing, so whether ctDNA liquid biopsy is the right tool is a bit of a gray area. There have been studies examining concordance between tissue and liquid biopsy, and they are usually fairly concordant, but, again, this is still an evolving area. It is also likely that additional education and experience are needed in using ctDNA (eg, with allele fractions and the pathogenicity of identified alterations) to select patients for therapy.

Next-generation imaging with PSMA positron emission tomography (PET) is another noninvasive means of prostate cancer profiling. For the selection of patients with metastatic castration-resistant prostate cancer for lutetium Lu 177 vipivotide tetraxetan, which was recently approved, the studies all use PSMA PET scans to identify those who qualify and may benefit. It is a very unique and relatively specific imaging biomarker. At the 2022 Genitourinary Cancers Symposium, there was a presentation by Buteau et al showing that the avidity of tumors on the PET scan actually may impact the likelihood of response. So, I think that PSMA PET is going to be a very helpful tool for selecting patients who will benefit the most from this targeted radioligand therapy.