In recent years, we have made great progress with genomic markers such as BRCA2 and with molecular biomarkers such as PSMA. I think that having 2 poly (ADP-ribose) polymerase (PARP) inhibitors available for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) has encouraged people to do more genomic testing. There are 2 types of genomic testing: testing for germline gene mutations that are inherited and testing the tumor itself for somatic mutations. And, in general, up to one-quarter of patients with mCRPC will have one of these DNA damage repair mutations, the most common being BRCA2, that will make them a candidate for a PARP inhibitor such as olaparib or rucaparib. You can obtain a lot of information from germline testing alone, but I favor testing for both somatic and germline mutations; doing so can increase the yield, as noted by Perez et al in abstract 595P at the ESMO Congress 2021.

People are also enthusiastic about PSMA because of its applications in diagnostic imaging and in treatment, with PSMA-targeted radioligand therapy emerging. Lutetium-177 (¹⁷⁷Lu)–PSMA-617 was the focus of several studies presented at the ESMO Congress 2021. If you compare PSMA with BRCA2, I will say that both are predictive markers. Approximately 4 out of 5 patients with mCRPC will be PSMA positive, whereas only approximately 1 out of 5 individuals will have DNA damage repair mutations. That is, PSMA is present in somewhere on the order of 80% to 90% based on gallium or 18F PSMA scans. In contrast, if you give everyone with mCRPC a PARP inhibitor, the response rate will be very low because the chance of having the appropriate predictive mutation is only approximately 1 in 5.

The issue of when to test is important, whether you are testing for PSMA positivity or for the presence of BRCA2 mutations. In abstract 628P, Hardwick and colleagues presented an interesting study in which they looked at a series of patients with previously and newly diagnosed prostate cancer and determined whether they met the criteria for germline testing (ie, according to 2019 guidelines from the National Comprehensive Cancer Network). The authors were making a case for universal germline testing in patients with prostate cancer, suggesting that established guidelines have been too restrictive. They found that there were no differences in the rate at which pathogenic or likely pathogenic germline mutations were detected based on meeting or not meeting the criteria for testing. Why would that be? Well, we know that patients may not know, for instance, exactly what their father or mother died from or that they may have been adopted, so family history is not always complete. 

Regarding whether patients who are not PSMA positive might still benefit from a therapy such as ¹⁷⁷Lu-PSMA-617, the study by Tagawa et al was interesting (abstract 600P). PSMA expression was not a requirement for treatment, and most patients had post-treatment prostate-specific antigen decline with favorable biochemical and radiographic progression-free survival compared with historical non-PSMA controls. If you look at the data, responses were better with higher levels of PSMA expression. But the whole debate around this is whether testing for PSMA expression will be necessary. The majority of patients probably do have some expression. Given these findings, I think that PSMA is a predictor of response, but perhaps it will not be so critical to test patients for PSMA expression, as the majority will wind up expressing it and experiencing some benefits.