There is no question that prostate-specific antigen (PSA) is a foundational biomarker in prostate cancer, as it can provide important prognostic and predictive information, and an elevated PSA following surgery or radiation signals biochemical failure. Although PSA screening is an invaluable tool, widespread PSA screening has been associated with the overdiagnosis and the overtreatment of prostate cancer, and so, the US Preventive Services Task Force did not recommend routine PSA screening in 2008 and 2012. While, at one time, the pendulum swung a bit too far in the direction of no screening, it is now coming back to the center. 

Presentations of prostate cancer with metastases at the time of diagnosis had been on the rise in the United States, and here at the 2021 Genitourinary Cancers Symposium, Sharma and colleagues (abstract 228) reported that states with larger declines in PSA screening had larger increases in the incidence of metastatic prostate cancer at diagnosis from 2002 to 2016. This highlights the importance of PSA screening as a useful tool for early detection. However, we want to detect potentially lethal cases, not those that lack malignant potential. Thus, combining PSA screening with other tests, such as PSA isoforms, SelectMDx liquid biopsy (MDxHealth), or 4Kscore (OPKO Health, Inc), among others, may reduce overdiagnosis and overtreatment. By finding a balance among screening, diagnosis, and treatment, we can promptly identify and treat those who are at risk for metastatic disease.

Nuclear medicine is increasingly becoming a part of the multidisciplinary team, and the next abstract in this section focused on a targeted radioligand therapy that is in development for men with metastatic castration-resistant prostate cancer (mCRPC) who progress on second-line treatment. Initial results of the phase 2 TheraP trial showed a significant improvement in PSA (ie, a ≥50% reduction) with ¹⁷⁷Lu-PSMA-617 (Lu-PSMA) compared with cabazitaxel (66% vs 37%) in men with mCRPC who progressed on docetaxel (with 91% of patients receiving prior enzalutamide or abiraterone). In abstract 6, Hofman and colleagues reported longer progression-free survival at a median follow-up of 18.4 months with Lu-PSMA compared with cabazitaxel (1-year rate: 19% vs 3%). While these response rates were modest, I consider this improvement meaningful since this population mainly included patients who progressed on 2 lines of therapy. Those treated with Lu-PSMA also had a significant improvement in patient-reported outcomes, including fatigue, social functioning, and insomnia. In my opinion, this study is a game changer because it suggests that Lu-PSMA may be an alternative to additional chemotherapy and could potentially be integrated earlier in the disease course. Once overall survival data are available, we will better understand how to incorporate Lu-PSMA into the treatment arsenal for mCRPC. 

It is exciting to see that we are catching up, with the development of molecular targets. And the importance of predictive biomarkers is also becoming increasingly evident in advanced prostate cancer. Microsatellite instability (MSI) is a tissue-agnostic biomarker that predicts response to the immune checkpoint inhibitor pembrolizumab. Abstract 16 reported the prevalence of MSI in African American men, a population known to have higher prostate cancer incidence and prostate cancer–specific mortality rates. Khashab et al retrospectively analyzed next-generation sequencing results from tissue assay and/or liquid biopsy assay for MSI and detected MSI-high status with similar frequencies among African American and non–African American men (3.7% vs 3.6%). While MSI-high does not occur at high rates, it is important to identify it when present. Another significant finding from this analysis is that there was 100% concordance in MSI-high detection between the tissue and liquid biopsy assays. Liquid biopsies are a minimally invasive alternative to tissue biopsies that can detect MSI markers and monitor the response to pembrolizumab. I think that these findings suggest that we can rely more on liquid biopsies and that we do not always need to have tissue, but more studies are needed here. 

McKay and colleagues here in San Diego performed a biomarker analysis from a randomized phase 2 study of olaparib with or without cediranib in men with mCRPC to identify radiographic progression-free survival in the overall population and in subgroups of patients by homologous recombination gene status. They reported in abstract 7 that homologous recombination deficiency, defined by the presence of homozygous deletions or deleterious mutations in DNA repair genes (including BRCA1, BRCA2, and ATM), was present in 31% of patients (26/84). Furthermore, the benefit with olaparib and cediranib was more evident among men with homologous recombination–deficient mCRPC compared with those with homologous recombination–proficient mCRPC, warranting further investigation.