Despite its limitations, prostate-specific antigen (PSA) continues to be a useful biomarker and an important prostate cancer screening tool. In abstract 51 from the 2022 Genitourinary Cancers Symposium, Burgess et al shared some chilling trends in prostate cancer–specific mortality that mirrored the 2008 to 2012 position of the US Preventive Services Task Force (USPSTF) against routine PSA screening. Mortality rates had been declining prior to 2012, but the progress slowed and then came to a standstill from 2014 to 2019—a change that was accompanied by decreased PSA screening and increased metastatic disease diagnoses. These mortality trends were inconsistent with the mortality trends that were observed across all malignancies during the same period. 

What we are seeing now with these data is that, sure enough, when you do not screen for prostate cancer, mortality goes up. And these prepandemic data do not capture the impact of more recently missed screening opportunities and cancer diagnoses. The USPSTF updated its guidance in 2018, giving PSA screening a grade C rating for men aged 55 to 69 years, but this rating is, in my view, inappropriate. I would like to see this changed to grade B or grade A. Even going back to 2012, around the time of the USPSTF’s grade D recommendation, level-1 evidence from the multinational European Randomized Study of Screening for Prostate Cancer reported a 29% lower rate of prostate cancer mortality in the PSA screening arm after adjusting for noncompliance. 

Today, a decade later, PSA screening can be part of a more comprehensive risk assessment that is performed before going to biopsy. You can incorporate additional tools such as the Prostate Health Index or urinary markers such as ExoDx (Exosome Diagnostics). And active surveillance for low-risk disease is increasingly becoming an option that can be tailored to individual risk and can reduce anxiety, toxic effects, and costs. So, it is really a different era now, and I believe that the USPSTF should update the C rating in parallel with these changes.

Genomic markers have also been generating controversy. Testing for mutations that involve DNA damage response and repair genes, including those in the homologous recombination repair (HRR) pathway, has been in the spotlight in recent years, as these mutations are thought to confer sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors in men with metastatic castration-resistant prostate cancer (mCRPC). Currently, olaparib and rucaparib are the 2 US Food and Drug Administration (FDA)–approved PARP inhibitors for mCRPC. 

Two studies on PARP inhibitors generated a great deal of interest at this year’s symposium: PROpel (abstract 11) and MAGNITUDE (abstract 12). Both studies were preliminary, reporting on radiographic progression-free survival (rPFS) and not overall survival, so the results could change with time. However, the findings generated some heated exchanges among the experts during a plenary session, and there was ample commentary on social media during the session and afterward. 

The PROpel study is evaluating olaparib plus abiraterone acetate and prednisone (AAP) in the first line for mCRPC (abstract 11). The MAGNITUDE trial is evaluating niraparib plus AAP in patients with mCRPC (abstract 12). In PROpel, significant improvements in rPFS were observed in patients on olaparib plus AAP compared with placebo plus AAP, irrespective of HRR status. In MAGNITUDE, niraparib plus AAP improved rPFS in those with HRR but not in those without HRR. 

Results from the PROpel study suggest that you might not need to do the testing to identify mutations such as BRCA, ATM, or others, and you might just be able to give olaparib early on to a newly diagnosed patient with mCRPC. Results from the MAGNITUDE trial suggest that you would need to do the testing if you are considering niraparib, since only the men who have those mutations would respond. This left many people scratching their heads, and I think that more work is needed to understand these findings.

Finally, prostate-specific membrane antigen (PSMA) is a molecular imaging marker that can also potentially be targeted. This area is a bit of a new frontier for us here, in the sense that we only recently started doing PSMA-based positron emission tomography (PET) imaging at our institution. PSMA-targeted radioligand therapies such as lutetium-177 (¹⁷⁷Lu)–PSMA-617 are in development. Although ¹⁷⁷Lu-PSMA-617 is not approved yet,* abstract 10 was very interesting to me because it suggested that PSMA PET activity or intensity might predict which patients may respond to ¹⁷⁷Lu-PSMA-617. Again, much more work needs to be done, as this is another emerging area. But the bottom-line take-home message from abstract 10 is that PSMA uptake intensity might be a part of predicting treatment response to PSMA-targeted radioligand therapy.

*Addendum: On March 23, 2022, subsequent to this interview, the FDA approved lutetium Lu 177 vipivotide tetraxetan (formerly referred to as ¹⁷⁷Lu-PSMA-617) for the treatment of progressive PSMA-positive mCRPC. The FDA also approved a complementary gallium-68–based agent indicated for PET of PSMA-positive lesions.