5 4 The researchers also said that, in a multivariable logis- tic regression, age at initial PCa diagnosis and self-identi- fied race were significantly associated with any PGV. “In a racially diverse, real-world cohort of individuals with PCa, lower PGV rates were identified compared to prior academic cohort studies,” the study advised. “Outside of ATM and CHEK2, PGV rates were similar across the majority of clinical and pathological groupings. Our data support NCCN guideline-indicated universal genetic test- ing for patients with aggressive forms of PCa.” The VA has its own initiative, the Prostate Cancer, Genetic Risk, and Equitable Screening Study (ProGRESS). It seeks to determine if genetic testing can improve prostate cancer screening, using genetic informa- tion from saliva to measure a participant’s risk of develop- ing prostate cancer. Enrolled participants are randomized to receive either standard of care or precision prostate cancer screening information recommendations tailored to their indi- vidual genetic profile. The information is provided to participants and their healthcare providers, according to the ProGRESS website, which explains, “This preci- sion approach is not yet a part of routine prostate cancer screening but might help target screening to individuals at highest risk of developing prostate cancer while safely deferring screening for low-risk individuals.” As it stands now, prostate cancer screening, most com- monly by a prostate-specific antigen (PSA) test, modestly reduces prostate cancer related deaths but also increases the risks associated with overdiagnosis and overtreatment. That’s why neither the United States Preventive Services Task Force (USPSTF) or the VHA National Center for Health Promotion and Disease Prevention has a universal prostate cancer screening recommendation. Yet, an individual’s genetic profile might estimate a per- son’s risk for developing prostate cancer, including risk of metastatic or even lethal disease. That is especially impor- tant because of therapies like PARP inhibitors are a class of targeted cancer drugs that block the poly (ADP-ribose) polymerase (PARP) enzyme, which helps cells repair dam- aged DNA. The therapy disrupts DNA repair in cancer cells and, when combined with BRCA1/2 mutations, which already weaken DNA repair, the result is “synthetic lethality,” a process where the cancer cell cannot survive. The VA is so concerned about gathering more informa- tion about germline pathogenic variants that can inform targeted therapy for metastatic prostate cancer (mC), improve cancer early detection and risk reduction for family members, that it has taken some aggressive steps to increase update. Even though guidelines recommend germline genetic testing be offered to all men with mPC, only 10%-12% do so. In this study, led by the VA Puget Sound Health Care System and the University of Washington, both in Seattle, participants who provided verbal consent were mailed a saliva collection kit for a multigene cancer predisposition gene panel test. Results were disclosed to the patient and oncology provider. All steps were performed with genetic counseling support. Of 2,104 eligible patients, 1,952 veterans with mPC did not opt out. Of these, 681 (35%) provided consent and 459 (24%) completed testing, with 59 (13%) of those completing testing revealing a germline pathogenic vari- ant in a cancer risk gene. Of the 37 eligible for targeted therapy, 14 received targeted therapy, 18 did not yet have an indication for that therapy, and five were deceased without having received targeted therapy. “Participant completion of remote germline testing was facilitated at rates higher than the 10% previously reported,” the authors reported in the journal Cancer. “Remote genetic testing can augment uptake of testing in large, integrated healthcare systems.”2 Routine genetic testing for BRCA1/2 to determine eli- gibility for targeted therapy is just one of the new trends in managing advanced prostate cancer. Others include initiating PARP inhibitors to earlier stages of metastatic disease and, especially, combining PARP inhibitors with androgen receptor signaling inhibitors (ARSI) for a syn- ergistic effect. On June 1, 2023, the Food and Drug Administration approved AstraZeneca and Merck’s Lynparza (olaparib) in combination with abiraterone and prednisone/predniso- lone for BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC). The approval was based on the PROpel Phase III trial, published in NEJM Evidence.3 The authors concluded that the PROpel Phase 3 trial demonstrated that combining the PARP inhibitor olapa- rib with abiraterone significantly extended imaging-based progression-free survival (ibPFS) in first-line metastatic castration-resistant prostate cancer patients, regardless of homologous recombination repair (HRR) gene mutation status. It showed a median ibPFS of 24.8 months compared to 16.6 months with abiraterone and placebo. Prostate cancer patients with the mutations usually have aggressive disease, with BRCA2 carriers specifically often facing worse survival of about 4-8 years and a 5-year survival rate of about 39 to 57%, compared to noncarriers or BRCA1 carriers. A study published last year in European Urology Open Science noted that olaparib is one of the earliest approved
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