Pathogenic germline variants might be found in a relatively small percentage of prostate cancer patients, but they can make the prognosis much, much worse. Now, the future is looking brighter, with the VA and other healthcare systems spearheading more testing. At the same time, drug combinations involving PARP inhibitors are showing some success in lengthening survival.
Click to Enlarge: Other race and ethnicity includes Alaska Native, American Indian, Native Hawaiian, Other Pacific Islander who are not Hispanic or Latino, or multiracial. OR indicates odds ratio. Source: JAMA Network Open
PHILADELPHIA — How much of a role do pathogenic germline variants (PGV) play in raising prostate cancer risk?
That was the question raised by a recent VA-led study. The answer is especially important because it informs genetic testing practices.
The study led by the Corporal Michael Crescenz VAMC, the Perelman School of Medicine at the University of Pennsylvania and the Abramson Cancer Center, all in Philadelphia, abstracted genetic testing results for 12 PCa risk genes, clinical, pathological and family history of cancer variables from clinical records for 1,032 PCa patients who met National Comprehensive Cancer Network (NCCN) genetic testing criteria in oncology clinics and 3,602 PCa patients who underwent testing in the VA National Precision Oncology Program (VA-NPOP). The results of the preprint article were reported in medRxiv.1
The study team compared individual gene PGV rates in prostate cancer patients to cancer-free males. Also participating in the study were the VA Greater Los Angeles Healthcare System, the Puget Sound VAMC in Seattle and the Durham, NC, VAMC.
Results indicate that, of 4,634 prostate cancer patients, 5.4% had PGVs in one of 12 PCa risk genes. PGVs in BRCA2 (1.7%), ATM (1.3%), CHEK2 (1.1%), Lynch genes (0.9%), and BRCA1 (0.5%) were most common.
“The total PGV rate was significantly higher in 2825 self-identified white vs. 1,527 self-identified Black PCa patients (6.3% vs 3.7%, adjp=0.0024), although rates of BRCA2 and BRCA1 PGVs were similar (1.9% vs. 1.3%, adjp=0.0885 and 0.6% vs. 0.5%, adjp=0.8005, respectively),” the authors pointed out. “PGV rates were not significantly different in 311 Hispanic compared to 4188 non-Hispanic PCa patients (3.9% vs. 5.5%, adjp=1.000).”
Click to Enlarge: (A) Pathogenic germline variants (PGV) rates for individual genes in the Oncology Clinic cohort (n=1,032), VA National Precision Oncology Program cohort (NPOP, n=3,602), and total cohort combined (n=4,634). (B) PGV rates in total combined cohort for individual genes stratified by self-identified race/ethnicity (SIRE) White (n=2,825) and Black (n=1,527). (C) PGV rates in Hispanic (n=311) and Non-Hispanic (n=4188) patients with PCa. (D) PGV rates separated by age groups at initial prostate cancer diagnosis. Source: medRxiv
They added that, in self-identified white patients, PGV rates in ATM, BRCA1, BRCA2, CHEK2 and Lynch genes were significantly higher compared to two cancer-free male cohorts. In addition, BRCA2 and Lynch genes PGV rates were significantly higher in PCa patients compared to a cancer-free control cohort in SIRE-Black men.
The researchers also said that, in a multivariable logistic regression, age at initial PCa diagnosis and self-identified 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 testing 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 information from saliva to measure a participant’s risk of developing prostate cancer.
Enrolled participants are randomized to receive either standard of care or precision prostate cancer screening information recommendations tailored to their individual genetic profile. The information is provided to participants and their healthcare providers, according to the ProGRESS website, which explains, “This precision 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 commonly 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 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 person’s risk for developing prostate cancer, including risk of metastatic or even lethal disease. That is especially important 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 damaged 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 information 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 variant 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 eligibility 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 synergistic effect.
On June 1, 2023, the Food and Drug Administration approved AstraZeneca and Merck’s Lynparza (olaparib) in combination with abiraterone and prednisone/prednisolone 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 olaparib 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 treatment options for metastatic castration-resistant prostate cancer (mCRPC) and sought to determine the optimal olaparib strategy for treating it.4
To do so, the study team conducted a systematic review and network meta-analysis, searching the Cochrane, Embase, PubMed, and Web of Science databases using “mCRPC” and “olaparib” as keywords.
The researchers identified nine studies from seven clinical trials involving 2,355 patients. “For homologous recombination repair-mutated mCRPC, combination therapies did not demonstrate significant benefits compared with olaparib alone,” they wrote. “However, for BRCA-mutated mCRPC, olaparib combined with abiraterone improved PFS (HR = 0.61, 95% CrI = 0.41-0.91) and OS (HR = 0.41, 95% CrI = 0.21-0.80) significantly. These significant advantages of olaparib combined with abiraterone were also observed in patients from different prostate-specific antigen subgroups.”
The study suggested that olaparib combined with abiraterone “offers substantial benefits in BRCA mutated type (BRCAmt) mCRPC patients. For those with BRCA wild type homologous recombination repair-mutated mCRPC, olaparib monotherapy is effective.”
Other combinations include:
- Akeega (Niraparib + Abiraterone): Approved for metastatic castration-sensitive (mCSPC) and resistant (mCRPC) prostate cancer with BRCA2 mutations,
- Rucaparib: Used as a targeted therapy for BRCA-positive patients who have progressed after other treatments, and
- Upcoming/Novel PARP Inhibitors: Trials are testing new PARP inhibitors like saruparib (AZD5305) to treat high-risk BRCA-positive patients.
A continuing problem, however, is that just more than half, 51.2%, of mCRPC patients with BRCA1/2 alternations ever received a PARP inhibitor in a recent study, while 48.8% did not. The cohort study of 443 patients noted that Medicare insurance beneficiaries had higher odds of receiving a PARP inhibitor.
The report in JAMA Network Open suggested that, “despite the availability of biomarker-selected life-prolonging therapies, a sizeable number of patients with mCRPC and BRCA1/2 alterations do not receive PARP inhibitors, highlighting the need to improve awareness of the data and access to these agents.”5
- Crawford TB, Tayeb M, Barrett E, Al-Saleem T, et. Al. Pathogenic germline variants in a racially diverse real-world cohort of prostate cancer patients. medRxiv [Preprint]. 2025 Aug 15:2025.08.13.25333614. doi: 10.1101/2025.08.13.25333614. PMID: 40832411; PMCID: PMC12363747.Cancer Res Commun
- Montgomery B, Lynch JA, Brown J, Maxwell KN, et. Al. Remote delivery of cancer genetic testing in veterans with metastatic prostate cancer: A Million Veteran Program pilot study. Cancer. 2026 Feb 1;132(3):e70283. doi: 10.1002/cncr.70283. PMID: 41615269; PMCID: PMC12857595.
- Clarke NW, Armstrong AJ, Thiery-Vuillemin A, Oya M, et. Al. Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer. NEJM Evid. 2022 Sep;1(9):EVIDoa2200043. doi: 10.1056/EVIDoa2200043. Epub 2022 Jun 3. PMID: 38319800.
- Li Y, Li Z, Lu H, Shi P, Liu Y, Liu L, Chen K. PARP Inhibitor Olaparib and Its Combination Therapy in Metastatic Castration-resistant Prostate Cancer: A Systematic Review and Network Meta-analysis. Eur Urol Open Sci. 2025 Dec 31;84:1-12. doi: 10.1016/j.euros.2025.12.014. PMID: 41550797; PMCID: PMC12804617.
- Ostrowski M, Jo Y, Hage Chehade C, et al. Receipt of PARP Inhibitors in Patients With Metastatic Prostate Cancer Harboring BRCA1/2 Alterations. JAMA Netw Open. 2025;8(10):e2534968. doi:10.1001/jamanetworkopen.2025.34968
