<p>The importance of germline and somatic tumor testing for prostate cancer is growing due to the increased availability of highly effective targeted therapies. PARP inhibitors, in particular, have the potential to significantly improve patient outcomes.</p>

Despite the fact that life-prolonging therapies such as PARP inhibitors and pembrolizumab have been approved by the US Food and Drug Administration (FDA) based on underlying tumor genomic alterations for a number of years, a retrospective cohort study found that only 27.1% of patients with metastatic prostate cancer underwent next-generation sequencing in 2022. So, why are clinicians not testing people at a higher rate? I think one of the reasons might be that there used to be confusing messages from different societies about who should undergo tumor genomic or germline testing. Ten years ago, there were a lot of guidelines mentioning family history of high-risk prostate cancer and the ages of family members affected by prostate, ovarian, and pancreatic cancer. Fortunately, the messaging has gotten clearer.

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Busy practitioners not specializing in prostate cancer likely benefit from simpler and easier-to-understand messaging about who needs germline and somatic tumor testing. Every patient with metastatic prostate cancer should undergo germline and somatic tumor testing, and, in my view, every patient with localized high-risk prostate cancer should also undergo both types of testing because these individuals have a very high risk of developing metastatic disease.

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Somatic tumor testing is important for all patients with metastatic prostate cancer because, if testing results, such as a BRCA2 mutation, suggest a potential for a concurrent pathogenic germline variant, patients who were initially reluctant to undergo germline testing may be more willing. Somatic tumor tissue testing can also reveal microsatellite instability (MSI)–high status in a small number of patients, which matters because pembrolizumab is effective in treating MSI-high prostate cancer. There are also multiple clinical trials that patients may be eligible for based on their underlying tumor mutation status.

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We recently presented updated data on the PARP inhibitor talazoparib from the TALAPRO-2 trial at the 2025 ASCO Genitourinary Cancers Symposium. The all-comer population with metastatic castration-resistant prostate cancer in the TALAPRO-2 trial had an overall survival (OS) benefit of 8.8 months with talazoparib plus enzalutamide vs enzalutamide plus placebo at 45.8 vs 37.0 months. In the subgroup analysis of patients with and without BRCA1/2 and HRR gene alterations, there was also a differential magnitude of benefit. For example, patients who were HRR deficient had a 45.1% reduction in risk of death and a 14-month improvement in survival with enzalutamide plus talazoparib at 45.1 vs 31.1 months. Patients who did not have BRCA1/2 alterations had a 25.1% reduction in risk of death, with an OS-stratified hazard ratio of 0.749. Patients who did not have HRR gene alterations had a 21.8% reduction in risk of death, and patients with BRCA1/2 mutations had a 50.3% reduction in risk of death. Because of the OS benefit in the intention-to-treat population, we concluded that enzalutamide plus talazoparib should be considered as a treatment option for patients with metastatic castration-resistant prostate cancer. As a next step, we now need to understand why patients without gene alterations are also responding to this treatment, as I am sure that there are other markers driving the responses we have observed.