SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease.
The five year survival among patients first diagnosed with metastatic prostate cancer is approximately 30%. Early detection and treatment may improve outcomes. Risk factors for prostate cancer include age, ethnicity, and family history of prostate cancer. In individuals with a family history of prostate cancer in one or more first-degree relatives, the Relative Risk of prostate cancer increases approximately 2-3 fold, and the risk increases with an increasing number of affected relatives, and is inversely related to the age at time of diagnosis among those relatives.
It is estimated that approximately 40% of all diagnosed prostate cancers are inherited and prostate cancer risk also has been implicated in other familial cancer syndromes such as Hereditary Breast and Ovarian Cancer (HBOC) syndrome and Lynch Syndrome (LS). HBOC syndrome typically is found in families with early onset cancer and multiple cancer diagnoses such as, breast, ovarian and pancreatic cancer. Tumor suppressor DNA repair genes BRCA1 and BRCA2, has been implicated in prostate cancer, particularly in HBOC families. Patients with a BRCA1 mutation have a nearly 2-fold Relative Risk of prostate cancer among men less than 65 years, whereas those with BRCA2 mutations have a more than 7 fold Relative Risk. Further, patients with BRCA2 mutations are also associated with clinically aggressive disease, progression, and higher rates of cancer-specific mortality. It is estimated that the frequency of BRCA2 mutations ranges from 1-3%.
Somatic genomic testing in metastatic prostate cancer can offer insights into both prognosis and potential treatment responses, helping guide clinical decisions. Germline genetic testing can also yield similar insights, with the added benefit of revealing inherited cancer risks that may be relevant to patients relatives, including risks for cancers such as breast, pancreatic, colon, and endometrial. As a result, research has focused on determining which germline and somatic genetic tests deliver the most valuable information for individual patient cases.
The present ASCO guideline was developed by a multidisciplinary Expert Panel, following review of evidence on germline and somatic genomic testing for patients with metastatic prostate cancer. A total of 1,713 papers were identified in the literature search, and the recommendations are based on evidence from eight systematic reviews and six trials. This guideline is applicable to a patient who has a life expectancy of more than 6 months, is a candidate for systemic treatment, and for whom appropriate germline and somatic testing, including expertise in interpretation, is readily available.
This guideline addresses the following questions:
1) Why germline and somatic genomic testing should be offered?
2) The criteria for which patients should be offered testing?
3) Which test(s) to use?
4) When in the disease course testing should be considered?
5) Which biospecimens should be used for testing?
RECOMMENDATIONS
Clinical Question: Who should receive germline testing with NGS technologies?
Recommendation: All patients with metastatic prostate cancer should undergo germline genetic testing with next-generation sequencing technologies.
Clinical Question: Who should receive somatic testing with NGS technologies?
Recommendation: Those patients with metastatic prostate cancer (both Castrate Sensitive and Castrate Resistant Prostate Cancer) who are being considered for biomarker-directed systemic treatment should undergo somatic testing with next-generation sequencing technologies. While there are no current FDA-approved biomarker-directed treatments following somatic testing for metastatic Castrate Sensitive Prostate Cancer, somatic testing may be warranted in the presence of high-volume disease, or where there is a high likelihood the patient’s disease will progress to Castrate Resistant Prostate Cancer, where the patient is a candidate for future treatment with a biomarker-directed therapy (PARP inhibitor or checkpoint inhibitor).
Clinical Question: Who should receive sequential somatic testing with NGS technologies?
Recommendation: The panel recommends that sequential somatic testing may be offered when there has been a meaningful change in the patient’s status or treatment plan, especially in cases where prior tests were negative or uninformative (eg, insufficient or low tumor content).
Clinical Question: What are the strengths and weaknesses of primary tumor archival tissue versus fresh metastatic biopsy tissue versus ctDNA testing for somatic testing?
Recommendation: Archival tissue samples are preferred in initial testing. ctDNA is preferred when there is no accessible metastatic site to biopsy or for sequential testing. In the setting of minimal disease burden associated with low ctDNA fraction, metastatic biopsy is preferred.
Clinical Question: What are the key therapeutic impacts of germline or somatic testing for single-gene genetic variants (eg, BRCA1, BRCA2)?
Recommendation: Patients with pathogenic germline variants or somatic alterations in BRCA1 and BRCA2 demonstrate poorer outcomes, but are candidates for treatment with PARP inhibitor monotherapy, PARP inhibitor with Androgen Receptor Pathway Inhibitor combination therapy, and platinum-based agents.
Clinical Question: What are the key prognostic impacts of germline or somatic testing?
Recommendation: Treatment recommendations should not be made based on prognostic only biomarkers. However, they may be considered for directing patients to clinical trials. Germline information may still be important for patient counseling, informing hereditary risk for patients and families.
Pre-Test Genetic Counseling for Germline Testing
Before conducting germline testing, clinicians should ensure patients understand the following essential aspects:
- Purpose of Testing: Explain the goals and implications of germline genetic testing.
- Hereditary Nature: Emphasize that the results can reveal inherited cancer risks.
- Family Impact: Discuss how findings might indicate elevated cancer risks for relatives.
- Testing Options: Inform patients about the availability of gene panel testing.
- Possible Outcomes:
- Pathogenic/Likely Pathogenic Variants (P/LPVs)
- Variants of Uncertain Significance (VUS)
- Negative or Inconclusive Results
- Legal Protections: Outline patient protections under the Genetic Information Nondiscrimination Act (GINA).
- Cascade Testing: Stress the importance of testing family members when a P/LPV is found.
Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline. Yu EY, Rumble RB, Agarwal N, et al. J Clin Oncol. 2025;43:748-758. DOI:10.1200/JCO-24-02608.
