Genomic Testing in Advanced Prostate Cancer (2025 Guide)

Introduction: Genomic vs. Molecular Testing

Genomic testing analyzes cancer DNA to guide personalized treatment decisions.
Genomic testing focuses on the genetic makeup of cancer – examining DNA (or gene activity) in cancer cells to find mutations or patterns that drive the disease. This is different from broader molecular testing, which can include analyzing proteins or other biomarkers. In practice, genomic tests look at genes in the tumor (and sometimes inherited genes) to identify alterations. These alterations can predict how aggressive the cancer is or whether certain treatments will work. This guide will focus solely on genomic testing for advanced prostate cancer and how it informs care in 2025.

Comparison of Different Genomic Tests (Pros and Cons)

Different genomic tests are used in prostate cancer. Some test the tumor’s DNA for mutations, while others measure gene expression to gauge tumor behavior. The table below compares key genomic tests, highlighting their pros and cons:

Test	What it Measures	Pros	Cons
Germline Genetic Testing(hereditary panel)	Inherited DNA mutations (via blood or saliva).	– Detects inherited risk mutations (e.g. BRCA1/2). – One-time test (your germline DNA doesn’t change). – Findings can guide targeted therapy (e.g. PARP inhibitors if BRCA/ATM mutated) pubmed.ncbi.nlm.nih.gov .	– Does not reveal tumor-only mutations. – May find variants of uncertain significance (unclear meaning). – If a mutation is found, it has implications for family members (genetic counseling often advised).
Tumor Genomic Profiling(tissue NGS panel)	DNA mutations in a tumor sample (biopsy tissue).	– Identifies somatic (tumor-acquired) mutations across many genes in the cancer pmc.ncbi.nlm.nih.gov. – Can find “actionable” mutations (e.g. DNA repair gene mutations, MSI status) to match with therapies. – Widely recommended for metastatic prostate cancerpubmed.ncbi.nlm.nih.gov.	– Requires a tumor biopsy (invasive). – May miss tumor heterogeneity (only samples one tumor site). – DNA quality can degrade in stored tissue, which can affect results.
Liquid Biopsy Genomic Test (ctDNA panel)	Tumor DNA fragments in the blood (circulating tumor DNA).	– Non-invasive (simple blood draw). – Captures DNA from multiple tumors throughout the body (better reflects tumor diversity). – FDA-approved liquid tests exist (e.g. FoundationOne Liquid CDx) to detect mutations like BRCA1/2 for therapy selection.	– If the tumor isn’t shedding much DNA into blood, important mutations can be missed (false-negative). – Slightly lower sensitivity than tissue biopsy for some alterations. – A negative result may still require a tissue biopsy to be sure.
Decipher® Genomic Classifier(22-gene test)	Expression levels of 22 genes in prostate tumor tissue.	– Predicts risk of aggressive disease and metastasis. Higher Decipher score = higher chance of spread pmc.ncbi.nlm.nih.gov. – Helps guide treatment after surgery (e.g. whether to add radiation or hormone therapy if score is high). – Backed by studies showing it improves risk stratification pmc.ncbi.nlm.nih.gov.	– Only provides a risk score (prognostic); does not identify specific drug targets. – Primarily used for earlier stages (post-surgery or high-risk localized cancer) to inform additional treatment, not as useful once cancer is widely metastatic. – Requires tumor tissue from surgery or biopsy.
Oncotype DX® GPS(17-gene assay)	Expression of 17 genes in the prostate biopsy tissue.	– Predicts tumor aggressiveness in localized prostate cancer. Generates a Genomic Prostate Score (0–100) – higher score means more aggressive. – Helps decide if a man with early-stage cancer can do active surveillance or needs immediate treatment.	– Used mainly in localized prostate cancer (low to intermediate risk); not for advanced disease management. – Like Decipher, it’s prognostic only (estimates risk of progression), not directly tied to therapy selection in advanced cancer. – Needs adequate biopsy tissue.
Prolaris®(Cell Cycle Progression test)	Expression of 31 cell-cycle genes (plus 15 reference genes).	– Yields a “Cell Cycle Progression (CCP) score” indicating how quickly cancer cells are dividing. – Provides prognostic insight (higher score = higher risk of recurrence or cancer-specific death). – Can help with risk stratification similar to Oncotype (e.g. deciding on active surveillance vs treatment).	– Also mainly for localized disease prognosis, not for guiding specific therapies in advanced cancer. – A high score suggests aggressive cancer but doesn’t pinpoint which targeted treatment to use. – Less commonly used than Decipher or Oncotype in some practice settings.

Table: Comparison of genomic tests for prostate cancer, with their key advantages and disadvantages. NGS = next-generation sequencing; MSI = microsatellite instability.

Currently Approved Genomic Tests and Their Clinical Uses

Germline Genetic Testing (Inherited Mutations): All patients with metastatic prostate cancer are now advised to undergo germline genetic testing pubmed.ncbi.nlm.nih.gov. This is a blood or saliva test to check for inherited mutations in genes that predispose to cancer. The most relevant are DNA repair genes like BRCA1, BRCA2, ATM, CHEK2, among others. Finding an inherited mutation can direct therapy – for example, men with BRCA1 or BRCA2 mutations may benefit from PARP inhibitor drugs (which target tumors with defective DNA repair) pmc.ncbi.nlm.nih.gov. Germline results can also alert family members: if you carry a hereditary mutation, relatives might consider genetic counseling and screening (since up to ~10% of prostate cancers may be due to inherited mutations like BRCA2). In summary, germline testing is done once, and if a mutation is found it not only opens specific treatment options but also has implications for family cancer risk.

Tumor Genomic Profiling (Somatic Testing of Tumor DNA): In advanced prostate cancer, testing the tumor’s own DNA is critical for personalized treatment. Typically, this is done with a comprehensive genomic profiling panel on a tissue sample. Several multi-gene panel tests are FDA-approved for clinical use in cancers, including MSK-IMPACT (an in-house test at Memorial Sloan Kettering) and FoundationOne CDx. These assays sequence hundreds of cancer-related genes in the tumor to find mutations, deletions, or other alterations. In prostate cancer, tumor profiling is used to detect “actionable” mutations – changes that we have specific treatments for or that affect prognosis. Key findings doctors look for include:

Homologous Recombination Repair (HRR) gene mutations: About 20–25% of metastatic prostate cancers have mutations in genes like BRCA1, BRCA2, or ATM pmc.ncbi.nlm.nih.gov. If the tumor has one of these mutations (whether inherited or tumor-acquired), the patient can be treated with a PARP inhibitor (such as olaparib or rucaparib) which has been shown to slow cancer progression. For example, in a clinical trial, men with BRCA/ATM-mutant prostate cancer had significantly longer progression-free survival on olaparib than on standard therapy. This makes testing for these mutations crucial – it directly guides therapy that can extend survival pubmed.ncbi.nlm.nih.gov.
Mismatch Repair Deficiency or MSI-High status: A small subset (~3% of advanced prostate cancers) have defects in mismatch repair genes (e.g. MLH1, MSH2, MSH6, PMS2), leading to high microsatellite instability (MSI-high). This is important to identify because such tumors respond remarkably well to immunotherapy (PD-1 checkpoint inhibitors like pembrolizumab). In fact, pembrolizumab is FDA-approved for any MSI-high cancer, including prostate cancer, regardless of where it started. So, genomic tests often include an MSI analysis or sequencing of these genes. If an advanced prostate tumor is MSI-high, doctors can use immunotherapy which may lead to durable responses in those patients.
Androgen Receptor (AR) and other pathways: Nearly all prostate cancers are driven by the androgen receptor. Tumor genomic profiling can detect AR gene amplifications or mutations that confer resistance to hormonal therapies (though these are not yet tied to a specific alternative treatment, they explain treatment resistance). Changes in tumor suppressors TP53 or RB1 are also checked, as their loss is associated with more aggressive, treatment-resistant disease. While no specific targeted drug exists for TP53/RB1 loss, their presence may prompt consideration of earlier chemotherapy or clinical trial options. Another common alteration is loss of PTEN (found in ~40–50% of metastatic cases), which activates the PI3K-AKT pathway. This finding is becoming relevant as new drugs targeting AKT or PI3K (like ipatasertib) are being tested in clinical trials for PTEN-deficient prostate cancers. In the near future, a PTEN-loss tumor might be treated with an AKT inhibitor combined with standard therapy if ongoing trials are successful.

Tumor genomic testing can be done on the original prostate tumor or on a metastatic biopsy. Whenever possible, testing a metastatic tumor (if a new biopsy is feasible) is ideal, because the cancer can evolve over time. Profiling a recent metastatic sample gives the most up-to-date picture of the cancer’s mutations pmc.ncbi.nlm.nih.gov. If a new tissue biopsy is not safe or available, the next approach is often a liquid biopsy.

Liquid Biopsy Genomic Testing: Liquid biopsies analyze tumor DNA that is shed into the bloodstream (circulating tumor DNA, or ctDNA). In 2025, liquid biopsy has become an important tool, especially if tumor tissue is unavailable. The FDA has approved comprehensive blood-based genomic tests (like FoundationOne Liquid CDx) which can detect mutations in 300+ genes from a tube of blood pmc.ncbi.nlm.nih.gov. These tests are validated to identify the same key alterations mentioned above. For instance, FoundationOne Liquid CDx is an approved companion diagnostic to find BRCA1/2 mutations in metastatic prostate cancer patients – if positive, it indicates the patient is eligible for a PARP inhibitor pmc.ncbi.nlm.nih.gov.

Liquid biopsies offer some advantages: they are non-invasive and can be repeated over time. They may detect DNA from multiple tumor sites (capturing heterogeneity that a single tissue biopsy might miss). In fact, studies show ctDNA is detectable in ~88% of patients with advanced prostate cancer. However, if a patient has a low tumor burden or the tumor is not shedding much DNA, the liquid biopsy could come back negative even if mutations are present in the tumor. Therefore, a negative liquid biopsy doesn’t always rule out mutations – doctors might then do a tissue biopsy for confirmation. In practice, many oncologists use both approaches: if tissue biopsy is difficult, start with liquid biopsy; if it’s negative or unclear, try to get a tissue sample. Both tumor tissue and liquid genomic tests are now routine parts of managing advanced prostate cancer, as they uncover targets for newer treatments and clinical trials.

Genomic Classifier Tests (Decipher®, Oncotype®, Prolaris®): These are genomic tests that look at the patterns of gene expression in the tumor to predict its behavior, rather than identifying specific DNA mutations. They have been primarily developed and validated in earlier stages of prostate cancer (localized or locally advanced disease) to help with treatment decisions. For example:

Decipher: A 22-gene expression panel that provides a score from 0 to 1. It predicts the likelihood of metastasis and prostate cancer-specific mortality after initial treatment pmc.ncbi.nlm.nih.gov. In men who have had prostate surgery (prostatectomy), the Decipher score helps determine if additional therapy is needed. A high Decipher score means the cancer has a higher chance of spreading, so doctors may recommend adjuvant radiation and hormone therapy; a low score might spare the patient extra treatment if the risk of metastasis is low. Decipher is now included in guidelines for post-surgery decision-making – for instance, if a man has adverse features but an intermediate Decipher result, it might influence whether to give immediate radiation or not. This test is prognostic, not predictive of a certain drug benefit, but it refines risk stratification beyond clinical factors alone.
Oncotype DX Genomic Prostate Score (GPS): A 17-gene RT-PCR assay performed on biopsy tissue before any treatment. It stratifies men with low or intermediate-risk prostate cancer. The GPS score (0–100) correlates with the risk of adverse pathology and recurrence if the patient undergoes surgery. In practice, a low Oncotype score can support choosing active surveillance (deferring treatment) for a low-risk cancer, whereas a high score would favor definitive treatment. Like Decipher, this test is used at diagnosis or soon after, rather than in metastatic disease, but it represents an important genomic tool that guides initial management.
Prolaris: Another gene expression test measuring 31 cell cycle progression genes. It yields a CCP score indicating how fast the tumor cells are growing. Prolaris can be used on biopsy tissue or after surgery to predict 10-year prostate cancer mortality risk. It helps identify patients who might need more aggressive treatment despite seemingly low-risk clinical features, or vice versa.
ProMark: A protein-based assay (not DNA/RNA – it measures 8 protein biomarkers) included here for completeness. It’s less commonly used, but it also predicts prostate cancer outcomes from biopsy tissue.

For advanced prostate cancer patients who have already progressed to metastasis, these genomic classifier tests (Decipher, Oncotype, Prolaris) are generally not used to guide therapy – by that stage, the treatment decisions hinge on the mutations and clinical factors rather than these scores. However, many patients with “advanced” disease may have encountered these tests earlier in their journey (for example, Decipher after surgery to decide on radiation). In 2025, Decipher has broad evidence support (Level 1 evidence per NCCN for certain uses) and is becoming more standard in post-surgery planning, while Oncotype and Prolaris are options mainly for initial risk assessment. It’s important to know these names since they are often mentioned in prostate cancer care, but their role is to guide intensity of treatment(surgery, radiation, etc.) rather than select targeted drugs.

Emerging Genomic Tests in Clinical Trials

Research is ongoing to develop new genomic tests for prostate cancer. These emerging tests aim to solve current challenges – such as monitoring treatment resistance, predicting who benefits from what therapy, or detecting aggressive disease earlier. Here are a few notable developments in 2025:

AR-ctDETECT Liquid Biopsy Assay: One promising new test is a blood-based assay called AR-ctDETECT. This is a comprehensive circulating tumor DNA panel focusing on 69 genes (with emphasis on the androgen receptor pathway) dukecancerinstitute.org. It’s currently in clinical trials and not yet routinely available. Early studies show it can identify men whose cancers are not responding to standard hormonal therapy. In one trial, about 59% of men with metastatic castration-resistant prostate cancer had a positive AR-ctDETECT result (meaning tumor DNA was detectable in blood); those who were ctDNA-positive had significantly worse survival on androgen-receptor targeted therapy pubmed.ncbi.nlm.nih.gov. In short, this test might flag, via a blood draw, when a patient’s cancer has become very aggressive despite treatment. In the future, AR-ctDETECT or similar assays could help doctors decide when to switch therapies earlier – for example, if a man’s blood shows rising AR mutations or genomic instability while on hormonal therapy, it might indicate the need to move to chemotherapy or trial drugs sooner. This kind of real-time genomic monitoring is an active area of research.
Genomic Tests for Treatment Resistance and Neuroendocrine Transition: Advanced prostate cancers can evolve under therapy pressure – some transform into neuroendocrine prostate cancer (NEPC), an aggressive variant. Researchers are developing genomic signatures to detect NEPC or other resistance changes. For instance, genomic profiling of tumors that become NEPC shows loss of genes like RB1 and TP53 in over half of cases. Now, investigators are testing blood-based panels to catch such changes. While not yet standard, emerging tests might soon identify when a patient’s tumor is shifting subtype, prompting a change in treatment (e.g. adding platinum chemotherapy for neuroendocrine features). Similarly, repeated tumor sequencing at progression is being studied: by comparing a patient’s tumor genomics before and after developing resistance to a drug, scientists can pinpoint new mutations (such as AR ligand-binding domain mutations) that cause resistance. In coming years, we may have blood or tissue tests that quickly detect these resistance mutations and help guide the next line of therapy (this concept is often referred to as “adaptive therapy” guided by genomics).
New Predictive Gene Signatures: Beyond the currently used prognostic scores, research is ongoing to create genomic signatures that predict response to specific treatments. One example is the effort to predict who benefits from chemotherapy vs. novel hormonal therapy in castration-resistant prostate cancer. There are trials looking at genomic patterns (like DNA repair deficiency, cell cycle gene expression profiles, etc.) as biomarkers for optimal sequencing of treatments. Another area is using artificial intelligence on genomic data: by analyzing large genomic datasets of prostate tumors with AI, researchers hope to discover new combinations of gene alterations that could better classify tumors into subgroups that match the best therapy. While these advanced analytic approaches are experimental, they could yield future tests that provide a “molecular fingerprint” of an individual’s cancer and directly suggest the most effective treatment.
Expanded Panel Testing and Whole Genome Sequencing: Current clinical panels target known important genes (hundreds of them). In trials, some centers are performing whole genome sequencing (WGS) on prostate cancers to identify rare or complex alterations that panel tests might miss (for example, novel gene fusions or structural changes). WGS can reveal the full landscape of genomic changes. The challenge is interpreting all that data – most of those findings won’t have an available drug. However, exploratory studies using WGS are helping to discover new driver mutations and potential targets. As the cost of sequencing falls and our understanding grows, it’s conceivable that in a few years, WGS or large-scale sequencing could enter clinical practice for select advanced cases, especially if a patient has an aggressive cancer with no known mutations on the standard panel (looking for “hidden” genomic clues).

In summary, emerging genomic tests are pushing toward more dynamic and comprehensive profiling of prostate cancer. They are not yet part of routine care in 2025, but ongoing trials are evaluating their utility. Patients with advanced prostate cancer might consider enrolling in clinical trials for these cutting-edge tests, especially if standard genomic testing hasn’t provided clear answers or treatment options. It’s an exciting area – the goal is that future genomic tests will not only catalog mutations, but also continually inform when to switch treatments and which novel therapy might work best as the cancer changes.

Key Questions to Ask Your Doctor About Genomic Testing

When discussing genomic testing for advanced prostate cancer with your doctor, consider asking the following questions:

“Should I undergo genomic testing, and if so, which tests?” – Clarify if you need germline (inherited) testing, tumor DNA testing, or both, based on your case.
“What can these genomic tests tell us about my cancer?” – Understand the purpose: are they looking for inherited risk, predicting aggression, or finding drug-targetable mutations?
“How will the results affect my treatment plan?” – Ask if a positive finding could open up new treatments (like PARP inhibitors or immunotherapy) pubmed.ncbi.nlm.nih.gov and pmc.ncbi.nlm.nih.gov, or if a negative result might steer you toward other options.
“Do I need a new tumor biopsy for genomic testing, or can you use existing tissue?” – This covers the logistics and invasiveness. If a new biopsy is suggested, discuss its risks and benefits.
“What is the difference between testing my blood for tumor DNA versus testing the tumor tissue?” – Make sure you understand the pros and cons of a liquid biopsy vs. a solid tumor biopsy in your situation.
“If an inherited mutation is found, what does that mean for my family?” – Inquire about the implications of germline results, so you can inform relatives and possibly refer them for testing if needed.
“How often should we repeat genomic testing?” – Advanced cancers can change; ask if and when re-testing might be needed (for example, if the cancer progresses or after certain treatments).
“Are there any emerging genomic tests or clinical trials I should consider?” – Given rapid developments, your doctor might know of research studies (e.g. new liquid biopsy tests or sequencing trials) that you could join to access novel testing or therapies.

Being proactive with these questions will help you and your care team fully leverage genomic information in making treatment decisions.

References (2018–2025)

Yu EY, Rumble RB, Agarwal N, et al. (2025). Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline. J Clin Oncol, 43(6), 748–758. DOI: 10.1200/JCO.24.02608. PMID: 39787437 pubmed.ncbi.nlm.nih.gov
Bologna E, Ditonno F, Licari LC, et al. (2024). Tissue-Based Genomic Testing in Prostate Cancer: 10-Year Analysis of National Trends on the Use of Prolaris, Decipher, ProMark, and Oncotype DX. Clin Pract, 14(2), 508–520. DOI: 10.3390/clinpract14020039. PMID: 38525718 pmc.ncbi.nlm.nih.gov
Hatano K, Nonomura N. (2022). Genomic Profiling of Prostate Cancer: An Updated Review. World J Mens Health, 40(3), 368–379. DOI: 10.5534/wjmh.210072. PMID: 34448375 pmc.ncbi.nlm.nih.gov
Knutson TP, Luo B, Kobilka A, et al. (2024). AR alterations inform circulating tumor DNA detection in metastatic castration-resistant prostate cancer patients. Nat Commun, 15(1), 10648. DOI: 10.1038/s41467-024-54847-1. PMID: 39663356 pubmed.ncbi.nlm.nih.gov
Abida W, Patnaik A, Campbell D, et al. (2019). Microsatellite instability in prostate cancer and response to immune checkpoint blockade. J Clin Oncol, 37(Suppl 7), 202. DOI: 10.1200/JCO.2019.37.7_suppl.202. (Data on MSI-high frequency ~3% in advanced prostate cancer)
de Bono J, Mateo J, Fizazi K, et al. (2020). Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med, 382(22), 2091–2102. DOI: 10.1056/NEJMoa1911440. (PROfound trial: PARP inhibitor improved outcomes in BRCA/ATM-mutated prostate cancer)