In the mid 1990s, several genes were discovered that when mutated, increased the risk of inheriting certain cancers. These were the BRCA1 and BRCA2 genes associated with hereditary breast and ovarian cancers. Over the last 10 years, understanding this family of related DNA repair pathway genes has become important in the management of prostate cancer from screening through treatment of advanced disease.

While these inherited germline mutations may be identified in a relatively small percentage of patients, finding these pathogenic genes can have a major impact on the individual and their family. It is no longer sufficient to ask a man being screened or treated for prostate cancer about relatives just with prostate cancer. In the clinic setting, it is essential to ask for a more extensive family history to identify relatives with breast, ovarian, and pancreatic cancer, and gastrointestinal or other Lynch syndrome– associated tumors. If these tumors are present in other family members, it suggests that there may be an inherited germline mutation increasing cancer risk with further genetic testing and counseling warranted.

The most common inherited germline alterations that have been associated with increased prostate cancer risk are mutations in the BRCA2 gene. While mutations in this DNA repair pathway gene are the most common in advanced prostate cancer, dozens of other altered genes have been described, such as BRCA1, ATM, and CHEK2 to name a few.¹ Most of these mutated genes found in prostate cancer pathways do not directly cause prostate cancer but allow the cancer to progress, mostly by interfering with DNA repair. Germline mutations can be detected in 11.8% of metastatic vs 4.6% localized prostate cancer, with later data suggesting rates up to 25% in metastatic castration-resistant prostate cancer (mCRPC).²

While these mutated genes can be inherited, the mutations implicated in prostate cancer can also arise de novo in tumors. These identified noninherited pathogenic genes are referred to as somatic mutations. Both germline and somatic mutations can be detected in the tumor. Any mutations found in the germline or tumor can be important in guiding therapy of advanced disease. While inherited germline mutations can be detected with blood testing or a buccal swab, analysis of any mutations in the tumor itself requires tissue biopsy of the primary tumor, a metastasis, or through newer liquid biopsy techniques.

A variety of commercial assays are available that can analyze both solid tumor biopsies and liquid biopsy circulating tumor cell free DNA. This somatic tumor testing can reveal additional actionable mutations in advanced prostate cancer. These include the identification of mutations in homologous recombination repair (HRR) genes such as BRCA2 and others, mismatch repair genes (MLH1, MSH2, MSH6), and tumor mutational burden. All of these suggest potential treatment options for advanced prostate cancer including metastatic hormone-sensitive prostate cancer and mCRPC.

Somatic testing can identify a large panel of mutated genes that indicate agents such as poly (ADP-ribose) polymerase (PARP) inhibitors could be used in the setting of mutated HRR genes. In the setting of mismatch repair gene abnormalities or high tumor mutational burden, immunotherapeutic agents such as pembrolizumab can be considered. The utility of commercial somatic tumor assays is often further enhanced by providing treatment options that include single agents, combination agents, and investigational options based on current clinical trials.

One of the most important advances in the treatment of mCRPC is the use of PARP inhibitors. PARP enzymes are important for repairing single DNA strand breaks. The PARP mechanism is important in malignant prostate cancer cells by allowing the malignant cell to continue to grow under certain conditions. DNA HRR genes, such as BRCA2, BRCA1, ATM, and others, make proteins that repair double-stranded DNA breaks. When these HRR genes are mutated, as can be seen in advanced prostate cancer, errors in double-strand DNA repair genes can result in neoplastic growth.³ PARP inhibitors (olaparib, rucaparib, niraparib, talazoparib) interfere with single-strand DNA repair breaks, limiting the ability of a malignant cell harboring the mutated HRR DNA repair genes from growing. This mechanism of action of PARP inhibitors has been called “synthetic lethality.” The newest use of PARP inhibitors includes combining these agents with others, such as androgen receptor pathway blockers.

Genomic profiling by germline and somatic tumor testing are now effective precision medicine tools to optimize patient care with expanding roles in daily patient care. There is an unmet need to increase the use of genetic testing by urologists. Recent data suggest that only 1% of men with a history of prostate cancer reported undergoing specific germline testing compared with over 50% of patients with breast or ovarian cancer, with measures such as digital web tools being developed to improve these statistics.⁴

Table. Advanced Prostate Cancer AUA/Society of Urologic Oncology Guidelines Genetic Testing Considerations⁵

The Table summarizes the 2023 update of the AUA/Society of Urologic Oncology Advanced Prostate Cancer Guidelines that provide recommendations for the use of genetic testing in advanced disease including metastatic hormone-sensitive prostate cancer and mCRPC.⁵ Family history and confirmation of inherited germline mutations can inform screening and treatment options in localized and advanced disease. Advances in understanding genetic alterations in advanced prostate cancer have provided many more targeted options to men beyond traditional hormonal ablation and chemotherapy.