Personalizing Prostate Cancer Care With Genetic Testing, PARP Inhibitors

Dr. Kristen Scarpato explains the role of genetic testing in prostate cancer care: © stock.adobe.com.

Precision medicine has revolutionized the treatment of prostate cancer, in particular the use of genetic testing for specific DNA damage repair genes to determine which patients would benefit from treatment with PARP inhibitors. Therefore, understanding these advancements is crucial for patients, as they offer more personalized and effective treatment strategies.

“[Treatment is] not one-size-fits-all when it comes to managing patients with prostate cancer. Part of what makes prostate cancer such a unique and special process to manage is that there are so many different decision points: patient preference, prior treatment, prior surgical and medical history. The consideration of genetic testing can really help guide our treatments so that we're providing individual care to the unique human in front of us,” explained Dr. Kristen Scarpato.

During the CURE^Ò Educated Patient^Ò Prostate Cancer Summit, Scarpato discussed the use of genetic testing in men with prostate cancer and how it drives treatment decision-making, as well as highlighted various PARP inhibitors and their side effects.

She currently serves as an associate professor, director of the Residency Program, and vice chair of Education, all in the Department of Urology, Division Urologic Oncology, at Vanderbilt University Medical Center, in Nashville, Tennessee.

Genetic Testing in Prostate Cancer

Genetic testing is becoming an integral part of prostate cancer management, with expanding recommendations from guidelines like the National Comprehensive Cancer Network (NCCN).

According to testing guidelines, these genetic tests are ordered for patients with high risk disease that may impact their medical care, those with advanced or metastatic prostate cancer and men with localized disease exhibiting specific pathological findings, such as cribriform morphology or intraductal morphology, as seen under a microscope.

“[In these instances, providers] should offer germline testing to patients, because [it can have future] implications for the individual in the future, [especially] when it comes to counseling. [This helps us understand if the disease course might be more aggressive]” Scarpato explained. “[We also must consider] which medications may be available to that particular patient, and [if] they work in the [presence] of a genetic mutation.”

Further, if a patient has a germline mutation, family members may also get tested. In turn, early detection of a shared mutation can lead to earlier cancer screening and interventions, potentially leading to better outcomes.

Scarpato also explained the difference between germline and somatic testing. Germline testing refers to the cells in one’s body for mutations inherited from one’s parents, done via a blood test or cheek swab, and somatic testing is designed to evaluate genetic changes only within tumor cells analyzed from tumor tissue from a biopsy or surgical removal. Somatic mutations are acquired during a person's lifetime, are not present in every cell of the body, and can change over time.

“Oftentimes, we're doing both [germline and somatic testing], and usually they are concordant, meaning that they match, but not all the time,” she added. “Germline changes will be there forever. You never expect that test to give you a different result. Somatic [genes] can change over time, and that's something that you may see your doctor requesting a test at multiple points.”

In prostate cancer, certain inherited mutations, particularly in genes like BRCA1 and BRCA2, are known as homologous recombination repair gene defects. These mutations impair the cell's ability to repair damaged DNA, making the cancer more aggressive and also more susceptible to certain treatments.

“Genetic testing is really critical, and we see expanded recommendations across the landscape of prostate cancer, and we know that these are predictive of response to therapy,” Scarpato said.

PARP Inhibitors in Prostate Cancer

PARP, or poly ADP-ribose polymerase, is a class of enzymes in the body that are crucial for repairing damaged DNA. In cancer cells with defective DNA repair mechanisms due to mutations (like BRCA), PARP inhibitors block the PARP enzyme, preventing the cancer cell from repairing itself. This leads to the cancer cell's death, a concept known as "synthetic lethality."

PARP inhibitors, like Lynparza (olaparib) and Rubraca (rucaparib), were initially approved as single-agent therapy for patients with advanced prostate cancer who had progressed on prior therapies. These approvals were based on studies like PROFOUND and TRITON, which showed improved progression-free survival (meaning the cancer didn't worsen) and better PSA responses in patients with specific mutations.

“So, in our [treatment] guidelines, both of these medications are indicated [to treat these patients],” Scarpato said.

More recently, PARP inhibitors are being explored in combination with other prostate cancer treatments, such as androgen receptor pathway inhibitors Zytiga (abiraterone) or Xtandi (enzalutamide).

Scarpato explained that these combination therapies create a state where cancer cells are more responsive to therapy. Studies have shown that these combinations, even in the first-line setting (before other treatments have failed), can significantly improve outcomes, particularly for patients with BRCA mutations.

She also noted that PARP inhibitors are typically well tolerated, with common side effects including anemia, fatigue and gastrointestinal upset. Less common but more serious side effects can include blood clots or bone marrow problems. However, if side effects are too severe, the dose can be reduced, or the medication can be stopped.

“For patients with advanced prostate cancer, we're seeing PARP inhibitors either as single agents or in combination [regimens], indicated in many places,” Scarpato concluded. “These medications are being explored in many other studies for patients who don't have castration-resistant disease. We're seeing it move up earlier in the treatment landscape, because in the setting of a mutation, they really are demonstrating great efficacy.”

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