Metastatic Prostate Cancer: How Molecular Testing Can Impact Your Treatment Plan

DNA damage is an ongoing occurrence that necessitates a sophisticated web of repair mechanisms to uphold the integrity of the genome.

In healthy cells, DNA may sometimes act strangely. When that happens, DNA is repaired via several mechanisms including the homologous recombination repair (HRR) pathway. In the presence of HRR gene mutations (HRRm), cells are unable to effectively repair broken DNA — and that could lead to cancer.

The most famous of these Homologous recombination repair genes are called BRCA1 and BRCA2.

HRR gene mutations occur in approximately 25% of patients with advanced prostate cancer.

Understanding Hereditary Mutations

Mutations in HRR genes can be hereditary (germline) or sporadic or nonhereditary (somatic).

Around 5% to 15% of prostate cancers come from family traits (hereditary cancer), which means they might run in families. When men have certain special gene changes they inherited, the prostate cancer can be tougher than in those without these gene changes.

If a person’s dad, brother, or son had prostate cancer, his chances of inheriting it become two to three times higher. This chance gets even more likely if more family members had prostate, breast, or ovarian cancers. The age when a close family member got cancer matters, too.

Up to 15% of men with cancer that has spread (metastatic cancer), and 10% of men with cancer that hasn’t spread, have changes in certain genes related to fixing DNA, like BRCA2, BRCA1, ATM, CHEK2, PALB2, and other DNA repair genes (MLH1, MSH2, PMS2, MSH6).

How Can Molecular Testing Impact Your Treatment Plan?

“It gives us more tools to personalize that treatment. It gives us more information to understand how a cancer may respond to a treatment. And it gives us more information to make other new treatment options, things like clinical trials or potential options for you, as well,” Dr. McManus says.

“And I think that’s just going to increase as we do more and more studies and understand how these genetic changes drive prostate cancer. It helps us personalize that treatment and our discussion together even more. So I think it’s really exciting.”

Who Benefits From Molecular Testing?

National Comprehensive Cancer Network (NCCN) Guidelines recommend germline and tumor testing for HRRm in all patients with metastatic prostate cancer and consideration of testing for patients with regional disease.

“I think really any patient with prostate cancer can ask their doctor if they should get germline genetic testing or genetic testing, looking to see if they have an inherited mutation that may have made them more at risk for prostate cancer. That can impact your treatment and it can impact your family and potential screening for cancers for them in the future,” says Dr. McManus.

For patients with metastatic prostate cancer (that has spread outside of the prostate), it’s essential that you ask your doctor about genetic testing. These results could guide your treatment plan.

For patients with localized prostate cancer, some of these molecular profiling tests that are available to help guide treatment decisions are used in a little bit more nuanced ways and it is not necessarily right for every patient. It’s important to have a conversation with your oncologist, who knows all the details of your cancer journey.

“So for metastatic prostate cancer, it’s pretty straightforward to me,” Dr. McManus explains. “I think really every patient with metastatic prostate cancer should be having next-generation sequencing to help guide treatment decisions and making sure all medication therapies are being evaluated. Molecular profiling tests for localized prostate cancer are for very specific situations and there is some controversy around when to use them.”

PARP inhibitors for Prostate Cancer

“It’s really important that we have molecular testing available for cancer because these new treatments are based on having molecular testing showing that there is one of these BRCA mutations, that would make your cancer potentially susceptible and most responsive to this type of treatment,” says Dr. McManus.

As of today, there are two PARP inhibitors that can be used as a single therapy, the treatment of prostate cancer patients, including:

• Olaparib (brand name Lynparza)
• Rucaparib (brand name Rubraca)

These drugs are approved in the metastatic castrate-resistant prostate cancer (mCRPC) setting either before or after chemotherapy, as monotherapy drugs. Monotherapy refers to when doctors use one specific drug to fight your cancer instead of a combination of drugs.

These medications are only for patients who have certain mutations, such as BRCA 1 or 2 mutations.

More recently, the FDA approved a fixed dose combination of two drugs (niraparib and abiraterone) with prednisone. This new medication is a once-daily dual-action tablet (brand name Akeega). It includes a PARP inhibitor (niraparib) and an androgen biosynthesis inhibitor (abiraterone acetate).

Akeega is indicated with prednisone to treat adults with mCRPC and BRCA-positive mutations.

Other good news for metastatic castration-resistant prostate cancer has been the recent approval by the FDA, of the combination of enzalutamide (brand name Xtandi) and talazoparib (brand name Talzenna).

Talzenna is also a PARP inhibitor and this new combination (Xtandi + Talzenna) is approved for the treatment of adult patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).

What is Castration-resistant Prostate Cancer?

Castration-resistant prostate cancer (CRPC) is a type of cancer that keeps getting bigger even when the amount of testosterone in the body is very low or gone. It can also be called hormone-refractory or hormone-resistant prostate cancer. For it to be considered a castration-resistant prostate cancer, a patient’s testosterone levels are usually low (<50 ng/dL).

• Non-metastatic castration-resistant prostate cancer has not spread to other parts of the body (based on scans)
• Metastatic castration-resistant prostate cancer has spread to other parts of the body (such as lymph nodes or to the bones)

Your doctor can tell if you have castration-resistant prostate cancer when a blood test indicates that your prostate-specific antigen (PSA) level is going up and your testosterone level is low. Pictures from tests might also reveal that the cancer is getting bigger. Doctors might check how fast the PSA level is doubling, which is the time it takes for the PSA level to become twice as much, to help choose the right treatment.

Choosing the Best Treatment

• mCRPC patients with HRR mutations should be considered for PARP inhibitor monotherapy, following progression on a combination of androgen receptor inhibitors, such as Xtandi and Zytiga)
• Patients with progressive disease not harboring HRR mutations should be considered for chemotherapy or an alternate to PARP inhibitor therapy.

How Do PARP Inhibitors Work?

PARP stands for poly (ADP-ribose) polymerase (PARP). These medications work by preventing cancer cells from repairing their damaged DNA, which eventually leads to their death.

To spread, prostate cancer cells heavily rely on the PARP enzyme, a protein responsible for repairing cellular damage. However, the growth of cancer can be halted by employing a PARP inhibitor, which prevents the repair of tumorous cells by the PARP enzyme, effectively stopping cancer’s progression.

This is especially relevant for men with prostate cancer caused by a BRCA mutation, a gene mutation that increases the likelihood of prostate cancer. Tumor cells with BRCA mutations already struggle to repair damaged DNA, and a PARP inhibitor intensifies this difficulty, leading to the demise of cancer cells.

PARP Inhibitor Side Effects: What to Expect

Any medication you take to manage your cancer has pros and cons. The pros are that the drug keeps your cancer at bay. The cons are its potential side effects. Because PARP inhibitors are a type of chemotherapy, they can damage healthy cells along with cancer cells.

Fatigue is one of the most common side effects, affecting more than half of people who take these drugs.

These are some other side effects people who take PARP inhibitor drugs may experience:

• Diarrhea
• Constipation
• Belly pain or upset stomach
• Anemia (low numbers of red blood cells that carry oxygen to your body)
• Thrombocytopenia (low numbers of platelets that help your blood to clot)

Side effects are usually worst at the beginning of treatment, but they should gradually improve the longer you are on the medication. The first month on maintenance therapy can be a little rocky, since doctors are still trying to adjust the dose for the patient.

After the first month or two, you should level out and start to feel more comfortable on the medicine.

Questions to Ask Your Doctor

If you have been diagnosed with advanced prostate cancer, here are some questions you may consider asking your doctor to help understand your situation:

• What is the stage of my prostate cancer?
• How aggressive should my prostate cancer treatment be?
• Do I have any genetic mutation that would change the course of my treatment?
• Would I benefit from a PARP inhibitor? Am I more, or less, likely to respond to this treatment?
• What do you feel is the best initial treatment for me?
• Are there ways to manage the side effects of the treatment I receive?

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