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Exciting News for Women with Newly Diagnosed Ovarian Cancer

We’re excited to share results of three recent studies that provide hope for women with newly diagnosed ovarian cancer. The studies, reported at the annual meeting of the European Society of Medical Oncology and two of which were published in the New England Journal of Medicine recently, show that three different types of PARP inhibitors (niraparib, veliparib, and olaparib) are effective at delaying recurrence of disease for all women with ovarian cancer, regardless of BRCA1/2 mutation status. PARP inhibitors are a class of drugs that have been shown to be effective for treatment of cancers that have mutations in BRCA1, BRCA2, and other genes that are needed to repair damage to DNA through a cellular process called homologous recombination.

The new studies come at the heels of several FDA and European agency approvals over the past few years for the use of PARP inhibitors to treat women in the upfront and recurrent disease settings who have mutations in BRCA1, BRCA2, or other defects in homologous recombination. The studies show significant benefit of the PARP inhibitors for all women with ovarian cancer, not only for women with BRCA1/2 mutations and other homologous recombination defects.

These results are provocative and promising in that they demonstrate that there appears to be benefit using PARP inhibitors in women with newly diagnosed ovarian cancer either in combination with and following chemotherapy in the case of veliparib or following chemotherapy in the case of niraparib and olaparib. Importantly, these are the first studies that evaluate these drugs in women with and without BRCA mutations in the upfront setting and show improvement in progression free survival (PFS – the amount of time before disease comes back) in women who are homologous recombination deficient without BRCA mutations.

I would anticipate that based on these studies we will see an expansion in the use of PARP inhibitors for patients which will allow us to incorporate this promising class of drugs into more patients we see in the clinic facing their initial treatment for ovarian cancer. This is exciting news for ovarian cancer patients, where five year survival is about 45% and recurrence of disease remains alarmingly high.

 

Study Details:

PRIMA/GOG-3012 looked at PFS in women who were newly diagnosed with advanced ovarian cancer who responded to their initial treatment with platinum and received either PARP inhibitor (niraparib) or placebo as maintenance therapy. The study reported that women who had tumors with defects in homologous recombination (those with defects in BRCA1, BRCA2, and other genes) had much longer intervals before the cancer returned on niraparib maintenance therapy than on placebo (PFS of 21.9 months on niraparib maintenance and 10.4 months on placebo). Importantly, the study also showed that there was even benefit in women who were not homologous recombination deficient, with a PFS of 8.1 months in the niraparib group and 5.4 months in the placebo group, translating to a 32% reduction in the risk of progression. The study also analyzed overall survival at the 24 month interval and found that, while not statistically significant, there was a higher survival rate in the niraparib group (84%) as compared to the placebo group (77%).

VELIA/GOG-3005 evaluated newly diagnosed women with ovarian cancer for PFS after treatment (1) chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout), (2) chemotherapy plus veliparib followed by placebo maintenance, or (3) chemotherapy plus placebo followed by placebo maintenance. The study found that women who received veliparib with chemo, followed by veliparib maintenance had significantly longer PFS compared to women who received chemo plus placebo and placebo maintenance. As in other studies, women with BRCA1/2 mutations or other homologous recombination defects received more benefit and had longer PFS than women without. For example, women with BRCA1/2 mutations who had veliparib throughout had PFS of 34.7 months compared to 22 months for women with chemo alone. Interestingly, in the “intent to treat” population, which included 37% of women who were not BRCA mutation carriers or homologous recombination deficient, there was a PFS of 23.5 months with veliparib throughout compared to 17.3 months in the placebo group.

PAOLA (GINECO/EngOT-ov25) evaluated olaparib, a PARP inhibitor which was FDA approved to treat BRCA mutated patients with newly diagnosed ovarian cancer in December of 2018, in combination with an angiogenesis inhibitor (bevacizumab) in a broader group of patients which included patients who were not BRCA mutated and patients who were not homologous recombination deficient. As anticipated, the patients with tumors that had BRCA mutations had a significant improvement in PFS of 37.2 months compared to 21.7 months with placebo. Patients who had tumors with homologous recombination deficiency also derived benefit, with 28.1 month PFS in the treatment group compared to 16.6 months with placebo. However, olaparib had little effect in women who did not have BRCA-mutated tumor and were not HRD-positive. In this group, PFS was 16.9 months with olaparib and 16.0 months with placebo, suggesting that in women without these “biomarkers” there may not be a role for PARP inhibitors in the “upfront” setting.

European Society for Medical Oncology press releases on all three clinical trials:

PRIMA Trial Report

VELIA Trial Report

PAOLA Trial Report

 

Dan S. Veljovich, MD
Gynecologic Oncologist
Pacific Gynecology Specialists/Swedish Cancer Institute
Rivkin Center Board of Directors

Rivkin Center

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Higher Risk in the Ashkenazi Jewish Population

In the general population, around 1 in 400 people carry a BRCA1 or BRCA2 mutation. People of Ashkenazi Jewish ancestry have a 1 in 40 chance of carrying a BRCA mutation, making them 10 times as likely to carry a BRCA mutation as someone in the general population. Whether you’re a man or a woman, if you have a BRCA mutation then there is a 50% chance of passing the mutation on to your children, whether they are boys or girls. It’s important to note that these mutations significantly increase risk, but are not a guarantee a person will get cancer.

Why is the Ashkenazi Jewish population at higher risk?

Over 90% of the BRCA mutations found in the Jewish community are one of three “founder mutations”. A founder mutation is a specific gene mutation in a population that was founded by a small group of ancestors that were geographically or culturally isolated. Because the population was isolated, the rate of founder mutations in descendants is much higher than it would be if the population were larger and co-mingling with more genetically diverse populations. A large expansion in the population caused the current high frequency of the mutations in the Ashkenazi Jewish population. If you are of Ashkenazi Jewish ancestry, the chance of carrying a BRCA gene mutation compared to the general population is increased tenfold. BRCA mutations can be passed down from either your mother’s or father’s side, and may be associated with any of the following cancers:
  • Breast cancer
  • Ovarian cancer, fallopian tube, peritoneal cancer
  • Male breast cancer
  • Prostate cancer
  • Pancreatic cancer
  • Colon Cancer

Ready to take action? Knowledge is power. Take this short quiz to be proactive about your health.

Genes 101

Our bodies are made of many tiny building blocks called cells. Our cells contain a copy of our genome – all of the DNA genetic code we inherited from our parents. Our genome is organized into 46 chromosomes, 23 inherited from mom and 23 from dad. Each chromosome has hundreds or thousands of genes. Each gene has the instructions to make a protein that may control the structure or function of cells, can determine many things including how tall we are or the color of our eyes. Genes also contain instructions for many things inside of us that we cannot see, such as how our bones are formed or how our heart works. Each gene is made up of molecules called nucleic acids (A, T, C, and G). The specific sequence of the nucleic acids holds the instructions that control all the components and their functions in cells.

If the DNA sequence is changed, like a spelling mistake, the instructions may not make sense. The technical term for this change is “mutation,” meaning there is a change to the usual genetic code that may change the instructions stored in the gene. A mutation in a gene that repairs DNA damage or controls cell growth can increase the risk of developing cancer.

Sporadic vs Hereditary Cancers:

Ovarian and breast cancer can be either sporadic or hereditary. Sporadic cancers make up the vast majority (85-90%) of ovarian and breast cancers and are not associated with family history of either cancer or inherited cancer-associated mutations. Sporadic cancers arise from genetic mutations acquired in some cells of the body by events part of normal metabolism and environmental factors. This type of cancer can happen to anyone. Most acquired gene mutations are not shared among relatives or passed on to children.

Hereditary (also known as inherited, or familial) cancers are those that occur due to genetic mutations that are inherited from mom or dad. Other blood relatives may also share these same gene mutations. Parents give one copy of each gene to their children. If a parent has a genetic mutation in a gene, each of their children have a 50% chance of inheriting that mutation. Therefore, even in families with hereditary cancer, not all family members inherit the mutation that is causing cancer, and their risk of cancer is similar to the average person in the general population. Individuals who are suspected to have a family history with high incidence of ovarian, breast, and other cancers may be offered genetic testing to try to find the specific genetic mutation that may put them at risk. Importantly, individuals who do not have a known genetic mutation but have high incidence of ovarian, breast, or other cancers in their families are still considered at higher risk for developing those cancers.

Hereditary cancers often occur at an earlier age than the sporadic form of the same cancer, so experts often recommend starting cancer screening at a younger age for individuals at high risk for hereditary cancer. Hereditary cancers can also be more aggressive than the sporadic form of the same cancer. Individuals who have inherited a gene mutation may be at a higher risk for more than one type of cancer.

BRCA 1 and BRCA 2: Most Common hereditary breast and ovarian cancer

The genes that are most commonly involved in hereditary breast and ovarian cancer (HBOC) are BRCA1 and BRCA2. These genes are named for their link to breast (BR) cancer (CA), but they are also linked to ovarian cancer risk as well as other cancers. Both women and men can inherit mutations in these HBOC genes. BRCA1 and BRCA2 are tumor suppressor genes that have a usual role in our body of providing instructions on repairing DNA damage and preventing cancer. When a family has an inherited mutation in BRCA1 or BRCA2, this leads to an increase in cancer risk. Not every man or woman who has inherited a mutation in the BRCA1 or BRCA2 gene will develop cancer, but people who have a mutation do have a significanlty increased chance of developing cancer, particularly cancer of the breasts or ovaries.

While breast and ovarian cancers are the most common cancers diagnosed in people with BRCA1 and BRCA2 mutations, the risk of some other cancers is also increased. Men with BRCA1 and BRCA2 mutations have a higher risk of early-onset prostate cancer than men without mutations in either gene. Other cancers seen at increased rates, particularly in individuals with BRCA2 mutations, include pancreatic cancer and melanoma. Researchers are continuing to find new genes that are involved in hereditary breast and/or ovarian cancer so it is important to follow up with a genetic counselor on a regular basis if hereditary breast and ovarian cancer is likely in your family.

Talk to your family about your health history and take the Assess Your Risk quiz here

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