ANDIE, WHO ASKED THAT HER REAL NAME NOT BE USED, WAS DIAGNOSED WITH OVARIAN CANCER in April 2020 at age 52. She had visited her primary care doctor a few months earlier after feeling strangely bloated. Her doctor, who performed an ultrasound, didn’t see anything abnormal but referred Andie to a gastroenterologist. However, the start of the COVID-19 pandemic delayed her appointment.
When her symptoms intensified, she went to the emergency department, where a physician told her he suspected she had ovarian cancer. Further tests confirmed the doctor’s suspicions, and just a few days later, Andie started three rounds of chemotherapy with carboplatin and paclitaxel.
Like many people diagnosed with high-grade serous ovarian cancer, which is the most common type of ovarian cancer, Andie learned her disease had already spread to her abdomen. In July 2020, she had debulking surgery to remove as many of the tumors as possible, along with her uterus, ovaries, fallopian tubes, and omentum, the apron-like layer of tissue that covers the abdominal organs, where the cancer had spread.
After recovering from surgery, Andie completed three more rounds of chemotherapy. In October 2020, she got good news. She had no evidence of disease. Still, more than 70% of women with advanced ovarian cancer who experience a remission after surgery and chemotherapy will see the cancer return within three years. “The surgeon had talked to me, saying that they got all the cancer, but there wasn’t a guarantee that it wouldn’t recur,” she says.
Hoping to avoid that possibility, Andie’s oncologist recommended that she start on Lynparza (olaparib), a targeted therapy that blocks an enzyme called PARP that helps the cancer cells grow and repair themselves. “My doctor explained that olaparib could help me because I had the BRCA gene mutation,” says Andie, who learned through genetic testing that she had an inherited BRCA1 gene mutation. Research shows that people with BRCA mutations who take Lynparza after responding to chemotherapy live longer without the disease getting worse, which is known as progression-free survival.
She quickly adjusted to the tablet. “In the first couple weeks, I was a little sick, but then I handled that really well,” she says, so well that she resumed her work for an IT company near her home in Wisconsin. “I’m a cyclist, so I was out riding my bike 20 miles [at a time] and pretty much got back to my life.”
The plan was to take Lynparza for two years until January 2023. But she stopped taking the drug in October 2022 when a PET scan and a biopsy revealed that the cancer had metastasized to a lymph node in her chest. She and her oncologist had to consider next steps in her treatment.
Resetting the Clock
Andie’s treatment path is typical for many women who are diagnosed with advanced-stage, high-grade serous ovarian cancer. The initial treatment choice for this type of cancer is surgery to remove the cancer, along with a combination of carboplatin and paclitaxel chemotherapy. But even when the cancer is gone after treatment, it is known to come back.
Newer treatments have helped to extend remissions with some success, says John Weroha, a medical oncologist who specializes in gynecologic cancer at Mayo Clinic in Rochester, Minnesota. Of note, PARP inhibitors and anti-angiogenesis drugs have emerged as treatment standards for ovarian cancer, says Rob Coleman, a gynecologic oncologist with Texas Oncology in The Woodlands, Texas, and co-director of the Gynecology Oncology Group Partners Foundation.
The Food and Drug Administration (FDA) initially approved the anti-angiogenesis drug Avastin (bevacizumab) for ovarian cancer in 2014. The drug, which halts the growth of blood vessels that feed tumors, was approved to be used in combination with chemotherapy in patients whose ovarian cancer recurred and was no longer responsive to platinum-based chemotherapy. In 2018, the FDA approved the drug to be used in combination with chemotherapy treatment, followed by Avastin treatment alone. This move came after a study showed that women with newly diagnosed stage III and IV ovarian cancer who received Avastin in combination with chemotherapy after initial surgery and then continued use of Avastin had a median progression-free survival of 18.2 months compared with 12 months in women who received chemotherapy alone.
In addition, PARP inhibitors are approved to be used as maintenance therapy for women who have had a complete or partial response to initial platinum-based chemotherapy. Taken by mouth, PARP inhibitors, including Lynparza, Rubraca (rucaparib) and Zejula (niraparib), block an enzyme known as PARP, which repairs DNA damage in cells and can lead to growth in cancer cells.
Studies have shown PARP inhibitors can extend progression-free survival in the maintenance setting for newly diagnosed patients with advanced ovarian cancer whose cancer responds to platinum-based chemotherapy. However, patients who have BRCA1 and BRCA2 mutations—whether inherited or found only in the tumor—are more likely to respond to PARP inhibitors than patients who don’t have these mutations. The presence of BRCA mutations is one indicator that cells have an impaired ability to repair damaged DNA, a characteristic called homologous recombination deficiency (HRD). Women with any HRD-positive cancer, including those with other damaged DNA mechanisms besides BRCA mutations, also are more likely to respond to PARP inhibitors.
Choosing the right medicine often depends on tests to learn about specific features of a tumor.
The American Society of Clinical Oncology recommends that all women diagnosed with epithelial ovarian cancer be referred for genetic counseling and testing.
Women who have the BRCA1 or BRCA2 mutations, found in about 10% to 15% of ovarian cancer cases, are more likely to respond to maintenance therapy with PARP inhibitors. So it’s useful to undergo a blood or saliva test that checks for mutations that are inherited from parents, including the BRCA1 and BRCA2 mutations. In addition, physicians can send tumor tissue samples to check for somatic mutations, those that are not inherited but acquired. Tumors that have somatic BRCA mutations are also likely to respond to PARP inhibitors.
Normal BRCA genes help to repair DNA, but BRCA mutations signal a type of flaw in the DNA repair system called homologous recombination deficiency (HRD). “DNA makes mistakes all the time, but something in your tumor is not correcting it,” says gynecologic oncologist Stephanie Blank of the Mount Sinai Health System in New York City, who adds that as many as half of high-grade serous ovarian cancers test positive for HRD, including BRCA1- and BRCA2-mutated cancers.
Checking for HRD status involves looking at tumor tissue samples for “scars” on the genes, which indicate potential problems in the repair system. Women with HRD-positive cancer are more likely to respond to PARP inhibitors than women whose cancer is HRD-negative.
As antibody-drug conjugates (ADCs) emerge as a treatment for ovarian cancer, additional tests will look for relevant receptors on tumor cells that ADCs can leverage as an entry point to deliver chemotherapy to the tumor.
A study published in 2018 in the New England Journal of Medicine assessed the efficacy of using Lynparza as maintenance treatment in newly diagnosed people with advanced ovarian cancer who had inherited BRCA1 or BRCA2 mutations. Researchers found that after about three years, the risk of disease progression or death in women who took Lynparza was 70% lower than for those who took a placebo. Another analysis published in 2021 that covered five years of follow-up showed median progression-free survival in patients with the BRCA1 and BRCA2 mutation who took Lynparza was 56 months versus 13.8 months with a placebo. “We are getting some cures with PARP inhibitors, which is exciting,” says Stephanie Blank, director of gynecologic oncology for the Mount Sinai Health System in New York City, who has seen a few sustained responses to the treatment.
While these treatments are effective in lengthening remissions for the initial treatment of ovarian cancer after partial or complete response to chemotherapy, several companies have voluntarily withdrawn PARP inhibitors for maintenance in later-line treatments. Research had shown that patients with recurrences who took PARP inhibitors after multiple rounds of chemotherapy had decreased survival compared with those who used chemotherapy alone.
Quality of life also factors into decisions whether to use maintenance treatment. After she had her recurrence, Andie was prescribed Avastin, but she stopped taking the drug after she had severe headaches and developed high blood pressure. With PARP inhibitors, such as Lynparza, common side effects include nausea, fatigue, constipation and diarrhea. “The goal of maintenance is to have the disease not come back, obviously, but also to allow the patient to live life normally,” Blank explains. If intolerable or harmful side effects are interfering with a good quality of life, she says, the maintenance strategy needs to change—whether that’s a dose adjustment or a different choice of drug. She notes, however, that the side effects of PARP inhibitors often subside after about two months.
The Problem of Platinum Resistance
Although the majority of ovarian cancers respond to initial treatment with platinum-based chemotherapy, platinum resistance is a significant hurdle in keeping ovarian cancer at bay. One of the best scenarios is a cancer that is platinum-sensitive: A woman completes the chemotherapy treatment and experiences at least six months without a cancer recurrence. But if she has evidence of cancer growth, such as an elevated CA-125 blood test or imaging that shows the cancer has returned within six months of the last dose of platinum chemotherapy, her cancer is considered platinum-resistant. And if the cancer continues to grow even while she receives platinum chemotherapy, her disease is considered platinum-refractory, which means her treatment options are limited.
When Andie’s cancer recurred, her oncologist first recommended restarting carboplatin and paclitaxel. She had one round of treatment in October 2022. The following month, she was just minutes into her next carboplatin infusion when she experienced anaphylaxis. Her tongue grew itchy, she couldn’t breathe, and her oxygen levels dropped so sharply that she lost consciousness. Staff rushed her to the emergency department to give her IV medications to counter the allergic response, and she has not resumed platinum treatment since. Because the malignant lymph node in her chest grew larger within two months of a platinum infusion, Andie’s oncologist now considers her cancer platinum-resistant.
Once a patient has one ovarian cancer recurrence, future recurrences are likely. “In addition, with each subsequent line of therapy, the interim between responses—if they occur at all—are shorter,” says Coleman.
Oncologists are hopeful about a new class of drugs for ovarian cancer known as antibody-drug conjugates (ADCs). These medicines link a potent chemotherapy drug and an antibody that targets a specific protein on the surface of the cells to deliver a toxic payload directly to the cells. (To learn more about antibody-drug conjugates, see “ADCs Make Their Mark.”) The goal of this approach is to improve tumor response and the duration of that response, Coleman says, while also reducing the toxicity and side effects such as hair loss that occur with systemic chemotherapy.
In November 2022, the FDA granted accelerated approval to Elahere (mirvetuximab soravtansine), the first ADC for patients with platinum-resistant epithelial ovarian cancer who have received one to three prior systemic treatment regimens. To be a candidate for the treatment, a patient’s tumor cells need to have high levels of folate receptor alpha, a protein that allows the drug to gain access to the tumor cells. The accelerated approval was granted based on a trial in 106 patients who tested positive for the folate receptor alpha and had up to three prior lines of systemic therapy. In the study, the overall response rate was 32.4%, and the complete response rate was 4.8%. In addition, about 36% of women screened for the trial had adequate folate receptor alpha to qualify to take Elahere. A follow-up study showed that patients similar to those in the earlier trial had longer median overall survival and greater tumor response compared with patients who received the physician’s choice of chemotherapy.
Current trials are also testing Elahere as a maintenance therapy after front-line chemotherapy drugs, while upcoming trials will examine Elahere in combination with platinum-based chemotherapy as a first-line approach. And researchers are currently exploring ADCs that use other targets to gain access to ovarian cancer cells, including the proteins MUC-16, NaPi2B and Claudin 6.
Patients with HRD-negative tumors or whose disease stops responding may try different treatment combinations, Blank says. She points to the TOPACIO/Keynote-162 trial, which found that 25% of patients who had platinum-resistant ovarian cancer experienced a partial or complete response after taking the PARP inhibitor Zejula in combination with Keytruda (pembrolizumab), an immunotherapy drug. Unfortunately, immunotherapy alone has not worked well in treating most cases of ovarian cancer. “We’ve found that ovarian cancer is not as immunogenic as we might have hoped,” Blank says.
But immunotherapy might be useful in combination with other therapies. A 2021 study published in JAMA Oncology looked at Keytruda with Avastin and cyclophosphamide, a type of chemotherapy, in 40 women with platinum-sensitive or platinum-resistant ovarian cancer. The single-arm study showed that 47.5% of patients responded to treatment, with three women (7.5%) having a complete response. Of note, the treatment had little adverse impact on quality of life. Most patients completed therapy without any severe side effects, and nearly half reported no side effects.
Oncologists say these emerging treatments show promise in extending remissions for a difficult-to-treat cancer. A patient’s tumors may not completely vanish, “but if you can be on a treatment that’s very tolerable, you can live like that for a long time,” Blank says. “So it becomes more of a chronic disease you’re living with, and you can get through a lot of graduations and weddings that way. I think that’s a good thing.”
When her cancer recurred, Andie traveled to Mayo Clinic to explore her treatment options, including the possibility of clinical trials. As Cancer Today was going to press, she was starting the process of enrolling in a clinical trial. “At every point, when a treatment needs to be given, we should be considering clinical trials,” Weroha of Mayo Clinic says. “We need better treatments. And the only way we’re going to get those better treatments is through clinical trials.”
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