Recent developments in PARP inhibitor combinations and antibody-drug-conjugates are changing the landscape of ovarian cancer treatment.
Listen to, a transcript of "Optimism Abounds in Ovarian Cancer Research." [PLAY TIME: 13:57]
In spring 2021, Kathy Ventre, 56, of Cincinnati, sensed something wasn’t right. She felt what she describes as menstrual cramps. She also felt tenderness near her ovary, as though she were ovulating. Yet, she was five years past menopause.
Ventre wondered why she felt like she was going to menstruate. “I even had acne all over my face,” she says. “It was strange.”
She saw a gynecologist. “He did an exam and didn’t feel anything,” Ventre says. “But he said, ‘You took the time to come in, so let’s do an ultrasound.’ ”
She underwent both an abdominal and a transvaginal ultrasound. She also had a blood test to check for CA-125, a protein sometimes elevated in people with ovarian cancer. Above 35 units per milliliter is considered high — Ventre’s level was 300. A CT scan confirmed a tennis ball-sized mass on her left ovary.
Ventre’s instincts served her well.
“Ovarian cancer symptoms are vague,” says Dr. Amy Bregar, a gynecologic oncologist and surgeon at Massachusetts General Hospital in Boston. “Things like bloating, weight gain, feeling full after eating — all of us experience those symptoms at one point or another.”
In May 2021, Ventre had a complete hysterectomy. The diagnosis was stage 3 high-grade epithelial ovarian cancer. Twenty days later, she began chemotherapy, with six rounds of carboplatin and Taxol (paclitaxel).
Surgery followed by chemotherapy is the first-line treatment for many patients with ovarian cancer. But ovarian cancer recurs in approximately 70% of patients, according to the Ovarian Cancer Research Alliance. Still, there’s reason for optimism with the potential of new developments in ovarian cancer treatments.
What’s transpired in ovarian cancer research in the past few years has been revolutionary, says Dr. Anil K. Sood, a gynecologic oncologist at The University of Texas MD Anderson Cancer Center in Houston.
“There are many biologically targeted drugs, such as (the tumor blood vessel formation inhibitor) drug Avastin (bevacizumab), PARP [Poly (ADP-ribose)] inhibitors and antibody-drug conjugates such as Elahere (mirvetuximab soravtansine). There are also immunotherapies that are being developed and tested,” he says. “We want people to understand they have a lot more options now for treatment than we did 15 years ago. And that portfolio of options continues to expand rapidly.”
Elahere made history in 2022 as the first antibody-drug conjugate approved by the Food and Drug Administration (FDA) for treatment of patients with platinum-resistant ovarian cancer, and the first approval since 2014 for this patient population.
PARP inhibitors — drugs that block enzymes that repair damaged cell DNA, preventing cancer cells from making repairs, leading to their destruction — were primarily used starting in 2014 to treat patients with recurrent BRCA-mutated ovarian cancer and as maintenance for those with newly diagnosed and recurrent platinum- sensitive disease.
In 2022, three PARP inhibitors that had been approved by the FDA were voluntarily removed by their companies for efficacy issues, specifically Lynparza (olaparib), Rubraca (rucaparib) and Zejula (niraparib), Dr. Ursula A. Matulonis, chief of the division of gynecologic oncology and the Brock Wilson Family Chair at Dana-Farber Cancer Institute in Boston, says. Matulonis was co-principal investigator of the SORAYA trial, the findings of which were the basis of the FDA’s approval of Elahere.
Ovarian cancer treatments were traditionally were based on observation, surgery and chemotherapy. But antibody-drug conjugates — which, as explained by the National Cancer Institute, target proteins found on cancer cells, then latch onto the cells and deliver cancer-fighting drugs — are a more targeted approach.
Elahere’s approval by the FDA, Matulonis says, “is definitely a step forward for our patients.”
Epithelial carcinoma is the most common type of ovarian cancer. Tumors grow in the tissue that lines the fallopian tube or covers the ovary (epithelium). Pathologists assign a grade — low or high — based on how the tumor looks under a microscope. Epithelial carcinoma may also be serous subtype (beginning in the serous membrane) or nonserous.
There are also rare types of ovarian cancer, including mucinous carcinoma and ovarian clear cell carcinoma.
“Ovarian cancer is not one disease,” says Sood. “Getting the right diagnosis and making sure the right subtype is diagnosed are critically important.”
Information about a patient’s specific genetic mutations and a tumor’s molecular makeup helps oncologists recommend personalized targeted therapies such as PARP inhibitors.
“I had genetic testing and learned I had a mutation in the BRCA1 gene,” says Ventre. “That made me a good candidate for a PARP inhibitor.”
PARP inhibitors show promise in treating women with BRCA gene mutations. They also help people who have homologous recombination deficiency, a defect in the specific pathway cells use to repair themselves.
“PARP inhibitors are an important part of treating patients with ovarian cancer,” Sood says. “We also know there are many patients who, despite receiving a PARP inhibitor, either don’t derive benefit from it or it works for a period of time and then their cancer starts to grow.”
Sood and his colleagues recently studied ovarian cancer cell lines that were either homologous recombination (HR) deficient or HR proficient. Their goal was to “see if there are drugs that could amplify or improve the effectiveness of PARP inhibitors,” Sood says.
After testing cell lines with 335 different drugs, researchers found four drugs that combined well with Lynparza. They then evaluated clinical data on the toxicity of these drugs.
“Taking all that into account, we focused on a drug called CT-7439,
a specific inhibitor of cyclin- dependent kinase (CDK),” Sood says, noting initial validation studies indicate it combines well with Lynparza. “We’re excited about this.”
Pairing a PARP inhibitor with a CDK inhibitor could make PARP inhibitors more effective.
Sood hopes to test in animal models next to learn whether the combined drugs may provide more benefit than PARP inhibitors alone in some patients. He adds that researchers also hope to improve the effectiveness of PARP inhibitors and prevent adaptive resistance.
These findings are good news for women like Ventre, who experienced cancer recurrence after 18 months on Lynparza. A scan showed four small cancerous spots in her abdomen, so she’s now on a chemotherapy regimen of carboplatin and Gemzar (gemcitabine).
She says she’ll soon begin treatment with drug Avastin.
“My doctor is reluctant to do a PARP inhibitor again so fast because the cancer figured out a way to work around it,” she says.
The goal is to achieve stability and use Avastin as a maintenance therapy, according to Ventre, who is now a volunteer for the Ovarian Cancer Alliance of Greater Cincinnati and the Woman to Woman support and mentorship program from the Ovarian Cancer Research Alliance.
Improving surgery for ovarian cancer is another area of study. An abstract presented at the 2023 American Society of Clinical Oncology Annual Meeting found that in patients with ovarian clear cell carcinoma, surgical removal of lymph nodes (lymphadenectomy) was associated with improved disease-free survival. But more research is needed to determine whether lymphadenectomy is beneficial in some people.
Debulking surgery, in which surgeons remove as much of a tumor as they can, is the first step for most women with ovarian cancer.
“The standard of care remains open surgery,” Bregar says. “But there’s ongoing research investigating whether minimally invasive surgery can be used for ovarian cancer.”
Also being studied is when to perform surgery.
“For high-grade serous ovarian cancer, we know it probably doesn’t matter whether you have chemotherapy or surgery first,” she says. “But while it’s probably equivalent in terms of overall survival, there may be less risk and less toxicity to have chemotherapy first.”
Sood says operating first isn’t always effective — some patients have so much cancer that complete surgical removal isn’t possible.
“We’ve gone to more personalized approaches,” he says. “We do laparoscopic assessment upfront for those patients who are surgical candidates. Those who are most likely to benefit from surgery go to upfront surgery. Our complete resection rates are high in that group. Patients whose cancer is such that it cannot be removed upfront receive neoadjuvant chemotherapy and then have surgery after three to four cycles.”
Elle Simone Scott, 46, of Salem, Massachusetts, was diagnosed with stage 1C3 ovarian cancer in 2016. She had surgery to remove her right ovary and fallopian tube, followed by chemotherapy treatment.
When cancer recurred in 2020, it had spread into her bladder and bowel. She was treated with three rounds of Doxil (liposomal doxorubicin) and cisplatin before having a complete hysterectomy and resection of her bladder and bowel.
Surgery was followed by three more rounds of chemotherapy.
“After that, my doctor told me it was in my best interest to go on maintenance therapy,” Scott says. “He didn’t know if he could ever cure me, but he told me I could live with ovarian cancer chronically and still have a good quality of life.”
After surgery, Scott took Lynparza for a year. But she developed a “terrible face rash” and says the drug wasn’t effective. She then joined a clinical trial where participants received the immunotherapy drug Opdivo (nivolumab), Avastin and the PARP inhibitor Rubraca (rucaparib). She ended her participation after experiencing severe gastrointestinal side effects.
Scott, who has enrolled in a new clinical trial of the antibody-drug conjugate Enhertu and Lynparza in treating patients with HER2-expressing cancers, remains a proponent of participating in ovarian cancer research.
“If it weren’t for people who are willing to go through clinical trials, we wouldn’t have the groundbreaking medicine we have today,” she says, adding that if you’re in a clinical trial, it’s important to pay attention to your body. “When something doesn’t feel right, communicate with your medical team. Ask them to give you what you need to be successful.”
Research studies have led to deeper understanding of how best to treat patients with different ovarian cancer types. Bregar notes that chemotherapy doesn’t work as well in low-grade serous cancers (about 10% of ovarian cancers).
“Low-grade cancer tends not to be as sensitive to chemotherapy when compared with high-grade cancers,” she says. “These cancers may be more hormonally driven. This is why we think hormone maintenance is so important.”
Bregar and her colleagues recently published a retrospective study on the benefit of oral hormone therapy for a subset of patients with low- grade ovarian cancer after treatment with surgery and chemotherapy. Patients in this subset who received surgery and chemotherapy followed by hormone maintenance had a 60-month survival rate of 71% compared with 61% among patients who did not initiate maintenance hormonal therapy — an increase in life expectancy of about 3.6 months.
Using results from a randomized controlled trial showing benefits of hormone maintenance, Bregar and her colleagues looked back at previously treated patients. “What we found confirmed that patients with low-grade serous cancers benefit from hormone maintenance,” she says.
“For low-grade ovarian cancers, we know hormones work in the maintenance setting.”
Bregar also notes that a lack of screening for ovarian cancer often leads to later diagnosis. “Ovarian cancer is rare,” she says. “Lifetime risk is only 1.4%. Because symptoms are so vague and there’s no way to screen, it’s like finding a needle in a haystack.”
She says more research is needed on how to detect ovarian cancer sooner.
“Something I’m looking at is whether we can find a way to diagnose ovarian cancer early by doing what we call a uterine lavage, or washing of the uterus,” she says.
It also is critical to treat the whole person, not just their cancer.
“We know the psychological aspects or stress aspects of cancer are so important,” Sood says. Whole-person care is a critical focus for Dr. Tara Berman, a medical oncologist specializing in gynecology at the Inova Schar Cancer Institute in Fairfax, Virginia, and an expert in integrative oncology services. Earlier this year, Berman and her colleagues published a review of clinical research supporting the effectiveness of integrative modalities in ovarian cancer care.
According to Berman, these services include three components: mind and body practices, natural products and lifestyle modification.
“They’re not meant to supplant conventional cancer treatments,” she says. “Integrative oncology is about using other modalities in conjunction with standard of care to help improve quality of life and ideally, efficacy outcomes.”
Integrative oncology services, which include nutrition, exercise, massage, acupuncture and emotional support, help improve quality of life, she says. They also help patients tolerate and better adhere to treatment, Berman notes.
They can also help manage side effects. “Massage increases circulation and blood flow,” she says. “And acupuncture is helpful in the setting of chemotherapy-induced neuropathy.”
Berman says data are beginning to “scratch the surface” of integrative oncology’s potential — for example, the role of fat cells in certain cancers.
“Estrogen can be a driver for promoting the growth of cancer cells,” she says. “In some ovarian cancers, tumors have estrogen receptors. Even though we block estrogen by taking out the ovaries and giving certain hormonal medications, estrogen is also produced by fat cells. So, through diet and exercise, by reducing body mass index and the amount of fat in the body, we can effectively reduce estrogen levels.”
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