After eight years with no new treatments for ovarian cancer, PARP inhibitors and anti-angiogenics are benefiting patients.
Teri Woodhull has helped to direct her own treatment, recently joining a trial of a PARP inhibitor after learning of its promise in ovarian cancer.
- PHOTO BY: CHRISTA REED
Teri Woodhull is decidedly proactive. A strong family history of breast cancer led her to undergo a preventive bilateral mastectomy at age 30. Seventeen years later, she was diagnosed with stage 3b high-grade serous epithelial ovarian cancer.
“I do have a BRCA mutation, although I didn’t know until I was diagnosed,” Woodhull says, adding that, despite being highly educated and working in the health care field, she had been unaware of the role of BRCA mutations as a major risk factor for ovarian cancer.
While inherited mutations in BRCA1 and BRCA2 — both DNA repair genes — are often linked with the development of both breast and ovarian cancers, the gene mutations’ connection to breast cancer may be more widely known because of that disease’s higher prevalence and public profile. About 15 percent of women with ovarian cancer develop the disease due to hereditary factors, and BRCA mutations account for the vast majority of those cases.
That connection is becoming increasingly important when it comes to treatments for ovarian cancer: Some of the latest drugs approved, inhibitors of the enzyme poly ADP ribose polymerase (PARP), work specifically in women with BRCA mutations. Encouragingly, PARP inhibitors are also proving valuable for some patients who don’t have BRCA gene mutations. In addition, other drugs have been recently approved for patients with ovarian cancer regardless of whether they have inherited risk factors.
After an eight-year drought in the development of new drugs for the disease, progress was seen in 2014, with the approvals of Lynparza (olaparib), the first PARP inhibitor, indicated for use by itself in advanced disease; and Avastin (bevacizumab), a targeted anti-angiogenic monoclonal antibody meant for use with chemotherapy in certain recurrent ovarian cancers. While the approvals of the two drugs represented major breakthroughs for the treatment of ovarian cancer, neither drug has proved to prolong survival; instead, both improve progression-free survival (PFS), meaning they can lengthen the amount of time before the disease progresses.
In December 2016, more FDA approvals came through for ovarian cancer treatments, again for advanced disease: the PARP inhibitor Rubraca (rucaparib), along with a companion diagnostic to test for BRCA mutations, and an expanded approval for Avastin.
Designed for women with BRCA mutations, Rubraca was shown in trials to shrink ovarian tumors, but studies did not seek to determine whether it prolonged survival; that is being investigated. Avastin, not specifically for those with BRCA mutations, was shown to improve PFS and, in one study, suggested an improvement in overall survival, although that was not considered statistically significant.
The need for a host of new drugs for ovarian cancer stems from the complexity of the disease. “Our therapies tend to work well initially, but the cancer becomes resistant, and so it’s a tricky cancer to work with because it’s very heterogeneous. It’s got a lot of resistance mechanisms built in, and so it always seems to be able to evade what we do and pop back up with a resistant version,” says Elizabeth Swisher, M.D., Dream Team co-leader for the Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition.
AVASTIN AND OTHER ANTI-ANGIOGENICS
After debulking surgery, which was meant to get rid of as much tumor as possible, Woodhull enrolled in a clinical trial for Avastin, several years before the drug’s approval. Following 23 treatments taken every three weeks for 10 months after aggressive chemotherapy, she was deemed to have no evidence of disease.
Anti-angiogenics like Avastin work by inhibiting the development, growth and maintenance of blood vessels that feed cancerous tumors. Avastin does this by specifically binding vascular endothelial growth factor (VEGF) molecules, which would otherwise serve as a stimulant to develop new blood supply and growth to tumors. “It’s sort of like a sponge that is trying to sop up all the VEGF,” says Robert L. Coleman, M.D., professor and vice chair of clinical research in the Department of Gynecologic Oncology at the University of Texas MD Anderson Cancer Center in Houston.
Avastin was initially approved for ovarian cancer that did not respond well to platinum-based chemotherapy. Its most recent approval to treat ovarian cancer allows its use in patients who do respond to a platinum-based regimen, but who experience a recurrence after six or more months of treatment with the chemotherapy.
Having been an investigator in multiple studies of Avastin, Coleman says potential side effects include hypertension; protein in the urine, which can indicate illness; and a low but serious risk for bowel perforation — a risk heightened for patients with recent abdominal surgery, pre-existent inflammatory bowel disease or certain other risk factors. “But overall, it’s a relatively well-tolerated drug in the space where it’s indicated,” Coleman adds.
While other anti-angiogenics have been studied, none to date have demonstrated the overall treatment effect of Avastin in ovarian cancer.
“In multiple clinical scenarios, Avastin, alone and in combination with other chemotherapeutics and biological agents, has demonstrated a significant impact on response, symptom control and survivorship. However, as with most treatment approaches in this disease, resistance and adaptation emerges, driving the great need to understand the effects of treatment in the microenvironment and how to improve efficacy. New anti-angiogenesis drugs and anti-angiogenesis drug combinations are an active area of contemporary research,” says Coleman.
About two years after completing the Avastin trial, cancer returned in Woodhull’s abdominal cavity. “Because I’d been in a clinical trial, I was being followed more closely,” she says, “so they caught it really early.”
From there, Woodhull received 18 weeks of standard chemotherapy treatment with carboplatin and Taxol (paclitaxel). “To our shock and surprise, when I had the CT scan after the chemo, they found new masses that had developed during the chemo,” she explains.
Having dived into educating herself and getting deeply involved with the patient advocacy group Facing Our Risk of Cancer Empowered (FORCE), Woodhull knew that PARP inhibitors had shown promise in ovarian cancer. She embarked on a quest to locate a trial in which she could enroll, visiting major cancer centers until she found a fit with a San Francisco study of the then-experimental PARP inhibitor Zejula (niraparib). The study assessed niraparib as a maintenance drug, meaning that Woodhull is taking it after completing other treatments, in order to help prevent or delay cancer progression or recurrence. She says the drug has kept her cancer stable for more than a year and a half, also shrinking her tumors by 20 percent. In late March, Zejula was approved by the FDA as a maintenance treatment for with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancers who are in a complete or partial response to platinum-based chemotherapy; it joined Lynparza and Rubraca as available PARP inhibitors for ovarian cancer.
The phase 3 trial results for Zejula, presented in November 2016, showed a significant improvement in PFS for those taking the drug versus placebo, with median PFS at 21 months and 5.5 months, respectively. “For ovarian cancer, that’s a big deal,” says Woodhull. “That’s just a flavor of how these PARP inhibitors are so exciting for ovarian cancer patients.” Thomas J. Herzog, M.D., clinical director of the University of Cincinnati Cancer Institute in Ohio, who was a researcher on the Zejula study, echoes Woodhull’s excitement over the new treatment option. When it comes to comparing the PARP inhibitors, he notes that subtle differences exist in the drugs’ efficacy and toxicity profiles. “In essence, I think we need more experience with these and ... how they play out in real-world use in terms of toxicity, convenience and everything else we consider for patient use. I personally think that costs may end up being a deciding factor...with respect to PARP inhibitor selection, because from what we know right now ... they behave more similarly than they do differently regarding efficacy,” says Herzog.
Side effects of PARP inhibitors can include nausea and fatigue, with disturbances to blood counts occurring at higher doses or in combination with chemotherapy.
The drugs work by preventing cancer cells from repairing their DNA, which can be damaged by chemotherapy or radiation. Their indication in women with BRCA mutations is aimed at exploiting the lack of DNA repair capabilities in BRCA-mutated cells, which, when bolstered by PARP inhibitors’ prevention of DNA repair, results in something called synthetic lethality. That occurs when, due to problems with the expression of two or more genes, cancer cells die, whereas they could live if only one gene was experiencing such glitches.
Sometimes PARP inhibitors are used in combination with anti-angiogenesis drugs, even in women who don’t have inherited BRCA mutations.
According to Coleman, anti-angiogenesis drugs, as well as targeted drugs known as the VEGF tyrosine kinase inhibitors — which are also showing some promise in ovarian cancer — cause hypoxia, or a lack of oxygen, in the tumor microenvironment by blocking VEGF, which reduces vascularization. Hypoxia can reduce the efficiency through which homologous recombination DNA repair occurs, mimicking an environment like a BRCA mutation in patients who don’t have one. “That’s the hypothesis as to why using PARP inhibitors with an anti-angiogenesis inhibitor might be of value,” says Coleman.
Another reason PARP inhibitors may work in women without hereditary BRCA gene mutations is that some patients with ovarian cancer develop acquired alterations to BRCA1 or 2, as well as DNA repair defects. In all, half of high-grade ovarian tumors carry one or both of those changes, according to the My Cancer Genome database.
“Paradoxically, even though (the BRCA mutation) helped the cell become a cancer, it makes the cancer more vulnerable to certain types of treatments, such as PARP inhibitors and also chemotherapy,” explains Swisher, who is also a professor in gynecologic oncology and an adjunct professor in medical genetics at the University of Washington School of Medicine and director of the Breast and Ovarian Prevention Program at the Seattle Cancer Care Alliance. “When you give chemotherapy, you’re damaging DNA in your normal cells and your cancer cells. Now, if the cancer cell has less ability to repair the DNA than your normal cells, the normal cells can recover from the chemo and the cancer cells can’t.”
According to Swisher, PARP inhibitors are being explored in combination with a number of other agents, some of which have yet to be approved on their own. One caution is that, because cancer cells have the ability to self-modulate their DNA-repair capacity, the cells can sometimes outsmart PARP inhibitors, Swisher points out. This resistance mechanism, she says, highlights why drug combinations are constantly being studied.
NEW STRATEGIES BEING INVESTIGATED
Looking ahead, a new strategy for treating ovarian cancer is the use of monoclonal antibodies to target folate receptor alpha, an antigen that is often found on the surface of ovarian cancer cells. These drugs disable the receptor and prevent it from fueling the cancer.
Several such drugs are being tested in clinical trials, but mirvetuximab soravtansine (IMGN853), being tested in a phase 3 clinical trial, is the furthest along in the development process.
Scientists are also finding that many ovarian cancers overexpress the cyclin E1 gene, creating a potential target for treatment. Investigation into this strategy is very early, but has included the use of a CDK2 inhibitor and Velcade (bortezomib), a proteasome inhibitor often used in the treatment of the blood cancer multiple myeloma.
One idea arising out of early studies is that tumors that overexpress cyclin E tend to be resistant to PARP inhibitors, so treating them should involve finding a way to make the tumors responsive to PARP inhibitors. A 2016 study in cell lines showed that the histone deacetylase inhibitor Farydak (panobinostat) worked in that capacity. Immunotherapy approaches in early phases of study include PD-1 checkpoint inhibitors such as Keytruda (pembrolizumab); vaccines; and adoptive T cell transfer, in which immune cells are taken from a patient, genetically engineered in a lab to make them more effective in recognizing and fighting cancer, and then returned to the patient.
With all that the medical community now knows about ovarian cancer and its available treatments, genetic testing for everyone diagnosed with the disease is becoming ever more important. For one thing, Swisher says, finding out who has inherited genetic mutations can contribute to prevention strategies, which may include methods such as prophylactic removal of the ovaries.
“There’s about 20 percent of ovarian cancer that’s hereditary, and we are trying to improve access to genetic risk assessment so that we could be preventing all the predictable cancers that are hereditary,” she says. As for Ferguson, she said if it turns out that she needs additional therapy, she would first like to see another biopsy, as well as another gene profile. “Now, as cancer treatments move forward, they can take a look and know what treatments would be of benefit to you and which would not based on your profile,” she says. “It’s really amazing.”
According to Swisher, improving access to genetic testing means not only removing cost barriers, but making information about the process more available and eliminating the red tape involved in getting assessed. Disproportionate numbers of minorities, women in lower socioeconomic strata and those in rural areas are less likely to receive genetic testing, she says.
“We are very interested in making it much more widely available,” she says, adding, “We want to do two things: We want to decrease the number of women who get ovarian cancer and we want to improve the cure rate of those who do get it.”