On January 12, the Food and Drug Administration approved the first treatment for breast cancer patients who have inherited mutations in their BRCA genes. By zeroing in on these mutations, the drug can help improve the quality and length of life for patients whose disease has metastasized, or spread throughout the body.
This targeted therapy, called Lynparza (olaparib), has been on the market since 2014, when it was initially approved for treatment of ovarian cancer caused by the same mutations. Lynparza works by knocking out the DNA repair mechanism in BRCA-mutated tumor cells. It doesn’t act on other fast-replicating cells like chemotherapy does, making it significantly easier on the body, and expanding the treatment options for patients — many of whom had few available until now.
Of the roughly 250,000 women diagnosed with breast cancer each year, 1 to 5 percent have a BRCA1 or BRCA2 mutation. Some of these women develop what’s called “triple negative” breast cancer. That is, the three most common types of receptors — estrogen, progesterone, and HER2 receptors — that are known to fuel cancer growth are missing from their tumors. Common treatments like hormone therapy and drugs that target these receptors don’t work for these patients, who tend to be young, African-American, or Hispanic/Latina.
“The fact that we have a non-chemotherapy option for patients — they don’t lose their hair, and it has side effects that can be readily managed — it’s really quite a step forward,” says Susan Domchek, an oncologist at the University of Pennsylvania, who was involved in the phase 3 clinical trial of Lynparza.
The clinical trial, which was funded by AstraZeneca, formed the basis for Lynparza’s FDA approval. As part of the trial, Domchek and other researchers compared the effectiveness of the targeted therapy in 302 patients, roughly half of whom had triple-negative cancers. The patients were randomized into two groups: two-thirds were prescribed Lynparza, while the rest used a chemotherapy of their doctor’s choice. Nearly 60 percent of those taking Lynparza saw an effect. They didn’t have tumor progression (measured as a 20 percent increase in size) for 7 months, which was 2.8 months longer than patients using standard chemotherapy treatments.
“2.8 months doesn’t seem like much, right?” says Serena Nik-Zainal, a clinical geneticist at the University of Cambridge who wasn’t involved in the development of Lynparza. “But an extra 2.8 months, and a better quality of life with it — that does make a difference.”
The improved quality of life is because the drug is able to specifically target the cancer cells, she says. BRCA 1 and 2 cancers lack a pathway that normal cells use to repair breaks in DNA. Instead, they rely on a class of proteins called PARP proteins to fix damaged DNA, and help the cancer cells stay alive, grow, and divide. The PARP proteins are like the tumor’s crutches for DNA repair, says Nik-Zainal. But Lynparza prevents PARP proteins from being produced, completely shutting down a tumor cell’s ability to repair its DNA. “This tumor doesn’t have anywhere to go. It’s kind of lost its crutches as it were, and so the cells will die,” says Nik-Zainal.
Since normal cells have other methods of DNA repair, a PARP inhibitor like Lynparza doesn’t impact them. This is particularly important in comparison to chemotherapy, which attacks any fast replicating cells, like the lining of the gut or hair, Domchek points out. And while Lynparza did have a side effect of nausea in some patients, it tended to go away after the first thirty days, which is a significant improvement in quality of life compared to chemotherapy, Domchek says.
It’s important to have a variety of cancer drugs for each kind of tumor, so that doctors can chose the most effective ones early. Not only does this lead to better survival and remission, but better quality of life, says Nik-Zainal. For breast cancers with hormonal markers like estrogen, progesterone, or for breast cancers that are HER2 positive, there is an arsenal of such drugs with varying toxicities that doctors can prescribe to patients.
“Triple-negative breast cancer has really been the challenging one. Until now, all we’ve had has been chemotherapy. We didn’t have any other active approvals,” Domchek says. “This is the first non-chemotherapy medication that has been approved that’s relevant to triple-negative breast cancer.”
Domchek is already working on a larger, international study to see if Lynparza could be effective for early stages of breast cancer too. Early-stage patients would have received fewer treatments than patients in the recent trial who had metastatic breast cancer, she says. Their tumors would have developed less resistance because of chemotherapy, and so she thinks using the drug earlier has the possibility to be even more effective.
Other researchers are also testing the drug in combination with other therapies, to deliver Lynparza to more patients, with a wider variety of cancers. In Nik-Zainal’s work on cancer genetics, for example, she has found that it’s possible that close to 22 percent of breast cancers have BRCA 1 or BRCA2 mutations that developed spontaneously — a much higher number than those that are inherited. And it’s possible that these cancers would also be treatable with a PARP inhibitor, although that would need to be validated with clinical trials, she says.
Zainal is looking forward to Lynparza being used to help treat more patients. “If you can give people the right drug sooner in their journey of cancer, you [can] cure them faster,” she says.