Phase III Trial of Targeted Drug Shows Promise in Treating Metastatic Breast Cancer

Medical oncologist Mark Robson

Medical oncologist and clinical geneticist Mark Robson is leading research on new treatments for advanced breast cancer.

Update: On January 12, 2018 the FDA approved olaparib (Lynparza®) for patients with BRCA-positive, HER2-negative metastatic breast cancer who have been previously treated with chemotherapy.

Original post: The first phase III trial of a new class of drugs for breast cancer is reporting promising data. In the multicenter, international trial led by Memorial Sloan Kettering medical oncologist and clinical geneticist Mark Robson, the drug olaparib (Lynparza®) extended progression-free survival by an average of three months longer than treatment with standard chemotherapy. The results were presented at the annual meeting of the American Society of Clinical Oncology in Chicago and were simultaneously published in the New England Journal of Medicine.

Progression-free survival is the time the cancer remains under control without getting worse. All of the women in the study had metastatic breast cancer that was caused by an inherited mutation in the BRCA1 or BRCA2 gene and that was negative for the protein HER2.

Women taking olaparib reported a better quality of life than those getting chemotherapy.

Of the women in the study, 205 received olaparib and 91 received chemotherapy. Almost 60% of the women who were treated with olaparib responded to that treatment, compared with a response rate of about 30% for those who were treated with chemotherapy.

Olaparib can be taken at home as a pill. The women on olaparib reported a better quality of life than those getting chemotherapy intravenously.

“The biggest side effect of olaparib was nausea, which seemed to be worse at the beginning of treatment,” Dr. Robson says. “Some of the women also had fairly significant anemia. But for the most part, we were able to treat these side effects.” By comparison, women in the chemotherapy group experienced hair loss, fatigue, pain in the hands and feet, and low counts of both red and white blood cells.

Killing Cancer Cells by Blocking Their Repair Mechanism

Olaparib is in a class of drugs called PARP inhibitors, which work by blocking enzymes called poly (ADP-ribose) polymerases (PARPs). Members of this family of enzymes help repair breaks in DNA. If DNA cannot be repaired, cells cannot divide and will die. An emerging strategy in cancer therapy is to block PARPs’ repair role. Normal cells can overcome this type of attack, but certain cancer cells cannot.

The genes BRCA1 and BRCA2 are linked to inherited forms of breast and ovarian cancer, as well as several other cancers. They are known to make proteins that help cells repair DNA. This is why cancers caused by these mutations are particularly susceptible to PARP inhibitors, because they further prevent DNA repair.

This research is very much a first step. … To further improve treatment for this aggressive disease, there's still much work to be done.
Mark E. Robson medical oncologist

BRCA-related breast cancers run in families and tend to affect younger women. In fact, the average age of women in the current trial was only 44. Some of the women had just been diagnosed with metastatic cancer, and others had seen their metastatic cancer advance after earlier treatment.

An Important First Step

Olaparib was the first PARP inhibitor to be approved by the FDA for ovarian cancer. (Two more have followed.) Three other PARP inhibitors are currently being studied for advanced breast cancer, but olaparib is the first to have results from a phase III trial.

In addition to the current trial, which is still ongoing, olaparib is also being studied in the adjuvant setting, as a treatment to go along with surgery to prevent breast cancer from coming back. That trial has not yet reported findings.

The researchers say that if olaparib were ultimately approved for breast cancer, it could allow women with metastatic disease to postpone certain types of chemotherapy. This delay could last as long as the targeted therapy continues to work. Thus, olaparib could allow such women to avoid the side effects of chemotherapy for a longer period of time.

“This research is very much a first step,” Dr. Robson concludes. “Based upon the data from this study, we hope to have a useful treatment alternative for women with metastatic disease who also have BRCA mutations. But to further improve treatment for this aggressive disease, there’s still much work to be done.”

This trial was funded by AstraZeneca, the company that makes olaparib.