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Phase III Trial of PARP Inhibitor (Olaparib) Shows First Evidence of Improved Outcomes in Breast Cancer

The first phase III trial of a PARP inhibitor used to treat breast cancer reported promising data at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. Mark Robson, MD, Clinic Director of the Clinical Genetics Service and medical oncologist at Memorial Sloan Kettering Cancer Center (MSK), led the multicenter, international trial. He presented the study results in the plenary session of the ASCO annual meeting on June 4. “This landmark study is the first to demonstrate that a PARP inhibitor improves outcomes in women with BRCA-mutation-associated breast cancer compared with standard treatment,” explained Dr. Robson. “At MSK, we like to say that breast cancer is often described as a book with many chapters. We see this treatment option as an early chapter in a woman’s journey. The study showed that olaparib is a well-tolerated treatment that can extend the time until chemotherapy is necessary. Olaparib helps patients preserve their quality of life in the crucial early stages of their treatment journey.” Called OlympiAD, the randomized, open-label phase III study assessed the efficacy and safety of olaparib (Lynparza™), an oral PARP inhibitor, versus standard single-agent chemotherapy treatment. All of the patients in the trial had metastatic breast cancer that was caused by an inherited mutation in the gene BRCA1 or BRCA2 — either hormone receptor–positive or triple negative. They all had previously received anthracycline and taxane treatments and, if their cancer was hormone receptor–positive, a hormonal treatment. A total of 205 women in the study received olaparib and 91 received chemotherapy. The median patient age was 44, as women with BRCA mutations are significantly younger than the average breast cancer patient. The investigators reported that olaparib reduced the likelihood of progression by 42 percent and extended progression-free survival by an average of three months compared with standard chemotherapy (7 months versus 4.2 months, respectively). The length of time until second progression was also longer with olaparib. Objective response rates in olaparib versus chemotherapy were 59.9 percent and 28.8 percent, respectively. Treatment with olaparib, which can be taken at home as a pill, resulted in fewer severe side effects and in an overall higher quality of life when compared with standard chemotherapy. Olaparib was well tolerated, with only 5 percent of patients discontinuing treatment.

Triple-negative breast cancers, which don’t carry receptors for HER2 or the hormones estrogen or progesterone, are considered difficult to treat because they don’t respond to the newer therapies that have been effective for other types of breast cancer. Roughly 10 percent of triple-negative breast cancer patients have inherited BRCA mutations. Olaparib benefited patients with BRCA mutations who had triple-negative breast cancer in this study, and it is the first targeted therapy to have shown an improvement in outcomes in a phase III trial in this specific patient population.

“While this proof-of-concept research is critical, this is very much a first step. To better improve treatment for this aggressive disease, there’s still much work to be done, including exploring how these results may be improved with combination therapies,” said Dr. Robson. “We are thankful to the patients who took part in this, and all, clinical trials. Their participation is vital for us to continue developing and improving treatments.”

Olaparib was the first of three PARP inhibitors to be approved by the FDA for ovarian cancer. Three other PARP inhibitors are currently being studied for advanced breast cancer. In addition to this ongoing current trial, olaparib is also being studied in the adjuvant setting, in combination with chemotherapy, as a possible way to prevent breast cancer from coming back after surgery. That trial has not yet reported findings.

PARP [poly (ADP-ribose) polymerase] is an enzyme used by healthy cells to repair themselves. However, cancer cells also use PARP to repair DNA damage, thus extending their growth and possible lethality. Olaparib selectively binds to and inhibits PARP, preventing it from repairing DNA damage in cancer cells, particularly those cancer cells that have lost BRCA1 or BRCA2 function. This may help control the tumor or shrink it.

[MSK press release] [AstraZeneca press release] [ASCO abstract]

[Forbes article] [Reuters article] [Medscape article]