Impressive Results with Olaparib in BRCA-Mutant Early-Stage Breast Cancer

A drug from a new class in oncology, a PARP inhibitor called olaparib, was used for one year of adjuvant treatment. A prespecified interim analysis of the phase III OlympiA trial showed that, for patients with hereditary BRCA1/2 mutations and high-risk, early-stage, HER2-negative breast cancer, this significantly prolonged disease-free survival. The study was presented by Dr. Andrew Tutt at the meeting beginning on June 4, the 2021 ASCO Annual Meeting, and, in parallel, the journal NEJM published the results.

Key results of the OlympiA trial

• At 24 months of follow-up, adjuvant (postoperative protective) olaparib-treated patients were alive at a rate of 85.9%, while those receiving placebo were alive at a rate of 77.1%.
• The estimated 3-year distant disease-free survival rate was 87.5% for olaparib versus 80.4% for placebo.
• Compared with placebo, adjuvant olaparib reduced the risk of invasive disease-free recurrence by 42% versus placebo.
• Compared with placebo, olaparib provided a 43% reduction in distant disease-free survival.
• Side effects were consistent with the existing safety profile of olaparib, and no new safety signals emerged during the clinical trial. Grade 3 side effects were infrequent.

Significance

The OlympiA trial reported for the first time the effect of a PARP inhibitor on survival endpoints in breast cancer or in any adjuvant setting, and indicates that standard treatment will change for patients with early-stage breast cancer associated with a germline BRCA1/2 mutation.

Patients with early-stage, high-risk breast cancer with BRCA mutations who received olaparib for postoperative protection (adjuvant treatment) were more likely to remain alive without cancer and avoid metastasis at 3 years of follow-up. Side effects were limited and manageable. These findings support, in high-risk BRCA mutation-positive patients, adjuvant olaparib for 1 year after standard-of-care treatment. The results also support, for patients with breast cancer, testing for hereditary cancer genes through genetic testing as an approach.

Is an era of hereditary gene testing for all patients with breast cancer approaching?

BRCA mutations are associated with 5% to 10% of breast cancers.

Patients newly diagnosed with breast cancer associated with these mutations may present with aggressive, high-risk disease. Recurrence rates may be high after completion of multimodality treatment (surgery, radiation and chemotherapy), and additional new, effective treatments are needed.

Identifying a hereditary cancer gene mutation in a cancer is important in two ways:

1. In tumors with hereditary cancer mutations, new-generation drugs targeting a DNA repair enzyme, called PARP inhibitors, are highly effective
2. Knowing that a cancer is hereditary is very important for calculating the family's cancer risk and the patient's own risk of secondary cancers, and for taking the necessary precautions.

Details of the Olympia trial

In the double-blind phase III OlympiA trial, with triple-negative breast cancer and HER2-negative hormone receptor-positive breast cancer and BRCA1/2 positivity in high-risk early breast cancer, 1,836 patients were enrolled. Following treatment with surgery, radiotherapy and chemotherapy if necessary, patients randomly assigned to one of two groups received 1 year of adjuvant olaparib or placebo.

Dr. Tutt said, "We used strict criteria for invasive disease-free survival and distant disease-free survival, and those criteria were met for early reporting at the planned interim analysis".

Dr. Tutt said, "The Kaplan-Meier curves separate early, with an absolute difference of 8.8% between treatment arms at 3 years".

Compared with placebo, olaparib provided a 43% reduction in disease-free distant survival (that is, the risk of metastatic breast cancer, new cancer or death from any cause [ P < .0001]). The difference between treatment arms at 3 years was 7.1%.

Overall survival is still immature, but fewer deaths occurred in the olaparib arm.

Side effects

Side effects were consistent with the known safety profile of olaparib, and no new safety signals emerged during the trial. Olaparib did not increase the rate of serious adverse events, including hospitalization, leukemias or other cancers. Grade 3 or worse side effects in patients treated with olaparib included anemia (8.7%), neutropenia (4.8%), leukopenia (3.0%), fatigue (1.8%) and lymphocytopenia (1.2%).

Comment

The findings of the OlympiA trial underline, in patients diagnosed with high-risk early-stage breast cancer, the need for BRCA mutation genetic testing. These results may have an important impact on treatment decisions for this patient group, including the use of a postoperative protective PARP inhibitor for patients with BRCA mutation-positive early-stage breast cancer.