Adjuvant therapy with the PARP inhibitor olaparib for 1 year extended disease-free survival in patients with high-risk early-stage HER2-negative breast cancer with BRCA1/2 germline (inherited) mutations, according to a prespecified interim analysis of the phase III OlympiA trial presented at the 2021 ASCO Annual Meeting.¹ These findings were presented by lead author Andrew Tutt, MB, PhD, MBChB, Director of Breast Cancer Bow at the Toby Robins Research Centre, Institute of Cancer Research Unit at Guy’s Hospital King’s College, London.

Andrew Tutt, MB, PhD, MBChB

At 24 months of follow-up, 85.9% of patients treated with adjuvant olaparib were alive and free of recurrent invasive cancer and new second cancer (ie, invasive disease–free survival) compared with 77.1% of placebo-treated patients. The estimated 3-year distant disease–free survival rate was 87.5% with olaparib vs 80.4% with placebo.

“The OlympiA study results—the first reporting the effect of a PARP inhibitor as adjuvant therapy on survival endpoints in early BRCA1/2-mutated breast cancer or any adjuvant setting—suggest a possible addition to the standard of care for patients with germline BRCA1/2 mutation–associated early breast cancer who have levels of risk requiring neoadjuvant or adjuvant chemotherapy,” stated Dr. Tutt.

“Patients who received adjuvant olaparib were more likely to be alive without cancer and avoid metastasis at 3 years of follow-up. These findings support adjuvant olaparib for 1 year after standard-of-care treatment in patients with high-risk BRCA-mutated disease,” he added.

“These results are so important! This study demonstrates a significant reduction after 1 year of olaparib in invasive recurrences, second cancers, and distant events. Of note, these results support germline testing in increasing numbers of patients with breast cancer and may even open the door for more trials of PARP inhibitors in other BRCA-associated cancers as adjuvant therapy,” said 2020–2021 ASCO President Lori J. Pierce, MD, FASTRO, FASCO, at a premeeting press conference where the findings were previewed.

Lori J. Pierce, MD, FASTRO, FASCO

BRCA mutations are associated with 5% to 10% of breast cancers. Newly diagnosed patients with breast cancers associated with these mutations may present with aggressive, high-risk disease. After completion of multimodality therapy, recurrence rates can be high, and additional effective adjuvant therapies are needed.

Olaparib is a PARP inhibitor that targets a DNA repair defect in these cancers. It is already approved for treatment of patients with germline BRCA-mutated HER2-negative breast cancer.

Study Details

The double-blind OlympiA trial included 1,836 patients with high-risk early breast cancer that was HER2-negative, and BRCA1/2-positive, including triple-negative and hormone receptor–positive breast cancers. Following surgery, radiation therapy, and chemotherapy if needed, patients were randomly assigned to receive either 1 year of adjuvant olaparib or placebo.

“We used stringent criteria for invasive disease–free survival and distant disease–free survival,” Dr. Tutt explained. “At the planned interim analysis, these criteria were met for early reporting.” The primary endpoint of invasive disease–free survival was defined as the time from randomization until the first occurrence of ipsilateral invasive breast tumor, locoregional invasive disease, distant recurrence, contralateral invasive breast cancer, second primary invasive cancer, or death from any cause.

Key Results and Toxicity

For the primary results, compared with placebo, adjuvant olaparib reduced the risk of invasive disease–free recurrence (ie, local recurrence, metastatic recurrence, other new cancers) by 42% compared with placebo (P < .0001). At 3 years, the rate of invasive disease–free survival was 85.9% with olaparib vs 77.1% with placebo, an absolute difference of 8.8%.

Compared with placebo, olaparib achieved a 43% reduction in distant disease–free survival (ie, risk of metastatic breast cancer [P < .0001]). The difference between treatment arms was 7.1% at 3 years.

Overall survival is still immature, but fewer deaths occurred in the olaparib arm. “At this early timepoint [median of 2.5 years], given a stringent test for statistical superiority, there is no significant difference between treatment arms,” Dr. Tutt noted. The estimated 3-year overall survival rate was 92% for the olaparib-treated group and 88.3% for the placebo group. Follow-up for survival is ongoing.

Charles L. Shapiro, MD

The side effects were consistent with the 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. Adverse events of grade 3 or higher more common with olaparib included anemia, lower white blood cell count, and fatigue, but the rates were low.

Charles L. Shapiro, MD, Director of Translational Breast Cancer Research and Cancer Survivorship and Professor of Medicine, Mt. Sinai’s Icahn School of Medicine, New York City, said that OlympiA will be “practice-changing” for adjuvant therapy for BRCA1/2-positive breast cancer. “If it is fast-tracked to the FDA, olaparib will be the new standard of care,” he predicted. “Also, olaparib could be a reasonable choice in the prevention setting for BRCA1/2-positive patients.” 

DISCLOSURE: Dr. Tutt has stock and other ownership interests in Inbiomotion; has received honoraria from Medscape, Prime Oncology; has served as a consultant or advisor to Artios, AstraZeneca, Merck Serono, Pfizer, and Prime Oncology; has received institutional research funding from Artios, AstraZeneca, Merck KGaA, and Roche/Genentech; has received payment under his employer (ICR London) associated with patents held by ICR linked to the use of PARP inhibitors in BRCA1/2-deficient cancers; and has received reimbursement for travel, accommodations, and expenses from AstraZeneca and Pfizer. Dr. Pierce holds stock or other ownership interests in PFS Genomics, holds intellectual property in PFS Genomics and UpToDate, and holds uncompensated relationships with Bristol Myers Squibb and Exact Sciences. Dr. Shapiro reported no conflicts of interest.

REFERENCE

1. Tutt A, Garber JE, Kaufman B, et al: OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER2-negative early breast cancer. 2021 ASCO Annual Meeting. Abstract LBA1. Presented June 6, 2021.