Olaparib Is First PARP Inhibitor to Show Advantage in BRCA-Mutated Breast Cancer

August 2017 Vol 8, No 8

The PARP inhibitor olaparib significantly improved progression-free survival (PFS) compared with standard chemotherapy in women with HER2-negative metastatic breast cancer with a germline BRCA mutation. Disease progression was delayed by about 3 months with olaparib in the multinational, randomized, open-label phase 3 study known as OlympiAD, reported Mark E. Robson, MD, at the 2017 ASCO Annual Meeting.

The data also showed a meaningful improvement in health-related quality-of-life measures (HRQoL) in the olaparib arm.

OlympiAD provides proof of principle that breast cancers with defects in a specific DNA damage repair pathway are sensitive to a targeted therapy designed to exploit that defect, said Dr Robson, Director of the Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York City.

“OlympiAD is the first phase 3 study in metastatic breast cancer demonstrating benefit for a PARP inhibitor over an active comparator,” he said. “It is our opinion that olaparib could be an effective treatment option for women with BRCA mutations and metastatic HER2-negative breast cancer, including, importantly, women with BRCA mutations and triple-negative breast cancer.”

The 302 patients enrolled in OlympiAD had HER2-negative breast cancer with germline BRCA1 or BRCA2 mutations, either hormone receptor (HR)-positive or triple-negative. All patients had up to 2 prior rounds of anthracycline- or taxane-based chemotherapy for metastatic breast cancer, and those with HR-positive disease had received hormonal therapy. They were randomized in a 2:1 ratio to olaparib tablets, 300 mg twice daily, or single-agent chemotherapy (21-day cycles of either capecitabine, vinorelbine, or eribulin) at the treating physician’s discretion. (The dose of olaparib used in this study is different from the FDA-approved dose of 400 mg twice daily in capsular formulation for the treatment of BRCA-mutated ovarian cancer.) Treatment continued until disease progression confirmed by independent review or unacceptable toxicity.

Patients were evenly split between HR-positive and triple-negative disease. Seventy-one percent received prior chemotherapy for metastasis. At the time of data cutoff, 82% of olaparib recipients and 97% of chemotherapy recipients had discontinued treatment, 73% and 75%, respectively, for objective disease progression.

The median PFS was 7.0 months in the olaparib arm compared with 4.2 months in the chemotherapy arm (hazard ratio, 0.58; P = .0009). The median time from randomization to second progression or death was 13.2 months and 9.3 months in the olaparib and chemotherapy arms, respectively (hazard ratio, 0.57; P = .0033).

Overall survival (OS) data are not mature, but a preplanned interim analysis revealed no difference between the 2 groups in median OS (P = .5665).

Exploratory preplanned subgroup analysis showed a significant benefit for olaparib in PFS in patients treated previously with chemotherapy, those not receiving prior chemotherapy, those with triple-negative breast cancer, and those not receiving prior platinum-based treatment.

The rate of grade ≥3 adverse events was lower in the olaparib arm (36.6% vs 50.5%), as was the percentage of patients who discontinued the study drug due to adverse events (4.9% vs 7.7%) and the percentage with adverse events leading to dose reductions (25.4% vs 30.8%). The median treatment duration was more than 2-fold greater in the olaparib arm (8.2 vs 3.4 months).

HRQoL was assessed on a 100-point scale. The mean difference in global HRQoL across all study visits was 7.5 points in favor of olaparib (P = .0035). “The observed 7.5-point difference would be considered a small clinically significant difference,” said Dr Robson.

“This is really a major step forward in breast cancer,” said ASCO President Daniel F. Hayes, MD. “It’s almost as much a proof of principle as it is practice changing, as these drugs do work in breast cancer if we’re smart and if we’re precise. If we are precise in what we do, this is a drug that has fewer side effects and works better than what we’ve done in the past.”

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