PARP Inhibitor Improves Outcomes in BRCA-Mutated Breast Cancer

TON Web Exclusives - Breast Cancer

In the phase 3 OlympiAD trial, the poly ADP-ribose polymerase (PARP) inhibitor olaparib as monotherapy significantly improved progression-free survival (PFS) compared with standard chemotherapy in women with HER2-negative metastatic breast cancer who have a germline BRCA mutation.1 Disease progression was delayed by approximately 3 months with olaparib in the multinational, randomized, open-label study, reported Mark E. Robson, MD, Clinic Director of the Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York City, at the 2017 meeting of the American Society of Clinical Oncology (ASCO).

A meaningful improvement in health-related quality-of-life (HRQoL) measures was also realized 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.

“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 a germline BRCA1 or BRCA2 mutation, either hormone receptor (HR)-positive or triple-negative. All patients had received ≤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 (because olaparib tablets were used in this study, the dosage of olaparib patients received was different from the US Food and Drug Administration–approved dosage 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.

The numbers of patients who had HR-positive tumors and who had triple-negative tumors were comparable. Seventy-one percent of women had received prior chemotherapy for metastasis. At the time of data cutoff, 82% of olaparib recipients and 97% of chemotherapy recipients discontinued treatment; 73% and 75%, respectively, discontinued because of objective disease progression. The median follow-ups were 14.5 months and 14.1 months in the olaparib and chemotherapy arms, respectively.

The objective response rate was 59.9% in the olaparib arm versus 28.8% in the chemotherapy arm.

On an intent-to-treat basis, 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 versus 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 in median OS between the 2 groups (P = .5665).

Exploratory preplanned subgroup analysis showed a significant PFS benefit with olaparib, regardless of receipt of prior chemotherapy, in patients with triple-negative breast cancer, and in 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 were the percentage of patients who discontinued the study drug because of 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 Daniel F. Hayes, MD, FACP, FASCO, President of ASCO. “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.”

 

Reference

1. Robson M, Im S-A, Senkus E, et al. OlympiAD: phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). Presented at the American Society of Clinical Oncology Annual Meeting; June 2-6, 2017; Chicago, IL. Abstract LBA4.
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Last modified: August 7, 2017