Dr. Mark E. Robson presents LBA4.
Dr. Allison W. Kurian discusses LBA4.
Mark E. Robson, MD, of Memorial Sloan Kettering Cancer Center, presented the results of the Olympiad trial during the Plenary Session held June 4. Inhibition of poly (ADP-ribose) polymerase (PARP) when BRCA1/2 mutations are not present to aid in DNA damage repair can induce “synthetic lethality” in cancer cells, and some small studies suggested that PARP inhibition could be effective in patients with breast cancer when BRCA mutations are present, he said during a press briefing also held June 4.
Olympiad included 302 patients with HER2-negative metastatic breast cancer with a confirmed or suspected deleterious germline BRCA mutation. Patients were randomly assigned 2:1 to receive olaparib 300 mg tablets twice daily (205 patients) or to physician’s choice of chemotherapy (97 patients; 91 treated). The tablet formation was developed for patient convenience, and represents a slightly lower dose than the commonly available dose of 400 mg, taken in 8 capsules.
Patient characteristics were well-matched between the groups, with a median age of 44 and 45, respectively; most patients were white (65%), and about half of the patients had triple-negative breast cancer (TNBC). The most commonly used chemotherapy agents included capecitabine, eribulin, and vinorelbine.
The study met its primary endpoint of progression-free survival (PFS), assessed by blinded independent central review. The patients treated with olaparib had a median PFS of 7.0 months compared with 4.2 months with chemotherapy (hazard ratio [HR] 0.58, 95% CI [0.43, 0.80]; p = 0.0009). The overall survival (OS) data are not yet mature, but an interim analysis demonstrated a median OS of 19.3 months with olaparib and 19.6 months with chemotherapy (HR 0.90, 95% CI [0.63, 1.29]; p = 0.5665).
Time to second progression or death based on investigator assessment was similar between groups. The median was 13.2 months with olaparib compared with 9.3 months with chemotherapy (HR 0.57, 95% CI [0.40, 0.83]; p = 0.0033).
In the olaparib group, 60% of patients achieved a complete response compared with 29% of chemotherapy recipients; partial responses were seen in 9% and 2%, respectively. The median time to response was similar, at 47 days with olaparib and 45 days with chemotherapy, as was the median duration of response, at 6.2 months and 7.1 months, respectively.
Subgroup analyses showed that olaparib may be more effective specifically in TNBC. The HR for progression was 0.43 (95% CI [0.29, 0.63]) among patients with TNBC, but was 0.82 (95% CI [0.55, 1.26] among patients with estrogen receptor–positive and/or progesterone receptor–positive disease.
Grade 3 or higher adverse events (AEs) occurred in 36.6% of patients treated with olaparib and in 50.5% of patients treated with chemotherapy. AEs leading to drug discontinuations occurred in 4.9% and 7.7% of patients, respectively, and AEs leading to dose reductions occurred in 25.4% and 30.8%, respectively. The median duration of treatment was 8.2 months with olaparib and 3.4 months with chemotherapy. There was one death due to an AE in each group.
Among the AEs of any grade that occurred more frequently with olaparib were nausea, anemia, vomiting, and fatigue. Grade 3 or higher anemia was more common with olaparib, whereas grade 3 or higher neutropenia was more frequently seen in patients receiving chemotherapy.
An analysis of quality of life using the EORTC QLQ-C30 instrument showed an adjusted mean change with olaparib of 3.9 compared with -3.6 with chemotherapy. This yielded an estimated difference between the two of 7.5 (p = 0.0035), which Dr. Robson said would be considered a small, but clinically significant difference.
“Olympiad is the first phase III study in patients with metastatic breast cancer demonstrating benefit for a PARP inhibitor over an active comparator,” Dr. Robson said. “It is our opinion that olaparib could be an effective treatment option … including, importantly, in women with BRCA mutations and triple-negative disease,” he added.
2016–2017 ASCO President Daniel F. Hayes, MD, FACP, FASCO, commented on the study during the Press Briefing, calling it “a major step forward.” He said that this likely represents only a first step in this field, and there may be potential to add PARP inhibition to chemotherapy and perhaps move the therapy to the earlier metastatic setting or adjuvant setting.
Dr. Hayes said that in spite of improvement with olaparib, the curves ultimately come together, highlighting the need to understand acquired resistance mechanisms. “If we are precise with what we do,” he said, “this is a drug that has fewer side effects and works better than what we’ve done in the past.”
Allison W. Kurian, MD, MSc, of Stanford University School of Medicine, was the discussant for the trial during the Plenary Session. “I do think these results are practice-changing,” she said, although she highlighted several outstanding questions, including how olaparib would compare with anthracyclines and taxanes, which are more commonly used as first-line therapies rather than the chemotherapies in this study.