Analysis Confirms Safety of Olaparib in Breast Cancer

Susan M. Domchek, MD

An analysis of the phase III OlympiAD study presented at the 2017 San Antonio Breast Cancer Symposium (SABCS) showed that treatment discontinuation due to toxicity was less frequent with olaparib (Lynparza) monotherapy compared with chemotherapy in patients with HER2-negative metastatic breast cancer and a germline BRCA mutation.¹ Olaparib was well tolerated overall, according to Susan M. Domchek, MD, who presented the findings.

The rate of grade ≥3 adverse events (AEs) was lower with the PARP inhibitor olaparib versus treatment of physician’s choice (TPC; 36.6% vs 50.5%), according to findings from OlympiAD previously published in the New England Journal of Medicine (NEJM).² The duration of therapy was 2.5 times longer among patients receiving olaparib.

The OlympiAD findings published in NEJM also showed that olaparib reduced the risk of disease progression or death by 42% versus TPC (hazard ratio [HR], 0.58; 95% CI, 0.43-0.80; P = .001). The median progression-free survival was 7.0 months versus 4.2 months.

Based on these data, the FDA granted a priority review in October 2017 to a supplemental new drug application for olaparib for the treatment of patients with germline BRCA-positive, HER2-negative metastatic breast cancer who have previously received chemotherapy in the neoadjuvant, adjuvant, or metastatic settings

The analysis presented at SABCS focused on identifying the most frequent AEs observed in the OlympiAD trial. The study enrolled 302 patients, who were randomized to olaparib (n = 205) or single-agent TPC with capecitabine, eribulin, or vinorelbine (n = 97). Six patients who were randomized to TPC but declined study treatment because of allocation were excluded from safety analyses. Treatment continued until disease progression or unacceptable toxicity.

In the olaparib arm, 4.9% of patients discontinued due to toxicity, compared with 7.7% in the TPC arm. Treatment-related AEs responsible for discontinuation in the olaparib arm included anemia (2.0%), decreased platelet count (1.0%), and dyspnea, erythema nodosum, increased intracranial pressure, thrombocytopenia, and upper abdominal pain (0.5% each). In the TPC arm, AEs responsible for discontinuation were anemia (2.2%), neutropenia (2.2%), leukopenia, peripheral motor neuropathy, palmar-plantar erythrodysesthesia, radiation skin injury, and vomiting (1.1% each).

Among patients receiving olaparib, initial onset of anemia was usually in the first 3 months of therapy, and resolved in 75.6% of cases. Eighteen percent in the olaparib arm and 5.5% in the TPC arm required at least 1 blood transfusion. Of the patients receiving transfusion for anemia, 21.1% of olaparib patients and 50.0% of TPC patients were transfused for grade 1 or 2 anemia.

“The risk of developing anemia under olaparib remained fairly constant throughout exposure, with no evidence of a cumulative effect, and the risk of discontinuation due to anemia was low,” said Domchek, executive director of the Basser Center for BRCA, and director of the MacDonald Women’s Cancer Risk Evaluation Center, University of Pennsylvania. “We didn’t see a cumulative anemia; that’s always the concern when patients are on the drug.

“When you look at patients on chemotherapy, their transfusion requirements go up with time. That was not seen with olaparib.”

In the olaparib group supportive treatment of anemia at the investigators’ discretion was used for 20.5% of patients, compared with 11.3% of the TPC group. Supportive treatment included iron preparations in 12.7% and 8.8% of the olaparib and TPC groups, respectively; erythropoietin-stimulating agents in 5.9% and 1.1%; folic acid in 2.4% and 1.1%; and vitamin B12 in 3.9% and 2.4%, respectively.

Among olaparib-treated patients, there was no grade 3 nausea or vomiting, and dose reductions for nausea (1%) and vomiting (1%) were infrequent. The first incidence of nausea and vomiting during olaparib treatment generally occurred within the first month (approximately 30% of patients), and most resolved within 5 weeks or 2 days, respectively. Antiemetic or antinausea agents were used by 29.8% of patients in the olaparib arm compared with 34.0% in the TPC arm.

“We haven’t felt that there’s a need for prophylactic antiemetics but more making sure that people have access to an antiemetic if they start to notice nausea and manage it aggressively from there,” Domchek said.

Anecdotal experience was that nausea occurred early and then it subsided, “and it turned out to be true when you look at patient-reported outcomes,” she noted.

“It’s important that people recognize that nausea, fatigue, and anemia are the 3 major side effects. Nausea can be managed pretty readily by standard antiemetics and, when necessary, dose reduction. You need to let them know it might happen and encourage them to stay on and you get them through it.”

References

1. Domchek SM, Robson M, Im S-A, Senkus E, et al. Tolerability of olaparib monotherapy versus chemotherapy in patients with HER2-negative metastatic breast cancer and a germline BRCA mutation: OlympiAD. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Abstract P5-21-12.
2. Robson M, Im S-A, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523-533.