Neoadjuvant Olaparib Combo Fails to Surpass Carboplatin/Paclitaxel in HER2– Early Breast Cancer

Peter A. Fasching, MD

Long-term clinical data failed to show a benefit of neoadjuvant olaparib (Lynparza) plus paclitaxel vs carboplatin plus paclitaxel in patients with HER2-negative early breast cancer with homologous recombination deficiency (HRD). Results with a median follow-up of 49.8 months from GeparOLA (NCT02789332) were presented at the 2022 San Antonio Breast Cancer Symposium.¹

At a median follow-up of 49.8 months (range, 0.1-69.1) the 4-year invasive disease-free survival (iDFS) rate with olaparib plus paclitaxel (n = 69) was 76.0% vs 88.5% among 37 patients who received carboplatin vs paclitaxel. The unadjusted HR was 2.86 (95% CI, 0.83-9.90) and the adjusted HR for nodal status and germline mutational status was 3.6 (95% CI, 1.02-12.7).¹

Further, the 4-year locoregional recurrence rates were higher following treatment with olaparib and paclitaxel (10.3%) compared with carboplatin and paclitaxel (4.9%).

Additional long-term efficacy end points included distant disease-free survival (DDFS) and overall survival (OS). The 4-year DDFS rate with olaparib/paclitaxel was 81.2% vs 93.4% with carboplatin/paclitaxel (HR, 3.03; 95% CI, 0.67-13.67; log-rank P = .1290). The 4-year OS rate was 89.2% with the olaparib combination vs 96.6% with carboplatin (HR, 3.27; 95% CI, 0.39-27.20; log-rank P = .2444).¹

“[GeparOLA] was a small study with a low event rate,” Peter A. Fasching, MD, a professor in the Department of Obstetrics and Gynecology at the University Hospital Erlangen in Germany, said in a summary of the data. “It might be hypothesized that patients with a mutation, olaparib may replace platinum, keeping in mind that the toxicity profile was more favorable [for olaparib vs carboplatin/paclitaxel].”

Germline/somatic BRCA mutations were reported among 55.9% of patients in the olaparib arm (n = 38) and 56.8% of patients in the carboplatin/paclitaxel arm (n = 21). Outcomes were comparable with long-term follow-up in this subgroup for olaparib vs carboplatin/paclitaxel (HR, 1.16; 95% CI, 0.30-4.49; log-rank P = .8303).¹ “For patients who had no mutation in the tumor or the germline—[all of whom] were HRD high—then there is a similar event rate for the olaparib-treated patients [vs those with BRCA-mutant disease (7 events each)], but these patients treated with olaparib had an excellent prognosis.”

“There was no further subgroup that would indicate a difference, it was only the BRCA mutation status and, maybe related to that, age where patients younger than 40 years were in favor of the olaparib treatment [HR, 0.408; 95% CI, 0.25-6.62; P = .0529],” Fasching said.

The study included patients with early-stage HER2-negative disease that had an HRD-high tumor, defined as having a known germline or somatic BRCA1/2 mutation or a high HRD score via MyChoice assay (score ≥ 42). Patients were randomly assigned 2:1 to receive weekly paclitaxel (80 mg/m²) plus olaparib at 100 mg twice daily or the same regimen of paclitaxel plus carboplatin area under the curve 2 weekly. Both arms also received epirubicin/cyclophosphamide at 90 mg/m² and 600 mg/m², respectively, every 2 or 3 weeks.

Patients were not permitted to enroll if they had prior treatment with a PARP inhibitor. A total of 106 patients were included in the intention-to-treat population. “For the interpretation of the data it might be important to memorize that there was a disbalance in nodal positivity,” Fasching said. “In the platinum arm, 45.7% of patients had a nodal-positive status and in the olaparib arm there was only [approximately] 25%.”

“It’s important to realize that the inclusion [criteria] allowed both: either a tumor or germline mutation or HRD score high. Almost all patients had a tumor with a high HRD score; however, not all of them were mutated with regard to the BRCA genes,” Fasching said.

Of the enrolled population, 96 patients had a high HRD score. Among these patients, 46.2% had a mutation, 43.4% were intact, and 1 patient had insufficient quality o quantity of DNA available for measurement. Further, 3 patients had HRD low score all of whom had BRCA-mutant disease and 7 patients were not measurable for HRD status.

Other baseline characteristics were well balanced with a median age of 47.0 years (range, 25.0-71.0), approximately 60% of patients in both arms having cT2 disease status, and approximately 27% of patients having estrogen receptor– and/or progesterone receptor–positive disease. A Ki-67 index of greater than 20% was reported for 91.3% of patients in the olaparib arm vs 86.5% in the carboplatin/paclitaxel arm.^1,2

Pathological complete response (pCR) rate, the primary end point of the study, was previously reported in prior reports.² The pCR rate was 55.1% (90% CI, 44.5%-65.3%) with olaparib vs 48.6% (90% CI, 34.3%-63.2%) with carboplatin/paclitaxel. The pCR rates were the same for patients with germline/somatic BRCA mutations who received olaparib (n = 35) and carboplatin (n = 20) at 60%. There was a benefit observed with olaparib among the 30 patients with wild-type disease with a pCR of 50.0% vs 37.5% for those who received carboplatin/paclitaxel (n = 16).

Fasching noted that larger trials are needed to assess the use of olaparib further in patients with germline or somatic BRCA mutations and the role of neoadjuvant platinum-containing chemotherapy for patients without mutations.

References

1. Fasching PA, Schmatloch S, Hauke J, et al. Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency – long-term survival of the GeparOLA study. Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS5-02.
2. Fasching PA, Link T, Hauke J, et al. Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study). Ann Oncol. 2021;32(1):49-57. doi:10.1016/j.annonc.2020.10.471