October 2020: Results from GeparOLA study

The randomized GeparOLA (GBG 90) trial investigated olaparib in combination with paclitaxel in patients with a homologous recombination deficiency (HRD), HER2-negative early breast cancer. This was a non-comparative phase II design. Briefly, patients with untreated primary HER2-negative cT2-cT4a-d or cT1c with either cN+ or pNSLN+ or cT1c and TNBC or cT1c and Ki-67>20% BC with HRD were randomized either to paclitaxel 80 mg/m2 weekly plus olaparib 100 mg twice daily for 12 weeks or paclitaxel plus carboplatinum AUC2 weekly for 12 weeks, both followed by epirubicin/cyclophosphamide. Stratification factors were hormone receptor (HR) status (HR-positive vs HR-negative) and age (<40 vs ≥40 years). The primary endpoint was pathological complete response (pCR; ypT0/is ypN0). A two-sided one group χ2-test was planned to exclude a pCR rate of ≤55% in olaparib arm. Secondary endpoints were other pCR definitions, breast conservation rate, clinical/imaging response, tolerability and safety.

Between September 2016 and July 2018, 274 patients at 32 sites were screened, of whom 107 were randomized into the study and 106 (olaparib arm N=69 and carboplatinum arm N=37) started treatment. The median age was 47.0 years (range 25.0-71.0); 32 patients were aged <40 years; 36.2% of patients had cT1 tumors and 31.8% were cN-positive; the majority (86.8%) had grade 3 tumors and a Ki-67>20% (89.6%). Seventy-seven patients (72.6%) had TNBC and 56.2% confirmed g/tBRCA1/2 mutation status. A total of 104 patients underwent surgery (two patients in the olaparib arm did not have available data on surgery). In the olaparib arm, 38/69 patients had a pCR [55.1% (90% CI 44.5%-65.3%)] versus 18/37 with carboplatinum [48.6% (90% CI 34.3%-63.2%)]. The absolute difference of pCR rates between the arms was 6.4% (90% CI -10.3%-23.1%). Thus, an addition of olaparib to chemotherapy could not exclude a pCR rate of ≤55%. Stratified subgroup analysis showed higher pCR rates with olaparib in the cohorts of patients <40 years and those with HR-positive tumors. Overall, pCR rate in the gBRCA1/2 carriers was significantly higher than in non-carriers. In addition, the HR-positive gBRCA1/2 carriers had a higher pCR rate than the non-carriers but this effect was detected only in the olaparib group. With regards to safety, the treatment with olaparib was associated with a better safety profile than with carboplatinum.

In conclusion, while efficacy seemed to be similar, the treatment with olaparib resulted in a more favorable toxicity profile. Patients aged <40 years and those with HR-positive HRD tumors who were treated with olaparib showed a numerically higher pCR rate compared to carboplatinum. This effect has not yet been reported in breast cancer and prompts further investigation of using olaparib as part of neoadjuvant chemotherapy in patients with primary HRD-positive breast cancer.

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. 2020 Oct 21:S0923-7534(20)42963-1

• DOI: 10.1016/j.annonc.2020.10.471
  
• Link in PubMed https://pubmed.ncbi.nlm.nih.gov/33098995/