Based on the phase II ISPY2 adaptive trial in stage II–III breast cancer patients, Pusztai et al. reported that the combination of durvalumab and Olaparib with weekly paclitaxel neoadjuvant therapy (DOP) improved pCR rates from 20% to 37% in HER2-negative cancers (27% to 47% in TNBC, and 14% to 28% in HR-positive/HER2-negative cases). In HR-positive/HER2-negative cancers, only the highly proliferative, ER low, MammaPrint MP2 subset showed selective benefit with DOP. Immune response gene signatures were associated with pCR in both of the arms, and 12.3% patients in the experimental arm experienced expected grade 3 immune-related adverse events.
Contributed by Shishir Pant
ABSTRACT: The combination of PD-L1 inhibitor durvalumab and PARP inhibitor olaparib added to standard paclitaxel neoadjuvant chemotherapy (durvalumab/olaparib/paclitaxel [DOP]) was investigated in the phase II I-SPY2 trial of stage II/III HER2-negative breast cancer. Seventy-three participants were randomized to DOP and 299 to standard of care (paclitaxel) control. DOP increased pathologic complete response (pCR) rates in all HER2-negative (20%-37%), hormone receptor (HR)-positive/HER2-negative (14%-28%), and triple-negative breast cancer (TNBC) (27%-47%). In HR-positive/HER2-negative cancers, MammaPrint ultra-high (MP2) cases benefited selectively from DOP (pCR 64% versus 22%), no benefit was seen in MP1 cancers (pCR 9% versus 10%). Overall, 12.3% of patients in the DOP arm experienced immune-related grade 3 adverse events versus 1.3% in control. Gene expression signatures associated with immune response were positively associated with pCR in both arms, while a mast cell signature was associated with non-pCR. DOP has superior efficacy over standard neoadjuvant chemotherapy in HER2-negative breast cancer, particularly in a highly sensitive subset of high-risk HR-positive/HER2-negative patients.