Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial

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. [Display omitted] •Durvalumab plus olaparib improved chemotherapy efficacy in HER2-negative breast cancer•Immune-rich tumors had greater sensitivity to therapy•Among ER+ cancer, only Mammaprint MP2 cancers benefited from immune checkpoint therapy Pusztai et al. report findings from the I-SPY2 trial showing durvalumab and olaparib administered with paclitaxel improved pathologic complete response (pCR) rate in HER2-negative breast cancers, including TNBC and ER-positive cancers. Among the ER-positive/HER2-negative cancers, only the highly proliferative, estrogen receptor low, MammaPrint MP2 subset benefited from the combination therapy.