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.

在 II/III 期 HER2 阴性乳腺癌的 II 期 I-SPY2 试验中，对标准紫杉醇新辅助化疗（durvalumab/olaparib/紫杉醇 [DOP]）中添加 PD-L1 抑制剂 durvalumab 和 PARP 抑制剂 olaparib 的组合进行了研究。 73 名参与者被随机分配至 DOP，299 名参与者被随机分配至标准护理（紫杉醇）对照。 DOP 提高了所有 HER2 阴性 (20%–37%)、激素受体 (HR) 阳性/HER2 阴性 (14%–28%) 和三阴性乳腺癌 (TNBC) 的病理完全缓解 (pCR) 率（27%–47%）。在 HR 阳性/HER2 阴性癌症中，MammaPrint 超高 (MP2) 病例选择性地从 DOP 中受益（pCR 64% 与 22%），而在 MP1 癌症中未见获益（pCR 9% 与 10%）。总体而言，DOP 组中有 12.3% 的患者经历了免疫相关的 3 级不良事件，而对照组为 1.3%。与免疫反应相关的基因表达特征与双臂的 pCR 呈正相关，而肥大细胞特征与非 pCR 相关。对于 HER2 阴性乳腺癌，DOP 的疗效优于标准新辅助化疗，特别是对于高危 HR 阳性/HER2 阴性患者的高度敏感亚群。