In Reply We thank Lin and colleagues for their comments and interest in the TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial^1,2 of combination niraparib and pembrolizumab treatment in patients with recurrent ovarian cancer or triple-negative breast cancer (TNBC). We would like to address their comment that the objective response rate (ORR) for patients with ovarian cancer was not associated with tumor BRCA (tBRCA) mutation or homologous recombination repair (HRR) deficiency status. Although we expected that patients with tBRCA-mutated ovarian cancer would have better outcomes than patients with tBRCA wild-type mutations given the results from poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor monotherapy,³ intriguingly, we found that the ORR was comparable across all ovarian cancer biomarker subpopulations, with efficacy in patients without tBRCA mutations or HRR deficiency. In the TNBC population, the ORRs were higher in patients with tBRCA mutations as expected; however, the key finding was that responses were still observed in patients without tBRCA mutations. Hence, our overall conclusion was that this combination therapy demonstrated clinical activity irrespective of BRCA mutation. This was not entirely unexpected because preclinical evidence of synergism between PARP and PD-1 (programmed cell death 1) inhibition has been reported in HRR-deficient and HRR-proficient models.⁴

在回复我们感谢林和同事们在TOPACIO /主旨-162（Niraparib结合Pembrolizumab在患者与三阴性乳腺癌或卵巢癌）试验的意见和利益^{1 ，2}组合niraparib和pembrolizumab治疗患者的复发性卵巢癌或三阴性乳腺癌（TNBC）。我们想解决他们的意见，即卵巢癌患者的客观反应率（ORR）与肿瘤BRCA（t BRCA）突变或同源重组修复（HRR）缺乏状态无关。尽管我们期望t BRCA突变的卵巢癌患者比t BRCA的患者有更好的结局鉴于多聚腺苷二磷酸核糖聚合酶（PARP）抑制剂单药治疗的结果，野生型突变³令人着迷，我们发现ORR在所有卵巢癌生物标志物亚人群中均具有可比性，对无t BRCA突变或HRR缺乏的患者有效。在TNBC人群中，t BRCA突变患者的ORR高于预期。然而，关键的发现是在没有t BRCA突变的患者中仍然观察到了反应。因此，我们的总体结论是，无论BRCA如何，这种联合治疗均具有临床活性突变。这并不是完全出乎意料的，因为在HRR缺陷和HRR熟练的模型中已经报道了PARP和PD-1（程序性细胞死亡1）抑制之间协同作用的临床前证据。⁴