ADC 下一代 — 载荷创新
载荷创新是这一届 ADC 的 field-level 方向，不是又开一条赛道。T-DXd 已经在改一线标准；DAC 的临床还薄——Prelude 的 SMARCA2 降解剂单药缓解大约 15%，要从概念走到能卖，数字还差一截。
PARP抑制剂（PARPi）依靠“合成致死”机制改变了BRCA缺陷肿瘤的治疗格局：概念验证研究显示，口服olaparib单药在BRCA1/2突变的复发卵巢癌中即可带来客观缓解，且疗效与铂敏感程度相关 [3][4]；针对733例新诊断晚期卵巢癌的III期研究又确立了niraparib一线铂类化疗后维持治疗的地位 [2]。但耐药在临床上普遍存在——超过40%的BRCA1/2缺陷患者对PARPi原发不响应，同源重组修复恢复、复制叉保护等机制还会让更多患者随用药时间延长而失效 [1]。为绕开这一瓶颈，学界已尝试将PARPi与化疗之外的伙伴联合，如niraparib联合pembrolizumab的TOPACIO/KEYNOTE-162研究 [5]，以及前列腺癌中talazoparib联合enzalutamide的TALAPRO-2 [6]。
在2026年AACR年会上，Dana-Farber癌症研究所的Elizabeth Lee博士报告了一项I期研究：在HER2阳性的卵巢癌和子宫内膜癌中，将抗体偶联药物（ADC）T-DXd与PARP抑制剂联合使用。研究者的逻辑很直接——凭借ADC的靶向特异性，这一组合可能避开PARPi与化疗联合时出现的毒性；后续还计划开展更多研究。
该组合把两条既有线索接在了一起。一方面，T-DXd在妇科肿瘤中的活性正获得真实世界证据的印证：有队列研究描述了HER2表达的子宫内膜癌与卵巢癌患者接受T-DXd治疗的情况[7]，另有真实世界结果与DESTINY-PanTumor02研究一致，并在IHC 3+患者中观察到高缓解率[8]，而T-DXd的美国适应证近期也在扩大[9]。另一方面，ADC与PARPi的交汇已有先例：乳腺癌研究中，sacituzumab govitecan被提出可支持TOP1抑制与PARPi的序贯治疗策略[10]。相比之下，这项I期研究探索的是妇科肿瘤中两药的同步联合，相当于以ADC的靶向递送替代化疗来充当PARPi的联合伙伴，是对既有组合逻辑的一次延伸。
当然，这仍是I期阶段的信号：这条消息并未披露联用的具体PARPi品种、剂量、样本量与疗效数字，“毒性更低”也只是研究者基于ADC特异性的预期，尚待数据检验；PARPi的耐药难题 [1] 不会因联合而消失，据报道，T-DXd本身的耐药与DNA修复通路的靶向亦是Lee团队关注的方向[11]。计划中的后续研究，需要回答“合成致死”叠加靶向递送能否真正转化为经得起检验的疗效与安全性。
- 1.PARP inhibitor resistance: the underlying mechanisms and clinical implications · Mol Cancer 2020
- 2.Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer · N Engl J Med 2019
- 3.Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval · J Clin Oncol 2010
- 4.Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial · Lancet 2010
- 5.Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma · JAMA Oncol 2019
- 6.Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial · Lancet 2023
- 7.Real-world clinical outcomes of Trastuzumab Deruxtecan in ... · pmc.ncbi.nlm.nih.gov 2026
- 8.Abstract 1402: Real world clinical outcomes with trastuzumab ... · aacrjournals.org 2026
- 9.resistance and sequencing in breast cancer therapy · frontiersin.org 2026
- 10.Antibody–drug conjugates in breast cancer - PMC - NIH · pmc.ncbi.nlm.nih.gov 2026
- 11.Targeting DNA repair pathways for ADC-resistant HER2+ ... · vjoncology.com 2026
On Sunday at #AACR26, Elizabeth K. Lee presented a phase I dose-escalation clinical trial that enrolled patients whose tumors, regardless of cancer type, expressed HER2. Read the full recap in AACR Annual Meeting News: https://t.co/qbCjfAT2tH https://t.co/FK9mGhftfx
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