背景：Talazoparib（TALA）是一种聚（ADP 核糖）聚合酶抑制剂，被批准用于治疗 gBRCA1/2突变 HER2 阴性的局部晚期或转移性乳腺癌患者。

Background: Talazoparib (TALA) is a poly(ADP-ribose) polymerase inhibitor approved as monotherapy for treating adult patients (pts) with gBRCA1/2-mutated HER2-negative locally advanced or metastatic BC.

方法：这项 2 期非随机、单臂、开放标记研究（NCT03499353）评估了 Talazoparib（TALA）在新辅助治疗早期 gBRCA1/2 胚系突变 HER2-的乳腺癌患者的有效性和安全性。主要研究终点是完成新辅助 TALA 单药 1 mg qd（中度肾功能不全 0.75 mg）24 周后进行手术后，通过独立中央评价（ICR）评估的病理完全反应（pCR）。 次要终点包括研究者（INV）的 pCR 和 ICR 的残余癌症负担（RCB）（RcB：0 [pCR]，I [最小]，II [中度]，III [广泛]）。 可评估的人群包括在治疗开始时接受了至少 80％的 TALA 剂量并接受了乳腺手术和 pCR 评估的患者，以及在评估 pCR之前进展的患者。 意向性治疗（ITT）人群包括所有接受了至少 1 剂 TALA 剂量的患者。

Methods: This phase 2, non-randomized, single-arm, open-label study (NCT03499353) evaluated the efficacy and safety of TALA in the neoadjuvant setting for pts with early gBRCA1/2-mutated HER2-BC. Primary endpoint was evaluation of pathologic complete response (pCR) as assessed by Independent Central Review (ICR) after completing 24 weeks of neoadjuvant TALA monotherapy 1 mg QD (0.75 mg for moderate renal impairment) followed by surgery. Secondary endpoints included pCR by investigator (INV) and residual cancer burden (RCB) by ICR (RCB: 0 [pCR], I [minimal], II [moderate], III [extensive]). The evaluable population included pts who received at least 80% of the TALA dose prescribed at treatment start and underwent breast surgery and pCR assessment, plus those who progressed before pCR could be assessed. The intent-to-treat (ITT) population included all pts who received at least 1 dose of TALA.

结果：在接受 TALA 治疗的 61 位患者（ITT 和安全人群）中，有 48 位为可评估人群。所有乳腺患者均为三阴性。60 例患有腺癌，1 例患有鳞状细胞，组织学分期如下：I=20，II=27，III=14。平均年龄为 44.6 岁，平均病程为 4.5 周，平均治疗时间为 23.3wks，平均总相对剂量强度为 84.5％（ITT 人群）。pCR（由 ICR 和 INV 评估）和 RCB（由 ICR 评估）用于可评估人群和 ITT 人群如下表所示。10 名（16.4％）患者因疾病进展而中断。1 名患者因 COVID-19 限制而中断治疗，2 名患者有其他原因：尽早接受手术并撤回同意；9 名患者接受了＜80％的剂量。据报告有 98.4％的患者出现治疗紧急不良事件（AEs）（27.9％的 G1 级，23.0％G2、45.9％G3、1.6％G4）；最常见的是疲劳（78.7％；G154.1％；G221.3％；G33.3％），恶心（68.9％；G1，54.1％；G2，13.1％；G3，1.6％）和脱发（57.4％；G1，54.1％；G2，3.3％）。3 例（4.9％）因不良事件而终止治疗（G3 贫血[n=2]和 G3 眩晕[n=1]）。

Results: Of 61 pts treated with TALA (ITT and safety populations), 48 comprised the evaluable population. All pts had triple-negative BC. 60 pts had adenocarcinoma and 1 had squamous cell histology, with the following staging: I=20, II=27, III=14. Mean age was 44.6 years, mean duration of 4.5 wks since disease onset, mean duration of treatment of 23.3 wks, and mean overall relative dose intensity of 84.5% (ITT population). pCR (assessed by ICR and INV) and RCB (by ICR) for the evaluable and ITT populations are shown in the table below. Ten (16.4%) patients discontinued treatment due to progressive disease. One pt had a disruption of treatment as a result of COVID-19 restrictions, 2 pts for other reasons: to undergo surgery early and consent withdrawal; 9 patients received <80% dose. Treatment-emergent adverse events (AEs) were reported in 98.4% of pts (27.9% grade [G] 1, 23.0% G2, 45.9% G3, 1.6% G4); the most common were fatigue (78.7%; G1 54.1%; G2 21.3%; G3 3.3%), nausea (68.9%; G1 54.1%; G2 13.1%; G3 1.6%), and alopecia (57.4%; G1 54.1%; G2 3.3%). Three (4.9%) pts discontinued treatment due to AEs (G3 anemia [n=2] and G3 vertigo [n=1]) and continued on study.

结论：单药 TALA 治疗在新辅助治疗中的 pCR 率可与蒽环类和紫杉烷类联合化疗方案所观察到的 pCR 率相媲美，并且通常具有良好的耐受性。

Conclusions: TALA monotherapy in the neoadjuvant setting was active and showed pCR rates comparable to those observed with combination anthracycline and taxane-based chemotherapy regimens and was generally well tolerated.