背景：Talazoparib（TALA）是一種聚（ADP 核糖）聚合酶抑製劑，被批準用於治療 gBRCA1/2突變 HER2 陰性的局部晚期或轉移性乳腺癌患者。

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：這項 2 期非隨機、單臂、開放標記研究（NCT03499353）評估了 Talazoparib（TALA）在新輔助治療早期 gBRCA1/2 胚係突變 HER2-的乳腺癌患者的有效性和安全性。主要研究終點是完成新輔助 TALA 單藥 1 mg qd（中度腎功能不全 0.75 mg）24 周後進行手術後，通過獨立中央評價（ICR）評估的病理完全反應（pCR）。 次要終點包括研究者（INV）的 pCR 和 ICR 的殘餘癌症負擔（RCB）（RcB：0 [pCR]，I [最小]，II [中度]，III [廣泛]）。 可評估的人群包括在治療開始時接受了至少 80％的 TALA 劑量並接受了乳腺手術和 pCR 評估的患者，以及在評估 pCR之前進展的患者。 意向性治療（ITT）人群包括所有接受了至少 1 劑 TALA 劑量的患者。

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.

結果：在接受 TALA 治療的 61 位患者（ITT 和安全人群）中，有 48 位為可評估人群。所有乳腺患者均為三陰性。60 例患有腺癌，1 例患有鱗狀細胞，組織學分期如下：I=20，II=27，III=14。平均年齡為 44.6 歲，平均病程為 4.5 周，平均治療時間為 23.3wks，平均總相對劑量強度為 84.5％（ITT 人群）。pCR（由 ICR 和 INV 評估）和 RCB（由 ICR 評估）用於可評估人群和 ITT 人群如下表所示。10 名（16.4％）患者因疾病進展而中斷。1 名患者因 COVID-19 限製而中斷治療，2 名患者有其他原因：盡早接受手術並撤回同意；9 名患者接受了＜80％的劑量。據報告有 98.4％的患者出現治療緊急不良事件（AEs）（27.9％的 G1 級，23.0％G2、45.9％G3、1.6％G4）；最常見的是疲勞（78.7％；G154.1％；G221.3％；G33.3％），惡心（68.9％；G1，54.1％；G2，13.1％；G3，1.6％）和脫發（57.4％；G1，54.1％；G2，3.3％）。3 例（4.9％）因不良事件而終止治療（G3 貧血[n=2]和 G3 眩暈[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.

	Evaluable population (N=48)	ITT population (N=61)
pCR by ICR, n (%) [95% CI]	22 (45.8) [32.0, 60.6]	30 (49.2) [36.7, 61.6]
pCR by INV, n (%) [95% CI]	22 (45.8) [32.0, 60.6]	29 (47.5) [35.0, 60.1]
RCB by ICR, n (%) [95% CI]
RCB 0	22 (45.8) [30.0, 62.6]	30 (49.2) [34.0, 64.5]
RCB I	0	1 (1.6) [0.2, 12.1]
RCB II	15 (31.3) [18.0, 48.5]	17 (27.9) [16.1, 43.7]
RCB III	0	0
Missing	11 (22.9) [11.8, 39.8]	13 (21.3) [11.2, 36.7]

結論：單藥 TALA 治療在新輔助治療中的 pCR 率可與蒽環類和紫杉烷類聯合化療方案所觀察到的 pCR 率相媲美，並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.