近日，法国巴黎萨克雷大学Neeraj Agarwal团队研究了talazoparib联合恩杂鲁胺治疗HRR缺陷型转移性去势抵抗性前列腺癌男性患者的疗效与安全性。2025年7月16日出版的《柳叶刀》杂志发表了这项最新成果。

转移性去势抵抗性前列腺癌仍然无法治愈，并且在直接或间接参与同源重组修复（HRR）的DNA损伤修复基因改变的患者中具有特别的侵袭性。在TALAPRO-2的初步分析中，在携带HRR基因改变的转移性阉割抵抗性前列腺癌患者中，talazoparib +恩杂鲁胺与恩杂鲁胺+安慰剂相比，显著提高了放射无进展生存期（rPFS）。初步分析，总生存期不成熟。研究组报告了TALAPRO-2 hrr缺陷队列的最终预先指定的总生存分析、更新的rPFS、安全性和患者报告的结果。

TALAPRO-2是一项正在进行的国际随机、双盲、安慰剂对照的3期临床试验。HRR缺乏队列包括来自26个国家142家医院、癌症中心和医疗中心的随机分配的患者；该研究纳入了年龄≥18岁（日本≥20岁）的男性，他们患有无症状或轻度症状的转移性去势抵抗性前列腺癌，在研究开始时病情进展，既往未接受去势抵抗性前列腺癌延长生命的全身治疗，但正在接受持续的雄激素剥夺治疗。对患者进行肿瘤HRR基因改变的前瞻性评估，并随机分配（1:1）每日一次口服talazoparib 0.5 mg +恩杂鲁胺160 mg或恩杂鲁胺+安慰剂，根据既往治疗（是或否）分层治疗去雄敏感疾病。试验发起者、患者和研究者对talazoparib或安慰剂双盲，而恩杂鲁胺是开放标签的。主要终点是通过盲法独立中心评价的rPFS（从随机化到影像学进展或死亡的时间，以先发生者为准），总生存期（从随机化到全因死亡的时间）是一个关键的受α保护的次要终点，这两个终点都是在意向治疗人群中评估的。总生存率的随访将持续到计划的最终分析。为了在最终的总生存分析中具有统计学意义，分层log-rank检验的双侧p值需要小于等于0.024（基于O'； Brien-Fleming消费函数的组序贯设计）。对至少接受过一次研究药物剂量的患者进行安全性评估。

2018年12月18日至2022年1月20日期间，399例HRR缺乏的转移性去势抵抗性前列腺癌患者被随机分配（200例[50%]接受talazoparib +恩杂鲁胺治疗，199例[50%]接受恩杂鲁胺+安慰剂治疗）。在中位随访44.2个月（IQR 36.0 - 50.8）时，与恩杂鲁胺相比，talazoparib +恩杂鲁胺治疗的总生存率有统计学意义的改善(风险比[HR] 0.62；双面p = 0·0005)；talazoparib组的中位总生存期为45.1个月（95% CI为35.4 -未达到），对照组为31.1个月（27.3 - 35.4）。在BRCA1/2改变患者亚组（n=155[39%]）中，talazoparib +恩杂鲁胺组的中位总生存期未达到，而恩杂鲁胺组的中位总生存期为28.5个月(HR 0.50；p = 0·0017)；talazoparib组4年总生存率为53%，而对照组为23%。在没有BRCA1/2改变的患者中（n=244 [61%]）， talazoparib +恩杂鲁胺组的中位总生存期为42.4个月，而恩杂鲁胺组的中位总生存期为32.6个月(HR 0.73；p = 0·066)。更新后的rPFS更倾向于talazoparib +恩杂鲁胺与恩杂鲁胺(HR 0.47；0·0001;中位rPFS 30.7 vs 12.3个月)。没有发现新的安全信号；talazoparib +恩杂鲁胺最常见的3级或以上不良事件是贫血（86例[43%]患者）和中性粒细胞减少（39例[20%]患者）。

研究结果表明，与恩杂鲁胺加安慰剂相比，Talazoparib加恩杂鲁胺的生存率有统计学意义和临床意义的改善，进一步支持该组合作为HRR缺乏的转移性抗切除前列腺癌的标准治疗。

附：英文原文

Title: Talazoparib plus enzalutamide in men with HRR-deficient metastatic castration-resistant prostate cancer: final overall survival results from the randomised, placebo-controlled, phase 3 TALAPRO-2 trial

Author: Karim Fizazi, Arun A Azad, Nobuaki Matsubara, Joan Carles, André P Fay, Ugo De Giorgi, Jae Young Joung, Peter C C Fong, Eric Voog, Robert J Jones, Neal D Shore, Curtis Dunshee, Stefanie Zschbitz, Jan Oldenburg, Dingwei Ye, Xun Lin, Matko Kalac, A Douglas Laird, Dana Kennedy, Neeraj Agarwal

Issue&Volume: 2025-07-16

Abstract:

Background

Metastatic castration-resistant prostate cancer remains incurable and is particularly aggressive in patients with alterations in DNA damage repair genes involved directly or indirectly in homologous recombination repair (HRR). In the primary analysis of TALAPRO-2, talazoparib plus enzalutamide significantly improved radiographic progression-free survival (rPFS) versus enzalutamide plus placebo in patients with metastatic castration-resistant prostate cancer harbouring HRR gene alterations. At primary analysis, overall survival was immature. Here we report final prespecified overall survival analysis, updated rPFS, safety, and patient-reported outcomes in the HRR-deficient cohort of TALAPRO-2.

Methods

TALAPRO-2 is an ongoing international, randomised, double-blind, placebo-controlled phase 3 trial. The HRR-deficient cohort included randomly assigned patients from 142 hospitals, cancer centres, and medical centres in 26 countries; the study included men aged at least 18 years (≥20 years in Japan) with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer, progressive disease at study entry, and no previous life-prolonging systemic therapy for castration-resistant prostate cancer, but were receiving ongoing androgen deprivation therapy. Patients were prospectively assessed for tumour HRR gene alterations and randomly assigned (1:1) to once-daily oral talazoparib 0·5 mg plus enzalutamide 160 mg or enzalutamide plus placebo stratified by prior treatment (yes vs no) for castration-sensitive disease. The sponsor, patients, and investigators were masked to talazoparib or placebo, whereas enzalutamide was open label. The primary endpoint was rPFS (time from randomisation to radiographic progression or death, whichever occurred first) by blinded independent central review, and overall survival (time from randomisation to death due to any cause) was a key alpha-protected secondary endpoint, both assessed in the intention-to-treat population. Follow-up for overall survival was intended to continue until the planned final analysis. For statistical significance at the final overall survival analysis, the two-sided p value from the stratified log-rank test needed to be 0·024 or less based on a group sequential design with O'Brien–Fleming spending function. Safety was assessed in patients who had received at least one study drug dose. The trial is registered with ClinicalTrials.gov, NCT03395197.

Findings

Between Dec 18, 2018, and Jan 20, 2022, 399 patients with HRR-deficient metastatic castration-resistant prostate cancer were randomly assigned (200 [50%] to talazoparib plus enzalutamide and 199 [50%] to enzalutamide plus placebo). At a median follow-up of 44·2 months (IQR 36·0–50·8), treatment with talazoparib plus enzalutamide resulted in a statistically significant improvement in overall survival versus enzalutamide (hazard ratio [HR] 0·62 [95% CI 0·48–0·81]; two-sided p=0·0005); median overall survival 45·1 months (95% CI 35·4–not reached) in the talazoparib group versus 31·1 months (27·3–35·4) in the control group. In the subgroup of patients with BRCA1/2 alterations (n=155 [39%]), median overall survival was not reached for talazoparib plus enzalutamide versus 28·5 months for enzalutamide (HR 0·50 [95% CI 0·32–0·78]; p=0·0017); 4-year overall survival rates were 53% in the talazoparib group versus 23% in the control group. In patients without BRCA1/2 alterations (n=244 [61%]), median overall survival was 42·4 months for talazoparib plus enzalutamide versus 32·6 months for enzalutamide (HR 0·73 [95% CI 0·52–1·02]; p=0·066). Updated rPFS favoured talazoparib plus enzalutamide versus enzalutamide (HR 0·47 [95% CI 0·36–0·61]; p<0·0001; median rPFS 30·7 vs 12·3 months). No new safety signals were identified; most common adverse events of grade 3 or higher with talazoparib plus enzalutamide were anaemia (86 [43%] patients) and neutropenia (39 [20%] patients).

Interpretation

Talazoparib plus enzalutamide resulted in statistically significant and clinically meaningful improvement in survival versus enzalutamide plus placebo, further supporting this combination as a standard of care in HRR-deficient metastatic castration-resistant prostate cancer.

DOI: 10.1016/S0140-6736(25)00683-X

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00683-X/abstract