近日，美国犹他大学Karim Fizazi团队研究了talazoparib联合恩杂鲁胺治疗转移性去势抵抗性前列腺癌男性患者的疗效与安全性。这一研究成果发表在2025年7月16日出版的《柳叶刀》杂志上。

这项联合talazoparib和恩杂鲁胺的3期试验的初步分析表明，在未选择同源重组修复（HRR）基因改变的转移性阉切抵抗性前列腺癌患者中，与恩杂鲁胺加安慰剂相比，放射学无进展生存率（rPFS）显著提高。当时的总体生存数据尚不成熟。研究组报告了最终的预先指定的总生存分析，更新的rPFS描述性分析，以及未选择HRR基因改变的队列的安全性。

TALAPRO-2是一项随机、双盲、安慰剂对照的3期试验。在基因未选择的队列中，患者从北美、欧洲、以色列、南美、南非和亚太地区26个国家的200个中心随机分配，包括医院、癌症中心和医疗中心。无症状或轻度症状转移性去势抵抗性前列腺癌的成年男性（年龄≥18岁[日本≥20岁]）接受持续的雄激素剥夺治疗，并且之前没有对去势抵抗性前列腺癌进行过延长生命的全身治疗，随机（1:1）分配到talazoparib 0.5 mg +恩杂鲁胺160 mg或恩杂鲁胺+安慰剂，每日口服一次作为转移性去势抵抗性前列腺癌的初始治疗。根据HRR基因改变状态（HRR缺陷vs HRR不缺陷或未知）和去势敏感疾病的既往治疗（是vs否）进行分层。试验发起者、患者和研究者被蒙面给talazoparib或安慰剂，恩杂鲁胺是开放标签的。主要终点是盲法独立中心评价的rPFS，总生存期（从随机化到全因死亡时间）是一个基于事件的α保护的关键次要终点（最终总生存期分析的α阈值为0.022[双侧]），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。在接受至少一剂研究药物的患者中评估安全性。

2019年1月7日至2020年9月17日，研究组对993名患者进行了资格评估，其中188名（19%）患者被排除，805名（81%）患者被纳入并随机分配（402名[50%]接受talazoparib +恩杂鲁胺， 403名[50%]接受恩杂鲁胺+安慰剂）。在中位随访52.5个月（IQR为48.6 - 56.0）时，与恩杂鲁胺加安慰剂相比，talazoparib +恩杂鲁胺的总生存率显著提高(风险比[HR] 0.80；p = 0·016)；talazoparib组的中位总生存期为45.8个月（95% CI 39.4 - 50.8），而对照组为37.0个月（34.1 - 40.4）。在HRR缺陷患者中，talazoparib +恩杂鲁胺的总生存率优于恩杂鲁胺+安慰剂(n=169；Hr 0.55 [0.36 - 0.83]；p= 0.0035)，在HRR无缺陷或未知的患者中较少(n=636；Hr 0.88 [0.71 - 0.08]；p = 0·22)。更新后的rPFS也倾向于talazoparib +恩杂鲁胺 (HR 0.67 [0.55 - 0.81]；术;0·0001);talazoparib +恩杂鲁胺的中位rPFS为33.1个月，而恩杂鲁胺+安慰剂的中位rPFS为19.5个月。安全性与talazoparib的已知概况一致；talazoparib +恩杂鲁胺常见的3级或以上不良事件是贫血（195例[49%]vs恩杂鲁胺+安慰剂组18例[4%]）和中性粒细胞减少症（77例[19%]vs 恩杂鲁胺+安慰剂组6例[1%]）。

研究结果表明，talazoparib联合恩杂鲁胺可显著提高转移性去势抵抗性前列腺癌患者的总生存率，支持该联合治疗作为这些患者的标准初始治疗选择。

附：英文原文

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

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

Issue&Volume: 2025-07-16

Abstract:

Background

The primary analysis of this phase 3 trial combining talazoparib with enzalutamide demonstrated significantly improved radiographic progression-free survival (rPFS) versus enzalutamide plus placebo in patients with metastatic castration-resistant prostate cancer unselected for homologous recombination repair (HRR) gene alterations. Overall survival data were immature at that time. Here we report the final prespecified overall survival analysis, an updated descriptive analysis of rPFS, and safety in the cohort unselected for HRR gene alterations.

Methods

TALAPRO-2 was a randomised, double-blind, placebo-controlled, phase 3 trial. In the genetically unselected cohort, patients were randomly assigned from 200 centres, including hospitals, cancer centres, and medical centres, in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia–Pacific region. Adult men (aged ≥18 years [≥20 years in Japan]) with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer receiving ongoing androgen deprivation therapy, and with no previous life-prolonging systemic therapy for castration-resistant prostate cancer, were randomly assigned (1:1) to talazoparib 0·5 mg plus enzalutamide 160 mg or enzalutamide plus placebo, administered orally once daily as initial treatment for metastatic castration-resistant prostate cancer, stratified by HRR gene alteration status (HRR-deficient vs HRR-non-deficient or unknown) and previous treatment for castration-sensitive disease (yes vs no). The sponsor, patients, and investigators were masked to talazoparib or placebo, and enzalutamide was open label. The primary endpoint was rPFS by blinded independent central review, and overall survival (time from randomisation to death due to any cause) was an event-based α-protected key secondary endpoint (α-threshold at final overall survival analysis was 0·022 [two-sided])—both assessed in the intention-to-treat population. Follow-up for overall survival was intended to continue until the planned final analysis. Safety was assessed in patients who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03395197, and is ongoing.

Findings

Between Jan 7, 2019, and Sept 17, 2020, 993 patients were assessed for eligibility, of whom 188 (19%) patients were excluded and 805 (81%) patients were enrolled and randomly assigned (402 [50%] to talazoparib plus enzalutamide, 403 [50%] to enzalutamide plus placebo). At a median follow-up of 52·5 months (IQR 48·6–56·0), overall survival was significantly improved with talazoparib plus enzalutamide compared with enzalutamide plus placebo (hazard ratio [HR] 0·80 [95% CI 0·66–0·96]; p=0·016); median overall survival was 45·8 months (95% CI 39·4–50·8) in the talazoparib group compared with 37·0 months (34·1–40·4) in the control group. Overall survival favoured talazoparib plus enzalutamide over enzalutamide plus placebo in HRR-deficient patients (n=169; HR 0·55 [0·36–0·83]; p=0·0035) and to a lesser extent in HRR-non-deficient or unknown patients (n=636; HR 0·88 [0·71–1·08]; p=0·22). Updated rPFS also favoured talazoparib plus enzalutamide (HR 0·67 [0·55–0·81]; p<0·0001); median rPFS was 33·1 months for talazoparib plus enzalutamide versus 19·5 months for enzalutamide plus placebo. Safety was consistent with the known profile of talazoparib; common grade 3 or higher adverse events with talazoparib plus enzalutamide were anaemia (195 [49%] vs 18 [4%] patients with enzalutamide plus placebo) and neutropenia (77 [19%] vs six [1%] patients with enzalutamide plus placebo).

Interpretation

Combining talazoparib with enzalutamide significantly improved overall survival in patients with metastatic castration-resistant prostate cancer, supporting this combination as a standard-of-care initial treatment option for these patients.

DOI: 10.1016/S0140-6736(25)00684-1

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00684-1/abstract