Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous recombination repair (HRR). We aimed to compare the efficacy and safety of talazoparib (a PARP inhibitor) plus enzalutamide (an androgen receptor blocker) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC). TALAPRO-2 is a randomised, double-blind, phase 3 trial of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line therapy in men (age ≥18 years [≥20 years in Japan]) with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy. Patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0·5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label. The primary endpoint was radiographic progression-free survival (rPFS) by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is registered with () and is ongoing. Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to the talazoparib group and 403 to the placebo group). Median follow-up for rPFS was 24·9 months (IQR 21·9–30·2) for the talazoparib group and 24·6 months (14·4–30·2) for the placebo group. At the planned primary analysis, median rPFS was not reached (95% CI 27·5 months–not reached) for talazoparib plus enzalutamide and 21·9 months (16·6–25·1) for placebo plus enzalutamide (hazard ratio 0·63; 95% CI 0·51–0·78; p<0·0001). In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue; the most common grade 3–4 event was anaemia (185 [46%] of 398 patients), which improved after dose reduction, and only 33 (8%) of 398 patients discontinued talazoparib due to anaemia. Treatment-related deaths occurred in no patients in the talazoparib group and two patients (<1%) in the placebo group. Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations. Pfizer.

中文翻译：

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Talazoparib 加 enzalutamide 治疗一线转移性去势抵抗性前列腺癌患者 (TALAPRO-2)：一项随机、安慰剂对照 3 期试验

聚（ADP-核糖）聚合酶（PARP）和雄激素受体活性的共同抑制可能会产生抗肿瘤功效，而与同源重组修复（HRR）中涉及的DNA损伤修复基因的改变无关。我们的目的是比较他拉佐帕尼（一种 PARP 抑制剂）联合恩杂鲁胺（一种雄激素受体阻滞剂）与单用恩杂鲁胺治疗转移性去势抵抗性前列腺癌 (mCRPC) 患者的疗效和安全性。Talapro-2 是一项随机、双盲 3 期试验，比较他拉佐帕尼加恩杂鲁胺与安慰剂加恩杂鲁胺作为一线治疗，对象是正在接受持续治疗的无症状或轻度症状 mCRPC 的男性（年龄≥18 岁[日本≥20 岁]）雄激素剥夺疗法。患者来自北美、欧洲、以色列、南美、南非和亚太地区 26 个国家的 223 家医院、癌症中心和医疗中心。对患者肿瘤组织中的 HRR 基因改变进行前瞻性评估，并随机分配 (1:1) 至他拉佐帕尼 0·5 mg 或安慰剂组，加恩杂鲁胺 160 mg，每天口服一次。根据 HRR 基因改变状态（缺陷、非缺陷或未知）和先前在去势敏感环境中接受的延长生命治疗（多西他赛或阿比特龙，或两者：是或否）对随机分组进行分层。申办者、患者和研究人员对他拉佐帕尼或安慰剂进行了掩蔽，而恩杂鲁胺是开放标签的。主要终点是通过盲法独立中央审查在意向治疗人群中进行评估的影像学无进展生存期（rPFS）。对所有接受至少一剂研究药物的患者进行安全性评估。这项研究已在 () 注册并正在进行中。2019年1月7日至2020年9月17日期间，805名患者入组并随机分配（402名患者分配至talazoparib组，403名患者分配至安慰剂组）。他拉佐帕利组的 rPFS 中位随访时间为 24·9 个月（IQR 21·9–30·2），安慰剂组为 24·6 个月（14·4–30·2）。在计划的主要分析中，他拉佐帕利加恩杂鲁胺未达到中位 rPFS（95% CI 27·5 个月 - 未达到），安慰剂加恩杂鲁胺为 21·9 个月 (16·6–25·1)（风险比 0· 63；95% CI 0·51–0·78；p<0·0001）。在他拉佐帕尼组中，最常见的治疗引起的不良事件是贫血、中性粒细胞减少和疲劳；最常见的3-4级事件是贫血（398名患者中的185名[46%]），在剂量减少后有所改善，398名患者中只有33名（8%）因贫血而停用他拉佐帕利。他拉佐帕利组中没有患者发生与治疗相关的死亡，而安慰剂组中则有两名患者（<1%）发生与治疗相关的死亡。与标准护理恩杂鲁胺作为 mCRPC 患者的一线治疗相比，他拉佐帕利加恩杂鲁胺导致 rPFS 具有临床意义和统计显着性改善。最终的总体生存数据和额外的长期安全性随访将进一步阐明联合治疗对有或没有肿瘤 HRR 基因改变的患者的临床益处。辉瑞。