Fizazi Karim, Azad Arun A, Matsubara Nobuaki, Carles Joan, Fay André P, De Giorgi Ugo, Young Joung Jae, Fong Peter C C, Voog Eric, Jones Robert J, Shore Neal D, Dunshee Curtis, Zschäbitz Stefanie, Oldenburg Jan, Ye Dingwei, Lin Xun, Kalac Matko, Douglas Laird A, Kennedy Dana, Agarwal Neeraj
Department of Cancer Medicine, Institut Gustave Roussy, Centre Oscar Lambret, University of Paris-Saclay, Villejuif, France.
Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
Lancet. 2025 Jul 16. doi: 10.1016/S0140-6736(25)00683-X.
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.
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.
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).
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.
Pfizer.
转移性去势抵抗性前列腺癌仍然无法治愈，对于直接或间接参与同源重组修复（HRR）的DNA损伤修复基因发生改变的患者，其侵袭性尤其强。在TALAPRO-2的初步分析中，与恩杂鲁胺加安慰剂相比，他拉唑帕尼加恩杂鲁胺显著改善了携带HRR基因改变的转移性去势抵抗性前列腺癌患者的影像学无进展生存期（rPFS）。在初步分析时，总生存期尚未成熟。在此，我们报告TALAPRO-2的HRR缺陷队列的最终预先指定的总生存期分析、更新的rPFS、安全性和患者报告的结局。
TALAPRO-2是一项正在进行的国际、随机、双盲、安慰剂对照的3期试验。HRR缺陷队列包括来自26个国家的142家医院、癌症中心和医疗中心的随机分配患者；该研究纳入了年龄至少18岁（日本为≥20岁）的男性，患有无症状或轻度症状的转移性去势抵抗性前列腺癌，研究入组时疾病进展，且既往未接受过延长去势抵抗性前列腺癌患者生命的全身治疗，但正在接受持续雄激素剥夺治疗。患者接受前瞻性评估以确定肿瘤HRR基因改变，并随机分配（1:1）至每日一次口服他拉唑帕尼0.5mg加恩杂鲁胺160mg或恩杂鲁胺加安慰剂，按既往对去势敏感性疾病的治疗情况（是与否）进行分层。申办方、患者和研究者对他拉唑帕尼或安慰剂均不知情，而恩杂鲁胺为开放标签。主要终点是通过盲法独立中央审查的rPFS（从随机分组到影像学进展或死亡的时间，以先发生者为准），总生存期（从随机分组到因任何原因死亡的时间）是关键的α保护次要终点，两者均在意向性治疗人群中进行评估。总生存期的随访旨在持续至计划的最终分析。在最终总生存期分析中，基于采用O'Brien-Fleming花费函数的成组序贯设计，分层对数秩检验的双侧p值需≤0.024才有统计学意义。在接受至少一剂研究药物的患者中评估安全性。该试验已在ClinicalTrials.gov注册，NCT03395197。
在2018年12月18日至2022年1月20日期间，399例HRR缺陷的转移性去势抵抗性前列腺癌患者被随机分配（200例[50%]接受他拉唑帕尼加恩杂鲁胺，199例[50%]接受恩杂鲁胺加安慰剂）。在中位随访44.2个月（IQR 36.0 - 50.8）时，与恩杂鲁胺相比，他拉唑帕尼加恩杂鲁胺治疗使总生存期有统计学意义的显著改善（风险比[HR] 0.62 [95% CI 0.48 - 0.81]；双侧p = 0.0005）；他拉唑帕尼组的中位总生存期为45.1个月（95% CI 35.4 - 未达到），而对照组为31.1个月（27.3 - 35.4）。在BRCA1/2改变的患者亚组（n = 155 [39%]）中，他拉唑帕尼加恩杂鲁胺组的中位总生存期未达到，而恩杂鲁胺组为28.5个月（HR 0.50 [95% CI 0.32 - 0.78]；p = 0.001
