近日，英国癌症研究所和皇家马斯登医院Johann de Bono课题组探讨了奥拉帕尼治疗转移性去势耐药前列腺癌的疗效。相关论文于2020年4月28日发表在《新英格兰医学杂志》上。

DNA修复包括同源重组修复中涉及基因的多个功能丧失改变，与前列腺癌和其他癌症患者对聚腺苷二磷酸核糖聚合酶（PARP）抑制剂的反应有关。

研究组进行了一项随机、开放标签的3期临床试验，评估了PARP抑制剂奥拉帕尼治疗转移性去势耐药前列腺癌患者的效果，这些患者接受新激素（例如恩杂鲁胺或阿比特龙）治疗后疾病进展。

所有男性在预先指定的基因中都发生改变，直接或间接影响了同源重组修复。队列A（245例患者）的BRCA1、BRCA2或ATM中至少有一个改变； 队列B（142例患者）在其他12种预先指定的基因中至少有一个改变，这些基因均从肿瘤组织中确定。患者按2：1随机分配，分别接受奥拉帕尼或医师选择的恩杂鲁胺或阿比特龙（对照组）进行治疗。

在队列A中，奥拉帕尼组基于影像学的中位无进展生存期为7.4个月，显著长于对照组（3.6个月），在确定的客观缓解率和疼痛进展时间方面也有明显优势。队列A中奥拉帕尼组的中位总生存期为18.5个月，而对照组为15.1个月；对照组中疾病进展的患者有81%交叉接受奥拉帕尼治疗。对于总人群中（队列A和B）基于影像学的无进展生存期，奥拉帕尼组的患者获益亦显著优于对照组。奥拉帕尼组的主要毒副作用是贫血和恶心。

总之，对于患有转移性去势耐药前列腺癌的男性患者，他们在接受恩杂鲁胺或阿比特龙治疗后疾病进展，且基因改变影响了同源重组修复，与恩杂鲁胺或阿比特龙治疗相比，奥拉帕尼治疗可显著延长无进展生存期，提高缓解率，患者临床获益。

附：英文原文

Title: Olaparib for Metastatic Castration-Resistant Prostate Cancer

Author: Johann de Bono, M.B., Ch.B., Ph.D.,, Joaquin Mateo, M.D., Ph.D.,, Karim Fizazi, M.D., Ph.D.,, Fred Saad, M.D.,, Neal Shore, M.D.,, Shahneen Sandhu, M.D.,, Kim N. Chi, M.D.,, Oliver Sartor, M.D.,, Neeraj Agarwal, M.D.,, David Olmos, M.D., Ph.D.,, Antoine Thiery-Vuillemin, M.D., Ph.D.,, Przemyslaw Twardowski, M.D.,, Niven Mehra, M.D., Ph.D.,, Carsten Goessl, M.D.,, Jinyu Kang, M.D.,, Joseph Burgents, Ph.D.,, Wenting Wu, Ph.D.,, Alexander Kohlmann, Ph.D.,, Carrie A. Adelman, Ph.D.,, and Maha Hussain, M.B., Ch.B.

Issue&Volume: 2020-04-28

Abstract: Abstract

Background

Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate–ribose) polymerase (PARP) inhibition in patients with prostate and other cancers.

Methods

We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in BRCA1, BRCA2, or ATM; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician’s choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review.

Results

In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib.

Conclusions

In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone.

DOI: 10.1056/NEJMoa1911440

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1911440