Mateo Joaquin, Carreira Suzanne, Sandhu Shahneen, Miranda Susana, Mossop Helen, Perez-Lopez Raquel, Nava Rodrigues Daniel, Robinson Dan, Omlin Aurelius, Tunariu Nina, Boysen Gunther, Porta Nuria, Flohr Penny, Gillman Alexa, Figueiredo Ines, Paulding Claire, Seed George, Jain Suneil, Ralph Christy, Protheroe Andrew, Hussain Syed, Jones Robert, Elliott Tony, McGovern Ursula, Bianchini Diletta, Goodall Jane, Zafeiriou Zafeiris, Williamson Chris T, Ferraldeschi Roberta, Riisnaes Ruth, Ebbs Bernardette, Fowler Gemma, Roda Desamparados, Yuan Wei, Wu Yi-Mi, Cao Xuhong, Brough Rachel, Pemberton Helen, A'Hern Roger, Swain Amanda, Kunju Lakshmi P, Eeles Rosalind, Attard Gerhardt, Lord Christopher J, Ashworth Alan, Rubin Mark A, Knudsen Karen E, Feng Felix Y, Chinnaiyan Arul M, Hall Emma, de Bono Johann S
From the Institute of Cancer Research (J.M., S.C., S.S., S.M., H.M., R.P.-L., D.N.R., A.O., N.T., G.B., N.P., P.F., A.G., I.F., C.P., G.S., D.B., J.G., Z.Z., C.T.W., R.F., R.R., B.E., G.F., D. Roda, W.Y., R.B., H.P., R.A., A.S., R.E., G.A., C.J.L., A.A., E.H., J.S.B.), the Royal Marsden NHS Foundation Trust (J.M., S.S., R.P.-L., A.O., N.T., D.B., Z.Z., R.F., D. Roda, R.E., G.A., J.S.B.), and University College London Hospital (U.M.), London, Queen's University, Belfast (S.J.), University of Leeds, Leeds (C.R.), Churchill Hospital, Oxford (A.P.), University of Liverpool, Liverpool (S.H.), Beatson West of Scotland Cancer Centre, Glasgow (R.J.), and Christie Hospital, Manchester (T.E.) - all in the United Kingdom; the University of Michigan, Ann Arbor (D. Robinson, Y.-M.W., X.C., L.P.K., F.Y.F., A.M.C.); Weill Cornell Medical College, New York (M.A.R.); and Thomas Jefferson University, Philadelphia (K.E.K.).
N Engl J Med. 2015 Oct 29;373(18):1697-708. doi: 10.1056/NEJMoa1506859.
Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.
We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.
Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.
Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).
前列腺癌是一种异质性疾病，但目前的治疗并非基于分子分层。我们推测，具有DNA修复缺陷的转移性、去势抵抗性前列腺癌对奥拉帕利抑制聚（二磷酸腺苷[ADP] - 核糖）聚合酶（PARP）有反应。
我们进行了一项2期试验，转移性、去势抵抗性前列腺癌患者接受奥拉帕利片剂治疗，剂量为400 mg，每日两次。主要终点是缓解率，根据实体瘤疗效评价标准1.1版定义为客观缓解，或前列腺特异性抗原水平降低至少50%，或循环肿瘤细胞计数从每7.5 ml血液中5个或更多细胞确认减少至每7.5 ml血液中少于5个细胞。对强制肿瘤活检样本进行靶向二代测序、外显子组和转录组分析以及数字聚合酶链反应检测。
总体而言，入组50例患者；所有患者均曾接受多西他赛治疗，49例（98%）接受过阿比特龙或恩杂鲁胺治疗，29例（58%）接受过卡巴他赛治疗。49例可评估患者中有16例有反应（33%；95%置信区间，20%至48%），12例患者接受研究治疗超过6个月。二代测序在49例可评估患者中的16例（33%）中鉴定出DNA修复基因的纯合缺失、有害突变或两者皆有，这些基因包括BRCA1/2、ATM、范可尼贫血基因和CHEK2。在这16例患者中，14例（88%）对奥拉帕利有反应，包括所有7例BRCA2缺失患者（4例双等位基因体细胞缺失，3例胚系突变）和5例ATM异常患者中的4例。生物标志物组套的特异性为94%。贫血（50例患者中的第10例[20%]）和疲劳（6例[12%]）是最常见的3级或4级不良事件，这些结果与先前关于奥拉帕利的研究一致。
对于前列腺癌对标准治疗不再有反应且存在DNA修复基因缺陷的患者，使用PARP抑制剂奥拉帕利治疗可导致高缓解率。（由英国癌症研究等机构资助；ClinicalTrials.gov编号，NCT01682772；英国癌症研究编号，CRUK/11/029。）
