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RENO Study: Clinical characteristics, treatment patterns and survival results in patients with metastatic renal cell carcinoma in Northern Spain RENO 研究:西班牙北部转移性肾细胞癌患者的临床特征、治疗模式和生存结果
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-01 DOI: 10.1053/j.seminoncol.2024.02.002

Background

The current available evidence on the management of metastatic renal cell cancer (mRCC) in real life is scarce in our environment. We present a summary of the existing real-world data and the results of an analysis describing the clinical characteristics, treatments, and health outcomes of patients with mRCC in northern Spain.

Methods

Retrospective observational study. Adult patients diagnosed with mRCC between Jan 2007 and Dec 2019 were included. Epidemiological, efficacy and toxicity data were collected. Median overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan-Meier method.

Results

A total of 829 patients were included (median age at diagnosis:63 years;73% men). Median follow-up was 180 months. The preponderant histology was clear cell (85%). In 50% the initial diagnosis was advanced disease. The distribution according to IMDC prognosis was good (24%), intermediate (50%) and poor (26%). The most frequent metastatic locations were lung (68.3%) and lymph node (41.0%). Most patients (95%) received a first line (1L) systemic treatment, 60% were treated with a second line (2L) of therapy and 37% received third line (3L). A VEGFR-TKIs was the most common treatment (1L: 90%, n = 507; 2L: 49%, n = 233; 3L: 54%, n = 156) followed by mTOR inhibitors (1L: 2%, n = 4; 2L: 27%, n = 126; 3L: 23%, n = 68) and immunotherapy (1L: 3.7%, n = 25; 2L: 27%, n = 126). Median OS was 24.5 months in the general population. According to IMDC prognostic groups, OS was 52.5, 25.7 and 9 months respectively. From the start of the 1L, 2L, and 3L treatment, median PFS was: 1L: 7.8 (6.8–9.0); 2L: 4.9 (4.3–5.5); 3L: 4.3 (3.8–4.8) months. No unexpected toxicity was reported.

Conclusions

The Real-World Data on the management of mRCC in Northern Spain are comparable in epidemiology, efficacy, and safety to studies conducted in other areas of the world. The significant reduction in the number of patients receiving second and subsequent lines of therapy hampers the access to new therapies developed in this context.

在现实生活中,有关转移性肾细胞癌(mRCC)治疗的现有证据并不多。我们总结了现有的真实世界数据,并对西班牙北部 mRCC 患者的临床特征、治疗方法和健康结果进行了分析。回顾性观察研究。研究纳入了 2007 年 1 月至 2019 年 12 月期间确诊为 mRCC 的成年患者。收集了流行病学、疗效和毒性数据。采用卡普兰-梅耶法确定中位总生存期(OS)和无进展生存期(PFS)。共纳入 829 名患者(诊断时的中位年龄:63 岁;73% 为男性)。中位随访时间为 180 个月。组织学特征以透明细胞为主(85%)。50%的患者最初诊断为晚期疾病。IMDC预后分布为良好(24%)、中等(50%)和较差(26%)。最常见的转移部位是肺部(68.3%)和淋巴结(41.0%)。大多数患者(95%)接受一线(1L)系统治疗,60%接受二线(2L)治疗,37%接受三线(3L)治疗。VEGFR-TKIs是最常见的治疗方法(1L:90%,507例;2L:49%,233例;3L:54%,156例),其次是mTOR抑制剂(1L:2%,4例;2L:27%,126例;3L:23%,68例)和免疫疗法(1L:3.7%,25例;2L:27%,126例)。一般人群的中位 OS 为 24.5 个月。根据IMDC预后分组,OS分别为52.5个月、25.7个月和9个月。从1L、2L和3L治疗开始,中位PFS分别为:1L:7.8(6.8-9.0)个月;2L:4.9(4.3-5.5)个月;3L:4.3(3.8-4.8)个月。无意外毒性报告。西班牙北部治疗 mRCC 的真实世界数据在流行病学、疗效和安全性方面与世界其他地区进行的研究相当。接受二线及后续治疗的患者人数大幅减少,阻碍了在此背景下开发的新疗法的使用。
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引用次数: 0
Invasive lobular breast cancer: Focus on prevention, genetics, diagnosis, and treatment 浸润性小叶乳腺癌:关注预防、遗传、诊断和治疗
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-01 DOI: 10.1053/j.seminoncol.2024.05.001

Invasive lobular cancer (ILC) is the most common of the breast cancer special types, accounting for up to 15% of all breast malignancies. The distinctive biological features of ILC include the loss of the cell adhesion molecule E-cadherin, which drives the tumor's peculiar discohesive growth pattern, with cells arranged in single file and dispersed throughout the stroma. Typically, such tumors originate in the lobules, are more commonly bilateral compared to invasive ductal cancer (IDC) and require a more accurate diagnostic examination through imaging. They are luminal in molecular subtype, and exhibit estrogen and progesterone receptor positivity and HER2 negativity, thus presenting a more unpredictable response to neoadjuvant therapies. There has been a significant increase in research focused on this distinctive breast cancer subtype, including studies on its pathology, its clinical and surgical management, and the high-resolution definition of its genomic profile, as well as the development of new therapeutic perspectives. This review will summarize the heterogeneous pattern of this unique disease, focusing on challenges in its comprehensive clinical management and on future insights and research objectives.

浸润性小叶癌(ILC)是乳腺癌特殊类型中最常见的一种,占所有乳腺恶性肿瘤的 15%。浸润性小叶癌的显著生物学特征包括细胞粘附分子 E-cadherin 的缺失,这促使肿瘤呈现出特殊的盘状生长模式,细胞排列成单列,分散在整个基质中。此类肿瘤通常起源于乳腺小叶,与浸润性乳腺导管癌(IDC)相比更常见于双侧,需要通过影像学进行更准确的诊断检查。它们在分子亚型上属于管腔癌,表现为雌激素和孕激素受体阳性和 HER2 阴性,因此对新辅助疗法的反应更难预测。针对这一独特乳腺癌亚型的研究大幅增加,包括对其病理学、临床和手术治疗、基因组特征的高分辨率定义以及新疗法前景的开发。本综述将总结这种独特疾病的异质性模式,重点关注其综合临床管理方面的挑战以及未来的见解和研究目标。
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引用次数: 0
Isolated lung metastases from pancreatic ductal adenocarcinoma (PDAC): Diagnostic and therapeutic challenges of a different disease 胰腺导管腺癌(PDAC)的肺转移:不同疾病的诊断和治疗难题
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-01 DOI: 10.1053/j.seminoncol.2024.04.001

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, mostly due to the high rate of distant dissemination. However, growing evidence shows that isolated lung recurrence or metastases (ILM) from PDAC are not only less common, but also correlated with a better prognosis. Lung-only recurrence after surgery occurs later in time and is associated with more favorable prognostic characteristics of the primary tumor. Moreover, recent findings suggest that this specific site of metastases is characterized by an immunologically “hot” microenvironment and a more favorable molecular profile that could possibly justify its clinical behavior. Thus, ILM from PDAC emerge as a distinct entity, that might also benefit from a different therapeutic approach, possibly with the integration of surgery and de-intensified chemotherapy regimens, especially in selected patients. In this review we delve into the current scientific evidence on the clinical and biological characteristics of isolated LM from PDAC, also focusing on concerns with their diagnostic process and the therapeutic options for the management of this subset of patients.

胰腺导管腺癌(PDAC)的预后很差,主要原因是远处播散率很高。然而,越来越多的证据表明,PDAC 的肺部孤立复发或转移(ILM)不仅不常见,而且预后较好。术后仅肺部复发发生的时间较晚,且与原发肿瘤更有利的预后特征相关。此外,最近的研究结果表明,这一特定部位的转移瘤具有免疫 "热 "微环境和更有利的分子特征,这可能会证明其临床表现的合理性。因此,来自 PDAC 的 ILM 是一个独特的实体,它也可能受益于不同的治疗方法,可能是手术和去强化化疗方案的结合,尤其是在选定的患者中。在这篇综述中,我们将深入探讨目前有关 PDAC 分离出的 LM 的临床和生物学特征的科学证据,并重点关注其诊断过程和治疗该亚群患者的治疗方案。
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引用次数: 0
Real-world experience with CDK4-6 inhibition in the old and oldest old with a diagnosis of breast cancer 在确诊患有乳腺癌的耄耋老人中使用 CDK4-6 抑制剂的实际经验
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-01 DOI: 10.1053/j.seminoncol.2024.01.003

This study describes characteristics, toxicity and survival in old patients with HR+/HER2-breast cancer (BC) treated with CDK4/6 inhibitors. Retrospective observational study that included patients ≥ 75 years with HR+/HER2-BC treated with CDK4/6 inhibitors between 2017 and 2021. Patients’ general and cancer-related data were collected. Comprehensive Geriatric Assessment scales were gathered. Adverse events reported before each cycle were included. At the end of the follow-up period, mortality was retrospectively registered from medical records. All 19 patients (94.7% women, median age 77.9 ± 10.1) were at risk of frailty (G8 ≤ 14) and malnutrition (MNA-SF ≤ 11). Most were independent (52.7% Lawton ≥ 6), had no cognitive impairment (89.5%, MMSE ≥ 24), poor physical performance (70%, SPPB < 8; 62.5% TUG ≥ 12’’) and polypharmacy (72.2%). Almost half had stage IV disease (47.1%). Palbociclib+letrozole was the most frequently prescribed treatment (36.8%). All patients developed some toxicity (94.7% hematologic, 36.8% renal) but except one, grade ≤ 2. Over the 42-month follow-up period, 10 reported progression and 8 died. The median survival time was 19.9 ± 3.4 months. Five months after starting treatment, the probability of survival was 73%. At 30 months, 53% of patients survived. We found a high risk of frailty and drug toxicity in this small sample. Most patients presented hematologic toxicity but to a low degree. The probability of survival increases with treatment.

本研究描述了接受CDK4/6抑制剂治疗的HR+/HER2-乳腺癌(BC)老年患者的特征、毒性和生存情况。回顾性观察研究纳入了2017年至2021年间接受CDK4/6抑制剂治疗的≥75岁HR+/HER2-BC患者。收集了患者的一般和癌症相关数据。收集了老年综合评估量表。包括每个周期前报告的不良事件。在随访期结束时,根据医疗记录对死亡率进行了回顾性登记。所有 19 名患者(94.7% 为女性,中位年龄为 77.9±10.1 岁)都有虚弱(G8 ≤ 14)和营养不良(MNA-SF ≤ 11)的风险。大多数人都能独立生活(52.7% Lawton ≥ 6),没有认知障碍(89.5%,MMSE ≥ 24),体能较差(70%,SPPB < 8; 62.5% TUG ≥ 12''),并服用多种药物(72.2%)。近半数患者为 IV 期疾病(47.1%)。帕博西尼+来曲唑是最常用的处方治疗(36.8%)。所有患者都出现了一些毒性反应(94.7%为血液学反应,36.8%为肾脏反应),但有一名患者除外,毒性等级≤2。在 42 个月的随访期间,有 10 人报告病情恶化,8 人死亡。中位生存时间为(19.9 ± 3.4)个月。开始治疗 5 个月后,患者的生存概率为 73%。30个月后,53%的患者存活。我们发现,在这个小样本中,体弱和药物毒性的风险很高。大多数患者出现血液毒性,但程度较轻。随着治疗的进行,存活几率也会增加。
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引用次数: 0
CAR T-cell therapy: A collaboration between authorized treatment centers and community oncologists CAR T 细胞疗法:授权治疗中心与社区肿瘤学家之间的合作
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-01 DOI: 10.1053/j.seminoncol.2024.02.001

With the approval of the first CAR T-cell products for hematological malignancies in 2017, these autologous cell therapies have changed the treatment paradigm for patients with relapsed or refractory (r/r) non-Hodgkin lymphoma (NHL), who have a poor prognosis and few effective treatment options. Despite the demonstrated clinical benefit in patients with r/r diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma, many patients who are eligible for CAR T-cell therapies do not receive them or are treated with CAR T cells as a later line of therapy at advanced stages of disease. Several barriers exist for referring patients to an authorized treatment center (ATC) for CAR T-cell therapy. Although most patients with NHL are treated by community-based oncologists, educational gaps may exist for some community oncologists about the availability of CAR T-cell therapies in certain indications, the overall treatment process, and how they can access these therapies for their patients. In addition to navigation of the referral process from the community setting to the ATC, other barriers include timely identification of candidates eligible for CAR T-cell therapy and logistical and reimbursement concerns. Here, we examine the patient CAR T-cell experience, which begins and ends in the community setting, and identify and discuss opportunities for improved collaboration between community oncologists and ATC physicians to help address barriers to treatment and enhance patient outcomes. Treatment decisions for a patient's second or third line of therapy for NHL are critically important, owing to declining probabilities for favorable outcomes with each successive line of therapy. For patients who are eligible, CAR T-cell therapies should be considered as early as possible in their treatment course. A better understanding of the CAR T-cell process, the patient's experience, and the collaboration necessary for timely patient identification, better access, and successful outcomes will enable more patients to benefit from CAR T-cell therapies.

随着 2017 年首批治疗血液恶性肿瘤的 CAR T 细胞产品获得批准,这些自体细胞疗法改变了复发或难治性(r/r)非霍奇金淋巴瘤(NHL)患者的治疗模式,这些患者预后较差,有效的治疗方案很少。尽管R/R弥漫大B细胞淋巴瘤、套细胞淋巴瘤和滤泡淋巴瘤患者的临床获益已得到证实,但许多符合CAR T细胞疗法条件的患者并没有接受这种疗法,或在疾病晚期才接受CAR T细胞作为后期疗法。将患者转介到授权治疗中心(ATC)接受 CAR T 细胞疗法存在一些障碍。虽然大多数 NHL 患者都是由社区肿瘤学家治疗的,但对于某些社区肿瘤学家来说,在 CAR T 细胞疗法在某些适应症中的可用性、整体治疗流程以及如何为患者获得这些疗法等方面可能存在教育差距。除了从社区环境到 ATC 的转诊流程之外,其他障碍还包括及时发现符合 CAR T 细胞疗法条件的候选者以及后勤和报销问题。在此,我们研究了患者在社区环境中开始和结束 CAR T 细胞治疗的经历,并确定和讨论了改善社区肿瘤学家和 ATC 医生之间合作的机会,以帮助解决治疗障碍和提高患者疗效。患者接受 NHL 二线或三线治疗的治疗决策至关重要,因为随着治疗线的不断延长,患者获得良好治疗效果的概率也在不断下降。对于符合条件的患者,应在治疗过程中尽早考虑 CAR T 细胞疗法。更好地了解CAR T细胞治疗过程、患者的经历以及及时发现患者、更好地获得治疗和成功治疗所需的合作,将使更多患者受益于CAR T细胞疗法。
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引用次数: 0
PARP inhibitors in ovarian cancer 卵巢癌中的 PARP 抑制剂
IF 4 3区 医学 Q2 ONCOLOGY Pub Date : 2024-02-01 DOI: 10.1053/j.seminoncol.2024.01.001
Ian S. Goldlust, Elena Guidice, Jung-min Lee

Poly-ADP-ribose polymerase inhibitors (PARPis) were first approved for the treatment of epithelial ovarian cancer (EOC), where as a maintenance therapy they transformed clinical management of this disease in both patients with and without homologous recombination deficiency. In this review, we provide a historical overview of PARPi use in EOC and discuss recent updates on overall survival data, highlighting their impact on regulatory approvals. We explore their potential as combination regimens with antiangiogenic and cell-cycle checkpoint inhibitors, as well as other small molecule inhibitors, to overcome resistance mechanisms and enhance therapeutic efficacy, providing a future perspective on the use of PARPis in EOC treatment.

聚 ADP 核糖聚合酶抑制剂(PARPis)首次被批准用于治疗上皮性卵巢癌(EOC),作为一种维持疗法,它们改变了同源重组缺陷和非同源重组缺陷患者的临床治疗。在这篇综述中,我们概述了 PARPi 用于 EOC 的历史,并讨论了最近更新的总生存率数据,强调了它们对监管审批的影响。我们探讨了 PARPi 与抗血管生成药、细胞周期检查点抑制剂以及其他小分子抑制剂联合治疗的潜力,以克服耐药机制并提高疗效,为 PARPi 在 EOC 治疗中的应用提供了一个未来视角。
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引用次数: 0
PARP1 roles in DNA repair and DNA replication: The basi(c)s of PARP inhibitor efficacy and resistance PARP1 在 DNA 修复和 DNA 复制中的作用:PARP 抑制剂疗效和抗药性的基础
IF 4 3区 医学 Q2 ONCOLOGY Pub Date : 2024-02-01 DOI: 10.1053/j.seminoncol.2023.08.001
Petar-Bogomil Kanev, Aleksandar Atemin, Stoyno Stoynov, Radoslav Aleksandrov

Genome integrity is under constant insult from endogenous and exogenous sources. In order to cope, eukaryotic cells have evolved an elaborate network of DNA repair that can deal with diverse lesion types and exhibits considerable functional redundancy. PARP1 is a major sensor of DNA breaks with established and putative roles in a number of pathways within the DNA repair network, including repair of single- and double-strand breaks as well as protection of the DNA replication fork. Importantly, PARP1 is the major target of small-molecule PARP inhibitors (PARPi), which are employed in the treatment of homologous recombination (HR)-deficient tumors, as the latter are particularly susceptible to the accumulation of DNA damage due to an inability to efficiently repair highly toxic double-strand DNA breaks. The clinical success of PARPi has fostered extensive research into PARP biology, which has shed light on the involvement of PARP1 in various genomic transactions. A major goal within the field has been to understand the relationship between catalytic inhibition and PARP1 trapping. The specific consequences of inhibition and trapping on genomic stability as a basis for the cytotoxicity of PARP inhibitors remain a matter of debate. Finally, PARP inhibition is increasingly recognized for its capacity to elicit/modulate anti-tumor immunity. The clinical potential of PARP inhibition is, however, hindered by the development of resistance. Hence, extensive efforts are invested in identifying factors that promote resistance or sensitize cells to PARPi. The current review provides a summary of advances in our understanding of PARP1 biology, the mechanistic nature, and molecular consequences of PARP inhibition, as well as the mechanisms that give rise to PARPi resistance.

基因组的完整性不断受到来自内源性和外源性的损害。为了应对这种情况,真核细胞进化出了一个复杂的 DNA 修复网络,该网络可以处理各种类型的病变,并具有相当大的功能冗余。PARP1 是 DNA 断裂的主要传感器,在 DNA 修复网络中的许多途径中都扮演着既定和推定的角色,包括单链和双链断裂的修复以及 DNA 复制叉的保护。重要的是,PARP1 是小分子 PARP 抑制剂(PARPi)的主要靶点,PARPi 被用于治疗同源重组(HR)缺陷肿瘤,因为后者因无法有效修复高毒性双链 DNA 断裂而特别容易受到 DNA 损伤的累积。PARPi 在临床上的成功促进了对 PARP 生物学的广泛研究,揭示了 PARP1 参与各种基因组交易的情况。该领域的一个主要目标是了解催化抑制与 PARP1 诱捕之间的关系。作为 PARP 抑制剂细胞毒性的基础,抑制和捕获对基因组稳定性的具体影响仍存在争议。最后,人们越来越认识到 PARP 抑制具有激发/调节抗肿瘤免疫的能力。然而,PARP 抑制剂的临床潜力因耐药性的产生而受到阻碍。因此,人们投入了大量精力来确定促进耐药性或使细胞对 PARPi 敏感的因素。本综述概述了我们对 PARP1 生物学、PARP 抑制的机理性质和分子后果以及产生 PARPi 抗药性的机制的认识进展。
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引用次数: 0
PARP inhibitors for prostate cancer PARP抑制剂治疗前列腺癌症。
IF 4 3区 医学 Q2 ONCOLOGY Pub Date : 2024-02-01 DOI: 10.1053/j.seminoncol.2023.09.003
Ossian Longoria , Nick Beije , Johann S. de Bono

Poly(ADP-ribose) polymerase (PARP) inhibitors have transformed the treatment landscape for patients with metastatic castration-resistant prostate cancer (mCRPC) and alterations in DNA damage response genes. This has also led to widespread use of genomic testing in all patients with mCRPC. The current review will give an overview of (1) the current understanding of the interplay between DNA damage response and PARP enzymes; (2) the clinical landscape of PARP inhibitors, including the combination of PARP inhibitors with other agents such as androgen-receptor signaling agents; (3) biomarkers related to PARP inhibitor response and resistance; and (4) considerations for interpreting genomic testing results and treating patients with PARP inhibitors.

聚(ADP-ribose)聚合酶(PARP)抑制剂改变了转移性去势耐受性癌症(mCRPC)患者的治疗前景,并改变了DNA损伤反应基因。这也导致基因组检测在所有mCRPC患者中广泛使用。目前的综述将概述(1)目前对DNA损伤反应和PARP酶之间相互作用的理解;(2) PARP抑制剂的临床前景,包括PARP抑制剂与其他药物(如雄激素受体信号剂)的组合;(3) 与PARP抑制剂反应和耐药性相关的生物标志物;以及(4)解释基因组检测结果和用PARP抑制剂治疗患者的考虑因素。
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引用次数: 0
Seminars in oncology 50th anniversary 肿瘤学研讨会 50 周年纪念。
IF 4 3区 医学 Q2 ONCOLOGY Pub Date : 2024-02-01 DOI: 10.1053/j.seminoncol.2024.02.003
Tito Fojo
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引用次数: 0
PARP inhibitors: A review of the pharmacology, pharmacokinetics, and pharmacogenetics PARP抑制剂:药理学、药代动力学和药物遗传学综述。
IF 4 3区 医学 Q2 ONCOLOGY Pub Date : 2024-02-01 DOI: 10.1053/j.seminoncol.2023.09.005
Yi Zeng , Oluwatobi Arisa , Cody J. Peer , Antonio Fojo , William D. Figg

PARP inhibitors have emerged as a promising class of anticancer agents approved for the treatment of ovarian, breast, prostate, and pancreatic cancer. These inhibitors target PARP enzymes involved in DNA repair pathways and exhibit remarkable efficacy in cancers with genetic deficiencies in the homologous recombination pathway responsible for mending DNA double-strand breaks. While all PARP inhibitors demonstrate potent and selective inhibition of PARP1 and PARP2, the key enzymes involved in DNA repair, each agent within the class possesses unique pharmacological profiles distinguishing them from one another.

This review aims to comprehensively examine the properties of the entire PARP inhibitor class while emphasizing individual pharmacologic and pharmacokinetic distinctions that inform clinical recommendations. Currently, four agents, namely olaparib, rucaparib, niraparib, and talazoparib, have obtained approval in the United States and Europe. Olaparib, the first approved PARP inhibitor, has been extensively studied and is indicated for a wider range of cancer types.

Niraparib and talazoparib, the more recent additions to the PARP inhibitor class, possess the longest half-lives and are formulated for convenient once-daily dosing, alleviating the pill burden for patients when compared to older agents. Moreover, talazoparib undergoes minimal hepatic metabolism, reducing the potential for drug-drug interactions. Notably, niraparib is the sole PARP inhibitor recommended for dose reduction in hepatically impaired populations, whereas talazoparib and olaparib should be dose reduced in renally impaired populations. The mechanisms underlying these dose adjustment recommendations are further explored in this review.

Additionally, this review briefly covers veliparib, a PARP inhibitor under development, and two recently approved PARP inhibitors in China, fuzuloparib and pamiparib. Although significant progress has been made in understanding PARP inhibitors, there are several unanswered questions that remain, necessitating further research across a broader spectrum of cancer types within this evolving class of anticancer agents.

PARP抑制剂已成为一类有前景的抗癌药物,被批准用于治疗卵巢癌、乳腺癌、前列腺癌和胰腺癌癌症。这些抑制剂靶向参与DNA修复途径的PARP酶,并在负责修复DNA双链断裂的同源重组途径中存在遗传缺陷的癌症中表现出显著疗效。虽然所有PARP抑制剂都对参与DNA修复的关键酶PARP1和PARP2表现出有效和选择性的抑制作用,但该类药物中的每一种都具有独特的药理学特征,将它们彼此区分开来。本综述旨在全面检查整个PARP抑制剂类别的特性,同时强调个体药理学和药代动力学差异,为临床建议提供依据。目前,olaparib、rucaparib、niraparib和talazoparib四种制剂已在美国和欧洲获得批准。奥拉帕尼是首个获得批准的PARP抑制剂,已被广泛研究,适用于更广泛的癌症类型。Niraparib和talazoparib是PARP抑制剂类别中最新添加的药物,具有最长的半衰期,配方方便,每天给药一次,与较老的药物相比,减轻了患者的药物负担。此外,他拉唑帕尼的肝脏代谢最小,降低了药物相互作用的可能性。值得注意的是,尼拉帕利是唯一推荐用于减少肝功能受损人群剂量的PARP抑制剂,而塔拉佐帕尼和奥拉帕尼应在肾功能受损人群中减少剂量。本综述将进一步探讨这些剂量调整建议的机制。此外,本综述还简要介绍了正在开发的PARP抑制剂veliparib,以及中国最近批准的两种PARP抑制剂,呋唑帕利和帕帕帕利。尽管在理解PARP抑制剂方面取得了重大进展,但仍有几个悬而未决的问题,需要在这类不断发展的抗癌药物中对更广泛的癌症类型进行进一步研究。
{"title":"PARP inhibitors: A review of the pharmacology, pharmacokinetics, and pharmacogenetics","authors":"Yi Zeng ,&nbsp;Oluwatobi Arisa ,&nbsp;Cody J. Peer ,&nbsp;Antonio Fojo ,&nbsp;William D. Figg","doi":"10.1053/j.seminoncol.2023.09.005","DOIUrl":"10.1053/j.seminoncol.2023.09.005","url":null,"abstract":"<div><p>PARP<span><span><span><span><span> inhibitors have emerged as a promising class of anticancer<span> agents approved for the treatment of ovarian, breast, prostate, and </span></span>pancreatic cancer<span><span>. These inhibitors target PARP </span>enzymes<span> involved in DNA repair pathways and exhibit remarkable efficacy in cancers with </span></span></span>genetic<span> deficiencies in the homologous recombination<span> pathway responsible for mending DNA double-strand breaks. While all </span></span></span>PARP inhibitors<span> demonstrate potent and selective inhibition of PARP1 and </span></span>PARP2, the key enzymes involved in DNA repair, each agent within the class possesses unique pharmacological profiles distinguishing them from one another.</span></p><p><span><span>This review aims to comprehensively examine the properties of the entire PARP inhibitor class while emphasizing individual pharmacologic and pharmacokinetic distinctions that inform clinical recommendations. Currently, four agents, namely </span>olaparib, </span>rucaparib<span>, niraparib<span>, and talazoparib<span>, have obtained approval in the United States and Europe. Olaparib, the first approved PARP inhibitor, has been extensively studied and is indicated for a wider range of cancer types.</span></span></span></p><p>Niraparib and talazoparib, the more recent additions to the PARP inhibitor class, possess the longest half-lives and are formulated for convenient once-daily dosing, alleviating the pill burden for patients when compared to older agents. Moreover, talazoparib undergoes minimal hepatic metabolism, reducing the potential for drug-drug interactions. Notably, niraparib is the sole PARP inhibitor recommended for dose reduction in hepatically impaired populations, whereas talazoparib and olaparib should be dose reduced in renally impaired populations. The mechanisms underlying these dose adjustment recommendations are further explored in this review.</p><p>Additionally, this review briefly covers veliparib<span>, a PARP inhibitor under development, and two recently approved PARP inhibitors in China, fuzuloparib and pamiparib<span>. Although significant progress has been made in understanding PARP inhibitors, there are several unanswered questions that remain, necessitating further research across a broader spectrum of cancer types within this evolving class of anticancer agents.</span></span></p></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"51 1","pages":"Pages 19-24"},"PeriodicalIF":4.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50162806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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Seminars in oncology
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