PARP抑制剂治疗去势抵抗性前列腺癌的研究进展北大核心

近年来随着基因组测序研究的进展使恶性肿瘤的精准治疗不断深入。针对合并特定的DNA损伤修复基因(DNA repair genes,DRGs)突变,包括同源重组介导修复(homologous recombin-mediated repair,HRR)基因突变的前列腺癌症患者,多聚腺苷酸二磷酸核糖聚合酶抑制剂(Poly ADP-ribose polymerase inhibitor,PARPi)可通过抑制DNA的修复介导存在该类基因突变的肿瘤细胞死亡。自2014年PARP抑制剂被首先批准用于晚期卵巢癌以来,针对DNA损伤修复基因突变和PARPi的研究不断进行,如今PARPi在前列腺癌患者尤其是转移性去势抵抗性前列腺癌(mCRPC)的治疗中表现不俗。本文就PARPi在mCRPC患者中的应用作一综述,对已发表和正在进行的临床试验结果进行讨论,为前列腺癌患者的个性化治疗提供更好的临床证据。     

PARP抑制剂耐药机理的研究进展

聚ADP-核糖聚合酶（Poly ADP-ribose polymerase,PARP）抑制剂（PARPi）是一组靶向携带BRCA1/2或其他同源重组因子有害突变的乳腺癌与卵巢癌的新型抗癌药物。 PARPi的临床应用已取得显著成果，是近年来临床肿瘤学的重大突破之一。然而，PARPi耐药正在成为一个严重的临床问题。研究和了解PARPi耐药机理对克服肿瘤耐药和提高疗效具有重要意义。最近的研究进展已经揭示了一些诱发PARPi耐药的机制，包括上调多药耐药基因，改变PARylation酶，重建同源重组修复和恢复复制叉稳定性。本文将综述这些变化如何导致癌细胞对PARPi产生耐药并讨论克服PARPi耐药的可能策略。     

聚腺苷二磷酸-核糖聚合酶抑制剂研究进展

肿瘤基因的不稳定性使其更容易产生并积累DNA损伤,但同时也会导致肿瘤DNA损伤修复功能发生部分丢失,使其更依赖于尚存的DNA修复路径,充分修复放化疗所致的DNA损伤,导致放化疗抵抗。聚腺苷二磷酸-核糖聚合酶[poly-（ADP-ribose）polymerase,PARP]抑制剂可以在同源重组修复缺陷（homologous recombination deficiency,HRD）肿瘤细胞中充分修复DNA损伤,产生协同细胞杀伤的作用。目前,多种PARP抑制剂（PARP inhibitor,PARPi）通过美国食品药品监督管理局（FDA）审批用于晚期卵巢癌患者,多项临床试验也正在评估PARPi单药或联合放化疗是否可以使更多患者获益,以及毒性是否可以耐受,研究对象也从卵巢癌扩大到乳腺癌、前列腺癌、直肠癌、肺癌、胰腺癌、腹膜肿瘤、头颈部肿瘤、脑瘤、鳞状细胞癌及肉瘤等。本文对已应用于临床的PARPi研究情况及面临的问题进行综述。      

艾恒治疗38例晚期实体肿瘤的近期疗效

目的 观察以艾恒为主的联合化疗治疗晚期实体肿瘤的疗效及毒副作用。方法 38例鼻咽癌、食管癌、胃癌、小细胞肺癌、肠癌、卵巢癌患者,应用以艾恒为主联合化疗方案,观察疗效及毒副反应。结果 PR 12例,总有效率为31.6％。主要毒副作用为外周感觉神经毒性,而血液学毒性、消化道副反应及肝肾毒性、脱发等轻微。结论 艾恒为主联合化疗治疗晚期实体肿瘤疗效良好,不良反应可以耐受,值得临床推广使用。     

艾恒治疗38例晚期实体肿瘤的近期疗效

目的 观察以艾恒为主的联合化疗治疗晚期实体肿瘤的疗效及毒副作用。方法 38例鼻咽癌、食管癌、胃癌、非小细胞肺癌、肠癌、卵巢癌患者，应用以艾恒为主联合化疗方案，观察疗效及毒副反应。结果 PR12例，部有效率为31.6%，主要毒副作用为外周感觉神经毒性，而血液学毒性，消化道副反应及肝肾毒性、脱发等轻微。结论 艾恒为主联合化疗治疗晚期实体肿瘤疗效良好。不良反应可以耐受，值得临床推广使用。     

多西他赛联合奥沙利铂治疗部分敏感复发性上皮性卵巢癌疗效评价

[目的]评价多西他赛联合奥沙利铂治疗部分敏感复发上皮性卵巢癌的临床疗效及安全性。[方法]回顾性分析应用多西他赛联合铂类方案治疗的43例部分敏感复发上皮性卵巢癌患者的临床资料。[结果]多西他赛＋奥沙利铂组（治疗组）总有效率为58.3%,1年生存率为87.5%,无进展生存时间为（7.2±2.6）个月,均略高于多西他赛＋卡铂组（对照组）,但无统计学意义（P〉0.05）。治疗组不良反应主要为血液系统毒性,其次为消化道反应和周围神经感觉异常。治疗组血液学毒性明显低于对照组,P=0.000;两组均无Ⅲ级至Ⅳ级胃肠道反应及周围神经感觉异常。[结论]多西他赛联合奥沙利铂方案治疗部分铂类敏感复发上皮性卵巢癌疗效较好,不良反应轻,可作为部分敏感复发上皮性卵巢癌的化疗方案。     

卵巢癌肿瘤干细胞耐药性及其治疗的研究进展

肿瘤干细胞是肿瘤组织内具有自我更新能力及无限增殖潜能的一群细胞,对外源细胞毒性药物耐受。卵巢癌肿瘤干细胞在卵巢癌发生、化疗耐药和复发过程中起重要作用。传统治疗对减小肿瘤体积有效,但是治疗后残留的卵巢癌干细胞成为卵巢癌复发和难治的根源,针对卵巢癌肿瘤干细胞的靶向治疗可能在抗卵巢癌治疗中具有重要作用,为临床彻底治愈卵巢癌带来希望。     

盐酸拓扑替康治疗顺铂耐药复发卵巢癌的临床研究

目的:评价盐酸拓扑替康治疗一线顺铂耐药复发卵巢癌的近期和远期疗效及安全性。方法:对一线含顺铂方案化疗耐药复发卵巢癌患者采用盐酸拓扑替康1.25mg/m2静滴(1~5)d,每21 d重复。治疗每2周期后评价疗效,CR或PR病例继续化疗直至疾病进展或毒性不能耐受。结果:共入组患者52例,可评价临床疗效49例,可评价血清CA12-5疗效48例,可评价毒性52例。临床和CA12-5总有效率分别为22.5%和29.2%,中位缓解期为6月,中位无疾病进展生存时间和总生存时间分别为10月和16月。主要毒副作用为中性粒细胞减少和白细胞减少,两者III/IV度毒性分别为44.2%和53.8%。非血液学毒性轻微。结论:盐酸拓扑替康单药治疗一线含顺铂方案化疗耐药复发卵巢癌疗效肯定,耐受性良好。     

卵巢癌手术加顺铂腹腔化疗的疗效观察

顺铂是现代治疗卵巢癌的第一代有效药物，静脉给药毒性反应较重。我院从１９８９年—１９９５年７月收治的６６例卵巢癌患者采用腹腔内注射顺铂的疗效观察，临床证实，此药物在腹腔积液中可以维持其游离浓度，药物可长时间直接与肿瘤接触，并可达肝、横膈、纵隔等部位治疗...     

国产盐酸拓扑替康治疗复发性卵巢癌的Ⅱ期临床研究

背景与目的:临床研究表明复发性卵巢癌患者采用以铂类为主的联合方案化疗疗效不理想,寻找二线补救化疗药物成为目前研究的重点。本研究目的是观察国产盐酸拓扑替康单药治疗复发性卵巢癌的近期疗效和不良反应。方法:采用多中心开放式研究。31例患者中29例符合入选标准,给予拓扑替康单药1.25mg·(m2·d)-1,静脉点滴,连用5天,每21天为一疗程,记录疗效和不良反应。结果:在可评价的21例的患者中,总缓解率为33.33%,而按ITT人群分析缓解率为24.14%(7/29),其中CR为3例,PR为4例。主要不良反应为血液学毒性,31.0%的患者和37.5%的疗程出现Ⅲ-Ⅳ度白细胞减少,而20.7%的患者和14.3%的疗程出现Ⅲ-Ⅳ度血小板减少。非血液学毒性较轻。结论:国产盐酸拓扑替康可作为治疗经铂类等药物治疗失败的晚期卵巢癌的有效药物。     

Review of Toxicities of PARP Inhibitors in Metastatic Castrate Resistant Prostate Cancer

There is emerging evidence for the use of poly (ADP-ribose) polymerase inhibitors (PARPi) in patients with mCRPC with patients harboring germline or somatic mutations deriving clinical benefit. However, the toxicity profile of PARPi in mCRPC is not well established. In March 2022 a literature search was conducted across 4 databases – Medline, PubMed, Cochrane Library and Embase. In total, 14 relevant studies were identified cumulating in 2066 patients that were treated with PARPi. The overall ORR to PARPi alone or in combination with other therapy was 37% (246/666). In 5trials that investigated PARPi alone, the ORR was 39% (141/361). Treatment emergent adverse events (TEAEs) of any grade were reported in 96% (1034/1080) in PARPi treatment arms. TEAEs of grade >= 3 were reported in 57% (611/1080). 45% (457/1006) experienced treatment interruption whilst 31% (310/989) required dose reductions. 11% (114/1006) of patients had their treatment discontinued directly as the result of toxicity associated with the trial medications. The most common hematological toxicity was anemia, reported in 490/1160 (42%) patients. and lowered white blood cell count were the next 2most common toxicities, reported in 186/655 (28%) and 133/729 (18%) respectively. The 3most common non-hematological toxicities reported were nausea, fatigue and anorexia reported in 440/1013 (43%), 340/1013 (34%) and 274/1013 (27%) patients respectively. Overall, TRAEs associated with individual PARPi are still emerging with hematological toxicities being most apparent. Further toxicities will be informed from future clinical trials to allow improved treatment selection, education and management of toxicities in prostate cancer.     

Therapeutic options following second-line platinum-based chemotherapy in patients with recurrent ovarian cancer: Comparison of active surveillance and maintenance treatment

Most women with advanced ovarian cancer respond to initial treatment, consisting of surgical resection and ≈6 cycles of platinum-based chemotherapy. However, disease recurrence occurs in most patients, and subsequent therapies become necessary. Historically, close monitoring following treatment (active surveillance) was the only available option, as continued maintenance chemotherapy treatment led to increased toxicity without providing any meaningful clinical benefit. Recently, targeted therapy with the angiogenesis inhibitor bevacizumab and the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib, niraparib, and rucaparib have demonstrated significant clinical benefits as maintenance treatment for recurrent disease. Despite consensus guidelines recommending their use, maintenance treatments are currently underutilized. Here, we review evidence from pivotal clinical trials of approved second-line maintenance treatments demonstrating efficacy in terms of progression-free survival and postprogression efficacy outcomes for patients with recurrent ovarian cancer. Adverse events frequently associated with bevacizumab include hypertension, proteinuria, and non-central nervous system bleeding, whereas PARP inhibitors are associated with nausea, vomiting, fatigue, and anemia. Patient-centered outcomes analyses show that PARP inhibitors provide significant benefits to patient health status, even when accounting for the toxicities associated with treatment. Many factors influence the selection of second-line maintenance treatment for patients with recurrent ovarian cancer, including the maintenance treatment received in the first-line setting. Overall, targeted maintenance treatment represents a new standard of care for patients with ovarian cancer, and we recommend that maintenance treatment should be offered to all eligible patients with recurrent ovarian cancer.     

Newly diagnosed ovarian cancer: Which first-line treatment?

Poly ADP -Ribose Polymerase (PARP) inhibitors (PARPi) were firstly licensed for maintenance treatment in recurrent, platinum-sensitive, platinum responsive epithelial ovarian cancer patients, harboring or not a BRCA mutation. Three new phase III trials – PAOLA1/ENGOT-OV25, PRIMA/ENGOT-OV26 and VELIA/GOG-3005 – showed that there is a role for PARPi also in first-line setting, as maintenance or in combination with platinum-based chemotherapy. Nevertheless the published trials raised several questions on what is the best treatment according to the molecular and clinical characteristics of the treated patients. This review focuses on the published data in order to inform clinician decision making on what could be the best sequence or combination of treatments for the three molecular defined cohorts of patients emerging in the first line trials (the carriers of a BRCA mutation (BRCAmut), those with a deficiency in homologous recombination system (HRd) and those with a proficient homologous recombination system (HRp)) and put the newly published data in the context of the ovarian cancer treatment landscape.     

Clinical presentation,diagnosis and management of therapy‐related hematological disorders in women with epithelial ovarian cancer treated with chemotherapy and poly‐ADP‐ribose polymerase inhibitors: A single‐center experience

We investigated the occurrence and management of therapy‐related hematological disorders (tr‐HDs) in women with epithelial ovarian cancer (EOC) exposed to poly‐ADP‐ribose polymerase inhibitors (PARPi), after previous chemotherapy. We analyzed 130 consecutive EOC patients treated with PARPi at the European Institute of Oncology, Milan. In line with the literature, overall survival of the entire population was 37% at 5.5 years (89% were advanced stages). Cell blood counts were collected prior to start PARPi, at each new cycle and at monthly intervals. Patients displaying persistent and/or marked hematological abnormalities underwent bone marrow evaluation, with cytogenetic and molecular analysis. Nine patients (6,9%) developed tr‐HDs, after a median 22.8 months of PARPi exposure. Two patients died early and could not be treated. Two patients have no indication for active treatment and are presently under close hematological monitoring. Five patients underwent chemotherapy followed, in three cases, by allogeneic hematopoietic transplantation: three patients are in complete remission of their hematological and gynecological malignancies at 13, 19, and 25 months; the remaining two patients died due to progression of their hematological disease. We show the potential risk of hematological disorders in EOC patients treated with chemotherapy and prolonged PARPi therapy. In our series, tr‐HDs incidence was higher compared to recent reports in large series. Our observations suggest careful monitoring in order to conclusively define, on large series and prolonged follow‐up, the actual risk of tr‐HDs in patients under PARPi. Notably, prompt diagnosis of hematological abnormalities and appropriate management allow achievement of remission from severe hematological complications, at least in most patients.     

PARP抑制剂应用后的卵巢癌三级预防

The tertiary prevention approaches of ovarian cancer include whole-person care, training of the patients to cooperate with physicians in the periods of treatment and follow-up, training program of the qualified surgeons, and recognition of biological behavior changes of relapse after PARPi therapy. Surgery remains the cornerstone in the management of ovarian cancer, but the role of surgery after PARPi remains unknown. Recently, the US FDA withdrew the indication of three PARP inhibitors in the treatment of recurrent ovarian cancer with ≥3 lines of chemotherapy because of their ≥30% increased death risk. Thus, we should pay more attention to the biological recurrence and chemoresistance caused by PARP inhibitors and post-progression survival in ovarian cancer. © 2023, CHINA RESEARCH ON PREVENTION AND TREATMENT. All rights reserved.     

What Is the Place of PARP Inhibitors in Ovarian Cancer Treatment?

Poly-ADP-ribose polymerase (PARP) inhibitors have been one of the most exciting developments in the treatment of ovarian cancer in recent years. Demonstration of anti-cancer activity has led to the European Medicines Agency (EMA) approval of the PARP inhibitor (PARPi) olaparib as maintenance therapy in women with BRCA-mutated (BRCAm) ovarian cancer with platinum-sensitive recurrence following response to platinum therapy and the US Food and Drug Administration (US FDA) approval of olaparib in relapsed germline BRCA-mutated (gBRCAm) ovarian cancer in women who have received at least three prior chemotherapy treatments, both occurring in 2014. Additional trials are underway or awaiting final analysis with olaparib, other PARPis, and PARPi combinations to further elucidate the activity of these drugs in various clinical settings. This review will focus on the current clinical experience and ongoing trials with PARPis in ovarian cancer.     

Use of poly ADP-ribose polymerase [PARP] inhibitors in cancer cells bearing DDR defects: the rationale for their inclusion in the clinic

Background

DNA damage response (DDR) defects imply genomic instability and favor tumor progression but make the cells vulnerable to the pharmacological inhibition of the DNA repairing enzymes. Targeting cellular proteins like PARPs, which cooperate and complement molecular defects of the DDR process, induces a specific lethality in DDR defective cancer cells and represents an anti-cancer strategy. Normal cells can tolerate the DNA damage generated by PARP inhibition because of an efficient homologous recombination mechanism (HR); in contrast, cancer cells with a deficient HR are unable to manage the DSBs and appear especially sensitive to the PARP inhibitors (PARPi) effects.

Main body

In this review we discuss the proof of concept for the use of PARPi in different cancer types and the success and failure of their inclusion in clinical trials.The PARP inhibitor Olaparib [AZD2281] has been approved by the FDA for use in pretreated ovarian cancer patients with defective BRCA1/2 genes, and by the EMEA for maintenance therapy in platinum sensitive ovarian cancer patients with defective BRCA1/2 genes. BRCA mutations are now recognised as the molecular targets for PARPi sensitivity in several tumors. However, it is noteworthy that the use of PARPi has shown its efficacy also in non-BRCA related tumors. Several trials are ongoing to test different PARPi in different cancer types. Here we review the concept of BRCAness and the functional loss of proteins involved in DDR/HR mechanisms in cancer, including additional molecules that can influence the cancer cells sensitivity to PARPi. Given the complexity of the existing crosstalk between different DNA repair pathways, it is likely that a single biomarker may not be sufficient to predict the benefit of PARP inhibitors therapies. Novel general assays able to predict the DDR/HR proficiency in cancer cells and the PARPi sensitivity represent a challenge for a personalized therapy.

Conclusions

PARP inhibition is a potentially important strategy for managing a significant subset of tumors. The discovery of both germline and somatic DNA repair deficiencies in different cancer patients, together with the development of new PARP inhibitors that can kill selectively cancer cells is a potent example of targeting therapy to molecularly defined tumor subtypes.

     

Incorporating Parp-inhibitors in Primary and Recurrent Ovarian Cancer: A Meta-analysis of 12 phase II/III randomized controlled trials

BackgroundThe second decade of 2000s is witnessing a new ovarian cancer (OC) paradigm shift thanks to the results recently obtained by a new class of targeted agents: the Poly(ADP-ribose)polymerase (PARP)-Inhibitors (PARPi). Aim of this meta-analysis is to analyze available results obtained with PARPi, administered alone or in combination with chemo- and/or target-therapies in terms of efficacy and safety for the treatment of recurrent and primary advanced OC.MethodsOn December 2019, all published phase II/III randomized clinical studies were systematically searched using the terms “[Parp-Inhibitor] AND [ovar*]”. Twelve phase II/III randomized controlled trials were identified, with a total number of 5171 patients included.ResultsResults demonstrated that PARPi account for a significant improvement of PFS in both recurrent and primary OC setting, independently from their administration schedule and independently from patients’ BRCA mutational status. Moreover, patients harboring a Homologous Recombination Deficiency (HRD) positive testing primary or recurrent OC progress significantly later after PARPi administration/association. Results also reported that PARPi increase the occurrence of severe (G3-G4) anemia. Furthermore, severe fatigue occurred more frequently among patients subjected to PARPi combined with chemotherapy and to PARPi plus Bevacizumab. Finally, a significant increase in severe high blood pressure occurrence was observed when PARPi was added to antiangiogenetics, compared to PARPi alone but a significant decrease in G3-G4 hypertension occurrence was found in PARPi plus bevacizumab users compared to Bevacizumab alone.ConclusionsPARPi are a valid option for the treatment of both primary and relapsed OC patients, with a relative low incidence of severe side effects.     

Phase II study of single-agent gemcitabine in heavily pretreated Japanese patients with recurrent ovarian cancer

BACKGROUND: Gemcitabine has been recommended as an active agent for salvage chemotherapy in patients with recurrent epithelial ovarian cancer, but no clinical study of this agent has been conducted for Japanese women with ovarian cancer. To evaluate the efficacy and feasibility of gemcitabine for heavily pretreated Japanese patients with recurrent epithelial ovarian cancer, we conducted a single-institute phase II clinical trial. METHODS: All patients had received a minimum of two previous chemotherapy regimens, In this study, gemcitabine was administered at 1000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. RESULTS: A total of 28 patients participated in this study. Although 5 patients (17.9%) needed dose reduction to 800 mg/m(2) because of thrombocytopenia and granulocytopenia, all patients completed an average of 6.7 courses (range, 2-24 courses). The overall response rate, including five partial responses, was 17.9% (95% confidence interval [C I], 6.0-36.9). The median time to progression was 8.8 months and the median survival period was 11.2 months. Grade 3/4 hematological toxicities included leucopenia, 35.7%; granulocytopenia, 39.3%; anemia, 46.4%; and thrombocytopenia, 10.7%. However, no grade 3/4 nonhematological toxicity was observed. The mean delay in treatment was 5.0 +/- 7.7 days (range, 0-15 days) in a total of 562 cycles. CONCLUSION: Single-agent gemcitabine is an effective salvage chemotherapy regimen in heavily pretreated Japanese patients with recurrent epithelial ovarian cancer.