背景:转移性去势抵抗性前列腺癌(mCRPC)仍然是一个尚未解决的医学挑战。大约20-25%的mCRPC患者在同源重组修复(HRR)途径基因中具有有害的种系或体细胞突变,参与双链DNA损伤的修复。这些突变中有一半是种系,而其余的完全是躯体。而聚ADP核糖聚合酶(PARP)抑制剂,比如奥拉帕尼和鲁卡帕尼布,在这个亚组中有效,由于相关的高成本,它们的广泛使用受到限制,尤其是在资源受限的环境中。值得注意的是,铂制剂如卡铂对DNA修复机制有缺陷的细胞有极好的敏感性;这种机制被称为合成致死性。卡铂,传统的,廉价的化疗剂,为此类患者提供了潜在的替代疗法。几个回顾性小病例系列支持这一假设。然而,目前尚无卡铂治疗HRR突变mCRPC患者的前瞻性临床试验.
目的:主要目的是评估每周三次卡铂治疗对mCRPC患者的客观反应率,这些患者在HRR通路基因中具有有害突变,并且先前使用过紫杉烷和/或新型抗雄激素药物治疗。次要目标包括无进展生存期,与健康相关的生活质量,卡铂的安全性。
方法:被诊断患有mCRPC的患者,其HRR通路突变先前曾接受多西他赛或新型抗雄激素药物(阿比特龙,恩扎鲁他胺,阿帕鲁胺,或达洛鲁胺)或两者都有资格。将测试直接或间接参与HRR途径的基因。在这项单臂第二阶段研究中,我们将筛选大约200名患者,招募49名患者,每三周施用卡铂(曲线下面积=5的给药),直至进展或不能容忍的副作用。主要终点将被评估为来自登记的血清PSA降低超过50%的患者的比例。次要结果包括无进展生存期-软组织疾病进展[根据实体瘤的反应标准评估,版本1.1]和使用前列腺癌临床试验工作组3标准的骨病变进展),使用癌症治疗的功能评估-前列腺问卷和欧洲癌症研究和治疗组织问卷以及卡铂的安全性(NCICTCAE5.0版)评估卡铂治疗期间与健康相关的生活质量。
结果:该试验于2023年9月开始注册。这个审判正在进行中,迄今为止,已经招募了12名患者,所有49名参与者都将按照计划进行招募.
结论:这项前瞻性II期试验代表了解决HRR通路突变mCRPC患者治疗缺口的关键一步,特别是在获得PARP抑制剂有限的人口区域。这项研究的结果将为临床实践提供信息,并指导未来的III期随机试验。最终改善全球患者的预后。
背景:印度临床试验注册(CTRI/2023/04/051507)。
BACKGROUND: Approximately 20%-25% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor a deleterious germline or somatic mutation in the homologous recombination repair (HRR) pathway genes, which is involved in the repair of double-stranded DNA damage. Half of these mutations are germline, while the remaining are exclusively somatic. While polyadenosine 5\'diphosphoribose [poly (ADP-ribose)] polymerase inhibitors, such as olaparib and rucaparib, are effective in this subgroup, their widespread use is limited due to the associated high cost, especially in resource-constrained settings. Notably, platinum agents like carboplatin have exquisite sensitivity to cells with defective DNA repair machinery. Carboplatin, a conventional, inexpensive chemotherapeutic agent, offers a potential alternative treatment in such patients. Several retrospective small case series support this hypothesis. However, there are no prospective clinical trials of carboplatin in patients with mCRPC with HRR mutations.
OBJECTIVE: The primary objective is to assess the objective response rate of 3 weekly carboplatin treatments in patients with mCRPC harboring deleterious mutations in the HRR pathway genes and previously treated with a taxane or a novel antiandrogen agent. The secondary objectives include progression-free survival, health-related quality of life, and safety profile of carboplatin.
METHODS: Patients diagnosed with mCRPC harboring HRR pathway mutations previously treated with docetaxel or novel antiandrogen agents (abiraterone, enzalutamide, apalutamide, or darolutamide) or both will be eligible. Genes involved directly or indirectly in the HRR pathway will be tested. In this single-arm phase II study, we will screen approximately 200 patients to enroll 49 patients, and carboplatin (dosing at the area under curve=5) will be administered every 3 weeks until progression or intolerable side effects. The primary end point will be assessed as the proportion of patients with a reduction of serum prostate-specific antigen by more than 50% from enrollment. Secondary outcomes include progression-free survival-soft-tissue disease progression (by response evaluation criteria in solid tumors, version 1.1, and bone lesion progression using Prostate Cancer Clinical Trials Working Group 3 criteria), health-related quality of life during carboplatin treatment using the Functional Assessment of Cancer Therapy-Prostate questionnaire and the European Organisation for Research and Treatment of Cancer questionnaire and safety profile of carboplatin (National Cancer Institute\'s Common Terminology Criteria for Adverse Events version 5.0).
RESULTS: The trial started enrollment in September 2023. This trial is ongoing, and 12 patients have been recruited to date. All 49 participants will be enrolled according to plan.
CONCLUSIONS: This prospective phase II trial represents a critical step toward addressing the therapeutic gap in patients with mCRPC harboring HRR pathway mutations, particularly in demographic regions with limited access to poly (ADP-ribose) polymerase inhibitors. Outcomes from this study will inform clinical practice and guide future phase III randomized trials, ultimately improving patient outcomes globally.
BACKGROUND: Clinical Trials Registry of India CTRI/2023/04/051507; https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=Njc0NjU=&Enc=&userName=.
UNASSIGNED: DERR1-10.2196/54086.