Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2
Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2
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DOI：
10.1200/jco.21.00003
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发表时间：
2021-08-01
影响因子：
45.3
通讯作者：
Domchek, Susan M.
中科院分区：
文献类型：
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作者：
Reiss, Kim A.;Mick, Rosemarie;Domchek, Susan M.
目的聚(ADP-核糖)聚合酶(PARPI)抑制剂奥拉帕利被批准用于晚期胰腺癌(PC)和BRCA1或BRCA2致病变种(PV)患者的维持治疗。这项由研究者发起的单臂II期研究评估了PARPI rucaparib在BRCA1、BRCA2或PALB2的生殖系或体细胞PV晚期PC的维持治疗中的作用。患者和方法符合条件的患者有BRCA1、BRCA2或PALB2中的晚期PC、种系(G)或体细胞(S)PV，并接受了至少16周的以铂为基础的化疗，没有发现铂耐药的证据。化疗停止，患者接受鲁卡帕利600 mg，每天两次口服，直到病情进展。主要终点是6个月时的无进展生存率(PFS)(PFS6)。次要终点包括安全性、ORR、疾病控制率、反应持续时间和总存活率。结果46例入选患者中，42例可评价(27例gBRCA2，7例gBRCA1，6例gPALB2，2例sBRCA2)。中位PFS为13.1个月(95%CI，4.4~21.8)，中位总生存期为23.5个月(95%CI，20~27)。12个月时PFS为54.8%。36例可测量疾病的ORR为41.7%(完全缓解3例，部分缓解12例，95%可信区间为25.5~59.2)，疾病控制率为66.7%(95%可信区间为49.0~81.4)。中位有效时间为17.3个月(95%可信区间为8.8~25.8)。GBRCA2(41%，11/27)、gPALB2(50%，3/6)和sBRCA2(50%，1/2)患者发生了反应。没有注意到新的安全信号。结论维持性Rucaparib是治疗BRCA1、BRCA2或PALB2中出现PV的铂类药物敏感的晚期PC的一种安全有效的治疗方法。在gPALB2和sBRCA2 PV患者中的有效性的发现扩大了PARPI可能受益于gBRCA1/2 PV携带者的人群。
PURPOSE Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved as maintenance therapy for patients with advanced pancreatic cancer (PC) and a germline BRCA1 or BRCA2 pathogenic variant (PV). This investigator-initiated, single-arm phase II study assessed the role of the PARPi rucaparib as maintenance therapy in advanced PC with germline or somatic PV in BRCA1, BRCA2, or PALB2. PATIENTS AND METHODS Eligible patients had advanced PC; germline (g) or somatic (s) PVs in BRCA1, BRCA2, or PALB2, and received at least 16 weeks of platinum-based chemotherapy without evidence of platinum resistance. Chemotherapy was discontinued and patients received rucaparib 600 mg orally twice a day until progression. The primary end point was the progression-free survival (PFS) rate at 6 months (PFS6). Secondary end points included safety, ORR, disease control rate, duration of response, and overall survival. RESULTS Of 46 enrolled patients, 42 were evaluable (27 gBRCA2, seven gBRCA1, six gPALB2, and two sBRCA2). PFS6 was 59.5% (95% CI, 44.6 to 74.4), median PFS was 13.1 months (95% CI, 4.4 to 21.8), and median overall survival was 23.5 months (95% CI, 20 to 27). The PFS at 12 months was 54.8%. ORR of the 36 patients with measurable disease was 41.7% (3 complete responses; 12 partial responses; 95% CI, 25.5 to 59.2), and disease control rate was 66.7% (95% CI, 49.0 to 81.4). Median duration of response was 17.3 months (95% CI, 8.8 to 25.8). Responses occurred in patients with gBRCA2 (41%, 11 out of 27), gPALB2 (50%, 3 out of 6), and sBRCA2 (50%, 1 out of 2). No new safety signals were noted. CONCLUSION Maintenance rucaparib is a safe and effective therapy for platinum-sensitive, advanced PC with a PV in BRCA1, BRCA2, or PALB2. The finding of efficacy in patients with gPALB2 and sBRCA2 PVs expands the population likely to benefit from PARPi beyond gBRCA1/2 PV carriers.