Background: The efficacy and safety of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, combined with fulvestrant and goserelin was assessed in premenopausal women with advanced breast cancer (ABC) who had progressed on prior endocrine therapy (ET).
Patients and methods: One hundred eight premenopausal endocrine-refractory women ≥18 years with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) ABC were among 521 women randomized 2:1 (347:174) to fulvestrant (500 mg) ± goserelin with either palbociclib (125 mg/day orally, 3 weeks on, 1 week off) or placebo. This analysis assessed whether the overall tolerable safety profile and significant progression-free survival (PFS) improvement extended to premenopausal women. Potential drug-drug interactions (DDIs) and ovarian suppression with goserelin were assessed via plasma pharmacokinetics and biochemical analyses, respectively. (ClinicalTrials.gov identifier: NCT01942135) RESULTS: Median PFS for premenopausal women in the palbociclib (n = 72) versus placebo arm (n = 36) was 9.5 versus 5.6 months, respectively (hazard ratio, 0.50, 95% confidence interval: 0.29-0.87), and consistent with the significant PFS improvement in the same arms for postmenopausal women. Any-grade and grade ≤3 neutropenia, leukopenia, and infections were among the most frequent adverse events reported in the palbociclib arm with concurrent goserelin administration. Hormone concentrations were similar between treatment arms and confirmed sustained ovarian suppression. Clinically relevant DDIs were not observed.
Conclusion: Palbociclib combined with fulvestrant and goserelin was an effective and well-tolerated treatment for premenopausal women with prior endocrine-resistant HR+/HER2- ABC. Inclusion of both premenopausal and postmenopausal women in pivotal combination ET trials facilitates access to novel drugs for young women and should be considered as a new standard for clinical trial design.
Implications for practice: PALOMA-3, the first registrational study to include premenopausal women in a trial investigating a CDK4/6 inhibitor combined with endocrine therapy, has the largest premenopausal cohort reported in an endocrine-resistant setting. In pretreated premenopausal women with hormone receptor-positive advanced breast cancer, palbociclib plus fulvestrant and goserelin (luteinizing hormone-releasing hormone [LHRH] agonist) treatment almost doubled median progression-free survival (PFS) and significantly increased the objective response rate versus endocrine monotherapy, achieving results comparable to those reported for chemotherapy without apparently interfering with LHRH agonist-induced ovarian suppression. The significant PFS gain and tolerable safety profile strongly support use of this regimen in premenopausal women with endocrine-resistant disease who could possibly delay chemotherapy.
患者和方法. 将521名女性按2:1（347:174）的比例随机分入氟维司群（500 mg）±戈舍瑞林联合palbociclib（125 mg/天, 口服给药三周, 停药一周）或安慰剂组, 其中包含108名年龄≥18岁、内分泌治疗无效、激素受体阳性（HR+）/人表皮生长因子受体2阴性（HER2−）ABC的绝经前女性。研究评估了在绝经前女性中该药物是否也具有总体良好（可耐受）的安全性特征以及患者的无进展生存期（PFS）是否也能得到显著改善。分别通过血浆药代动力学和生化分析评估了潜在药物相互作用（DDI）和戈舍瑞林对卵巢功能的抑制作用。（
结果. Palbociclib组（n = 72）与安慰剂组（n = 36）中绝经前女性的中位PFS分别为9.5和5.6个月（风险比：0.50；95%置信区间：0.29–0.87）, 与同一组中绝经后女性在PFS方面获得的显著改善一致。Palbociclib与戈舍瑞林联合给药组中最常报告的不良事件为任何级别与≤3级的中性粒细胞减少症、白细胞减少症以及感染。各治疗组间的激素浓度相似, 证实卵巢功能持续受到抑制。未观察到有临床意义的DDI。
结论. Palbociclib联合氟维司群与戈舍瑞林治疗既往内分泌治疗无效的HR+/HER2− ABC绝经前女性有效且可良好耐受。在关键ET联合给药试验中纳入绝经前和绝经后女性有助于发现用于治疗年轻女性的新药, 应被视为临床试验设计的新标准。
Keywords: Breast cancer; Fulvestrant; Goserelin; Neoplasm metastasis; Palbociclib; Premenopausal.
© AlphaMed Press 2017.