Palbociclib Combined with Fulvestrant in Premenopausal Women with Advanced Breast Cancer and Prior Progression on Endocrine Therapy: PALOMAa??3 Results

摘要

Background. The efficacy and safety of palbociclib, a cyclina??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 endocrinea??refractory women a?￥18 years with hormone receptora??positive (HR+)/human epidermal growth factor receptor 2a??negative (HER2a??) ABC were among 521 women randomized 2:1 (347:174) to fulvestrant (500 mg)a???±a??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 progressiona??free survival (PFS) improvement extended to premenopausal women. Potential druga??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 (na??=a??72) versus placebo arm (na??=a??36) was 9.5 versus 5.6 months, respectively (hazard ratio, 0.50, 95% confidence interval: 0.29a??0.87), and consistent with the significant PFS improvement in the same arms for postmenopausal women. Anya??grade and grade a?¤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 wella??tolerated treatment for premenopausal women with prior endocrinea??resistant HR+/HER2a?? 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. PALOMAa??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 endocrinea??resistant setting. In pretreated premenopausal women with hormone receptora??positive advanced breast cancer, palbociclib plus fulvestrant and goserelin (luteinizing hormonea??releasing hormone [LHRH] agonist) treatment almost doubled median progressiona??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 agonista??induced ovarian suppression. The significant PFS gain and tolerable safety profile strongly support use of this regimen in premenopausal women with endocrinea??resistant disease who could possibly delay chemotherapy.