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

Abstract

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.

Keywords: Breast cancer; Fulvestrant; Goserelin; Neoplasm metastasis; Palbociclib; Premenopausal.

Figure 1.

Investigator‐assessed PFS by treatment for the intent‐to‐treat subpopulations of premenopausal women (A), premenopausal women age ≤50 years (B), and postmenopausal women age ≤50 years (C). PFS was defined as the time from the date of randomization to the date or the first documentation of objective progression of disease or death due to any cause in the absence of documented progressive disease, whichever occurred first. PFS data were censored on the date of the last tumor assessment on study for patients who did not have objective tumor progression and who did not die while on study. CI was calculated based on the Brookmeyer and Crowley method [25]. Abbreviations: CI, confidence interval; NE, not estimable; PFS, progression‐free survival.

Figure 2.

Investigator‐assessed confirmed objective response and clinical benefit rate in premenopausal women. ^aOne‐sided exact test stratified by the presence of visceral metastases and sensitivity to prior hormonal therapy per randomization. ^bCBR was CR or PR or stable disease ≥24 weeks. ^cCI was calculated using the exact (Clopper‐Pearson) method [26]. Abbreviations: CBR, clinical benefit response; CI, confidence interval; CR, complete response; OR, odds ratio; ORR, objective response rate; PR, partial response; SD, stable disease ≥24 week.

Figure 3.

Biochemical plasma analyses for premenopausal women on day 15 for LH (A), FSH (B), and E2 (C). ^aSix patients had E2 concentrations that were not considered valid (i.e., below the quantification limit of 1.25 pg/mL or a volume too small for reanalysis). Abbreviations: CI, confidence interval; E2, estradiol; FSH, follicle‐stimulating hormone; IQR, interquartile range; LH, luteinizing hormone; max, maximum; min, minimum.