Elsevier

The Lancet Oncology

Volume 17, Issue 4, April 2016, Pages 425-439
The Lancet Oncology

Articles
Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial

https://doi.org/10.1016/S1470-2045(15)00613-0Get rights and content

Summary

Background

In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses.

Methods

In this multicentre, double-blind, randomised phase 3 study, women aged 18 years or older with hormone-receptor-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy were stratified by sensitivity to previous hormonal therapy, menopausal status, and presence of visceral metastasis at 144 centres in 17 countries. Eligible patients—ie, any menopausal status, Eastern Cooperative Oncology Group performance status 0–1, measurable disease or bone disease only, and disease relapse or progression after previous endocrine therapy for advanced disease during treatment or within 12 months of completion of adjuvant therapy—were randomly assigned (2:1) via a centralised interactive web-based and voice-based randomisation system to receive oral palbociclib (125 mg daily for 3 weeks followed by a week off over 28-day cycles) plus 500 mg fulvestrant (intramuscular injection on days 1 and 15 of cycle 1; then on day 1 of subsequent 28-day cycles) or placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival. Analysis was by intention to treat. We also assessed endocrine therapy resistance by clinical parameters, quantitative hormone-receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline. This study is registered with ClinicalTrials.gov, NCT01942135.

Findings

Between Oct 7, 2013, and Aug 26, 2014, 521 patients were randomly assigned, 347 to fulvestrant plus palbociclib and 174 to fulvestrant plus placebo. Study enrolment is closed and overall survival follow-up is in progress. By March 16, 2015, 259 progression-free-survival events had occurred (145 in the fulvestrant plus palbociclib group and 114 in the fulvestrant plus placebo group); median follow-up was 8·9 months (IQR 8·7–9·2). Median progression-free survival was 9·5 months (95% CI 9·2–11·0) in the fulvestrant plus palbociclib group and 4·6 months (3·5–5·6) in the fulvestrant plus placebo group (hazard ratio 0·46, 95% CI 0·36–0·59, p<0·0001). Grade 3 or 4 adverse events occurred in 251 (73%) of 345 patients in the fulvestrant plus palbociclib group and 38 (22%) of 172 patients in the fulvestrant plus placebo group. The most common grade 3 or 4 adverse events were neutropenia (223 [65%] in the fulvestrant plus palbociclib group and one [1%] in the fulvestrant plus placebo group), anaemia (ten [3%] and three [2%]), and leucopenia (95 [28%] and two [1%]). Serious adverse events (all causalities) occurred in 44 patients (13%) of 345 in the fulvestrant plus palbociclib group and 30 (17%) of 172 patients in the fulvestrant plus placebo group. PIK3CA mutation was detected in the plasma DNA of 129 (33%) of 395 patients for whom these data were available. Neither PIK3CA status nor hormone-receptor expression level significantly affected treatment response.

Interpretation

Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo, irrespective of the degree of endocrine resistance, hormone-receptor expression level, and PIK3CA mutational status. The combination could be considered as a therapeutic option for patients with recurrent hormone-receptor-positive, HER2-negative metastatic breast cancer that has progressed on previous endocrine therapy.

Funding

Pfizer.

Introduction

Management of resistance to endocrine therapy is among the most challenging aspects of breast cancer treatment and an active topic of research.1 Several publications2, 3 have postulated that responsiveness to endocrine therapy might be associated with oestrogen-receptor expression levels in hormonal-receptor-positive breast cancer. Studies4, 5, 6 of resistance to hormonal therapies and oestrogen-receptor biology have shown the fundamental role of signalling-pathway crosstalk with different oestrogen receptors and acquisition of oestrogen-receptor mutations in mediating resistance. Preclinical models also suggest that adaptive upregulation of growth-factor signalling is associated with acquired and de-novo resistance to endocrine therapies.7, 8 For example, the PI3K/AKT/mTOR pathway interacts directly and indirectly with oestrogen receptors, and activation of this pathway through mutations of PIK3CA (the most common potentially targetable mutation in oestrogen-receptor-positive breast cancer) or AKT confers resistance to selective oestrogen-receptor modulators and oestrogen-receptor degraders such as fulvestrant.9 Mutations in PIK3CA, the α-catalytic subunit of PI3 kinase, are a common genetic event in oestrogen-receptor-positive breast cancer.10 However, the clinical implications of modulation of this pathway by combining PI3K inhibitors with oestrogen receptor modulators or degraders, particularly fulvestrant, are still unclear, and many studies are underway.

Activation of the CDK4/CDK6/E2F axis is a common feature of luminal oestrogen-receptor-positive breast cancer. Hormonal therapies function partly through suppression of CDK4 and CDK6 activity, and reactivation of these kinases has been implicated in endocrine resistance.11 Studies12, 13, 14 have shown that endocrine-treatment-naive and endocrine-resistant preclinical luminal breast cancer cell lines are sensitive to both direct inhibition of CDK4 and CDK6 and show synergy when combined with hormonal therapy. In cell lines, the combination of CDK4 and CDK6 inhibition with fulvestrant resulted in decreased phosphorylation of the retinoblastoma tumour suppressor protein, leading to durable cell-cycle arrest and increased markers of cellular senescence, supporting the clinical investigation of this combination.12, 13, 14, 15

Palbociclib is an orally bioavailable selective inhibitor of CDK4 and CDK6 that prevents DNA synthesis by blocking progression of the cell cycle from G1 to S phase.16, 17 It is an efficacious first-line treatment for postmenopausal metastatic breast cancer.18 The interim results of the phase 3 trial (PALOMA-3),19 showed improved progression-free survival for women with metastatic breast cancer who were treated with fulvestrant and palbociclib (compared with fulvestrant and placebo) irrespective of menopausal status and line of therapy, (hazard ratio [HR] 0·42, 95% CI 0·32–0·56; p<0·001). Here we report the final results of this trial, with extended follow-up, in addition to various aspects of endocrine resistance and the effect of plasma PIK3CA mutational status by circulating free DNA (cfDNA) on treatment in these patients.

Section snippets

Study design and participants

PALOMA-319 is a prospective, randomised, double-blind, placebo-controlled phase 3 trial done in 144 centres in 17 countries (appendix p 1). It was a trial of fulvestrant with or without palbociclib plus or minus goserelin (a requirement for premenopausal or perimenopausal participants) in women with hormone-receptor-positive, HER2-negative metastatic breast cancer whose disease had progressed after previous endocrine therapy. All eligible patients had confirmed hormone-receptor-positive,

Results

Between Oct 7, 2013, and Aug 26, 2014, 521 patients were enrolled and randomly assigned to either fulvestrant and palbociclib (n=347) or fulvestrant and placebo (n=174; figure 1). Study enrolment is closed and overall survival follow-up is in progress. Baseline characteristics of the intention-to-treat population did not differ substantially between groups (table 1). 347 patients (67%) had metastasis to two or more sites, and 406 (78%) had measurable disease. In the palbociclib group, a larger

Discussion

In our study, progression-free survival improved significantly in patients with hormone-receptor-positive, HER2-negative metastatic breast cancer whose disease had progressed on previous endocrine therapy who received fulvestrant plus palbociclib compared with those who received fulvestrant plus placebo in the overall population and in most subgroups. Our findings confirm the important observation that endocrine monotherapy has limited efficacy in patients with disease progression after

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