ArticlesFulvestrant 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
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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These authors contributed equally