Predictors of prolonged benefit from palbociclib plus fulvestrant in women with endocrine-resistant hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer in PALOMA-3

Abstract

Background: The addition of palbociclib to fulvestrant improved clinical outcomes over placebo-fulvestrant in endocrine-pretreated metastatic breast cancer (MBC) patients in PALOMA-3. Here, we examined factors predictive of long-term benefit. Methods: Premenopausal-peri/postmenopausal patients with endocrine-resistant, hormone receptorepositive (HRþ)/human epidermal growth factor receptor 2enegative MBC were randomised 2:1 to fulvestrant (500 mg) and either palbociclib (125 mg/d; 3/1 schedule; n Z 347) or placebo (n Z 174). Baseline characteristics, mutation status and HR expression levels were compared in patients with and without prolonged benefit (treatment duration !18 months). Results: By August 2016, 100 patients (29%) on palbociclib-fulvestrant and 26 (15%) on placebo-fulvestrant demonstrated prolonged benefit, with long-term responders in both arms sharing common clinical characteristics. They usually had less disease burden at baseline versus those treated <18 months, such as having one disease site (40% vs 29% on palbociclib-fulvestrant and 69% vs 29% on placebo-fulvestrant), bone-only disease (32% vs 22% and 46% vs 17%) and were less heavily pretreated (69% vs 56% and 73% vs 60% had 2 prior therapies). Baseline tumour ESR1 and PIK3CA mutation rates were lower among long-term responders in both arms; median oestrogen receptor H-scores were similar, whereas progesterone receptor H-scores were higher among long-term responders. Conclusions: This exploratory analysis demonstrates that some patients with endocrineresistant MBC derive significant and prolonged benefit when treated with palbociclibfulvestrant, with fewer patients experiencing similar efficacy with placebo-fulvestrant. The current analysis did not identify specific molecular or clinical factors prognostic of long-term benefit with palbociclib-fulvestrant (ClinicalTrials.gov, NCT01942135).

Clinical implications of prospective genomic profiling of metastatic breast cancer patients

“…3, where the primary samples were collected post-endocrine therapy and had already developed an ESR1 alteration. ESR1 mutations arise due to prolonged treatment with tamoxifen and aromatase inhibitors; however, retrospective analysis of the PALOMA-2 and PALOMA-3 studies found that patients treated with a selective oestrogen degrader either alone or in combination with CDK4/6 inhibitors also showed development of ESR1 mutations [37][38][39]. As expected, TP53 alterations were the most prevalent across all samples.…”

The Emerging Role of ESR1 Mutations in Luminal Breast Cancer as a Prognostic and Predictive Biomarker of Response to Endocrine Therapy

“…Additionally, patients with ESR1 mutations treated with the combination had a better outcome than patients with ESR1 mutations receiving fulvestant monotherapy, suggesting that mutational status had a prognostic but not predictive value. In further support of their prognostic role, baseline tumor ESR1 mutation rates were found to be lower among long-term responders in both PALOMA-3 trial arms [55]. A recent analysis of plasma samples collected at baseline, cycle 1 day 15, and at the end of treatment (EOT) from patients recruited to PALOMA-3 showed that ESR1 mutations had a greater suppression by fulvestrant plus placebo compared to PIK3CA mutations but does not predict improvement in PFS on fulvestrant [56].…”

Ki67 and PR in Patients Treated with CDK4/6 Inhibitors: A Real-World Experience

“…A high PR expression was associated with prolonged benefit in patients receiving either palbociclib plus fulvestrant or placebo plus fulvestrant in the Paloma-3 trial, independently of the treatment arm [ 25 ]. Furthermore, a recent review and meta-analysis by Ramos-Esquivel et al [ 26 ] showed that the addition of CDK4/6i significantly improved PFS, overall response rate and clinical benefit regardless of age, performance status, and disease setting but not race.…”