BACKGROUND: Inhibition of phosphatidylinositol 3-kinase (PI3K) is a promising approach to overcome resistance to endocrine therapy in breast cancer. Pictilisib is an oral inhibitor of multiple PI3K isoforms. The aim of this study is to establish if addition of pictilisib to fulvestrant can improve progression-free survival in oestrogen receptor-positive, endocrine-resistant breast cancer. METHODS: In this two-part, randomised, double-blind, placebo-controlled, phase 2 study, we recruited postmenopausal women aged 18 years or older with oestrogen receptor-positive, HER2-negative breast cancer resistant to treatment with an aromatase inhibitor in the adjuvant or metastatic setting, from 123 medical centres across 21 countries. Part 1 included patients with or without PIK3CA mutations, whereas part 2 included only patients with PIK3CA mutations. Patients were randomly allocated (1:1 in part 1 and 2:1 in part 2) via a computer-generated hierarchical randomisation algorithm to daily oral pictilisib (340 mg in part 1 and 260 mg in part 2) or placebo starting on day 15 of cycle 1, plus intramuscular fulvestrant 500 mg on day 1 and day 15 of cycle 1 and day 1 of subsequent cycles in both groups. In part 1, we stratified patients by presence or absence of PIK3CA mutation, primary or secondary aromatase inhibitor resistance, and measurable or non-measurable disease. In part 2, we stratified patients by previous aromatase inhibitor treatment for advanced or metastatic disease or relapse during or within 6 months of an aromatase inhibitor treatment in the adjuvant setting and measurable or non-measurable disease. All patients and those administering treatment and assessing outcomes were masked to treatment assignment. The primary endpoint was progression-free survival in the intention-to-treat population for both parts 1 and 2 and also separately in patients with PIK3CA-mutated tumours in part 1. Tumour assessment (physical examination and imaging scans) was investigator-assessed and done at screening and after 8 weeks, 16 weeks, 24 weeks, and 32 weeks of treatment from day 1 of cycle 1 and every 12 weeks thereafter. We assessed safety in as-treated patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT01437566. FINDINGS: In part 1, between Sept 27, 2011, and Jan 11, 2013, we randomly allocated 168 patients to the pictilisib (89 [53%]) or placebo (79 [47%]) group. In part 2, between March 18, 2013, and Jan 2, 2014, we randomly allocated 61 patients to the pictilisib (41 [67%]) or placebo (20 [33%]) group. In part 1, we found no difference in median progression-free survival between the pictilisib (6·6 months [95% CI 3·9-9·8]) and placebo (5·1 months [3·6-7·3]) group (hazard ratio [HR] 0·74 [95% CI 0·52-1·06]; p=0·096). We also found no difference when patients were analysed according to presence (pictilisib 6·5 months [95% CI 3·7-9·8] vs placebo 5·1 months [2·6-10·4]; HR 0·73 [95% CI 0·42-1·28]; p=0·268) or absence (5·8 months [3·6-11·1] vs 3·6 months [2·8-7·3]; HR 0·72 [0·42-1·23]; p=0·23) of PIK3CA mutation. In part 2, we also found no difference in progression-free survival between groups (5·4 months [95% CI 3·8-8·3] vs 10·0 months [3·6-13·0]; HR 1·07 [95% CI 0·53-2·18]; p=0·84). In part 1, grade 3 or worse adverse events occurred in 54 (61%) of 89 patients in the pictilisib group and 22 (28%) of 79 in the placebo group. 19 serious adverse events related to pictilisib treatment were reported in 14 (16%) of 89 patients. Only one (1%) of 79 patients reported treatment-related serious adverse events in the placebo group. In part 2, grade 3 or worse adverse events occurred in 15 (36%) of 42 patients in the pictilisib group and seven (37%) of 19 patients in the placebo group. Four serious adverse events related to pictilisib treatment were reported in two (5%) of 42 patients. One treatment-related serious adverse event occurred in one (5%) of 19 patients in the placebo group. INTERPRETATION: Although addition of pictilisib to fulvestrant did not significantly improve progression-free survival, dosing of pictilisib was limited by toxicity, potentially limiting its efficacy. For future assessment of PI3K inhibition as an approach to overcome resistance to hormonal therapy, inhibitors with greater selectivity than that of pictilisib might be needed to improve tolerability and potentially increase efficacy. No further investigation of pictilisib in this setting is ongoing. FUNDING: F Hoffmann-La Roche.

• MeSH
• antagonisté estrogenového receptoru terapeutické užití   MeSH
• chemorezistence účinky léků   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• estradiol analogy a deriváty   terapeutické užití   MeSH
• fulvestrant MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   metabolismus   patologie   MeSH
• míra přežití MeSH
• nádorové biomarkery metabolismus   MeSH
• nádory prsu farmakoterapie   metabolismus   patologie   MeSH
• následné studie MeSH
• prognóza MeSH
• receptor erbB-2 metabolismus   MeSH
• receptory pro estrogeny antagonisté a inhibitory   metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• záchranná terapie * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antagonisté estrogenového receptoru MeSH
• estradiol MeSH
• fulvestrant MeSH
• nádorové biomarkery MeSH
• receptor erbB-2 MeSH
• receptory pro estrogeny MeSH

PURPOSE: To compare overall survival (OS) for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for advanced breast cancer. PATIENTS AND METHODS: The Fulvestrant First-Line Study Comparing Endocrine Treatments (FIRST) was a phase II, randomized, open-label, multicenter trial. Postmenopausal women with estrogen receptor-positive, locally advanced/metastatic breast cancer who had no previous therapy for advanced disease received either fulvestrant 500 mg (days 0, 14, 28, and every 28 days thereafter) or anastrozole 1 mg (daily). The primary end point (clinical benefit rate [72.5% and 67.0%]) and a follow-up analysis (median time to progression [23.4 months and 13.1 months]) have been reported previously for fulvestrant 500 mg and anastrozole, respectively. Subsequently, the protocol was amended to assess OS by unadjusted log-rank test after approximately 65% of patients had died. Treatment effect on OS across several subgroups was examined. Tolerability was evaluated by adverse event monitoring. RESULTS: In total, 205 patients were randomly assigned (fulvestrant 500 mg, n = 102; anastrozole, n = 103). At data cutoff, 61.8% (fulvestrant 500 mg, n = 63) and 71.8% (anastrozole, n = 74) had died. The hazard ratio (95% CI) for OS with fulvestrant 500 mg versus anastrozole was 0.70 (0.50 to 0.98; P = .04; median OS, 54.1 months v 48.4 months). Treatment effects seemed generally consistent across the subgroups analyzed. No new safety issues were observed. CONCLUSION: There are several limitations of this OS analysis, including that it was not planned in the original protocol but instead was added after time-to-progression results were analyzed, and that not all patients participated in additional OS follow-up. However, the present results suggest fulvestrant 500 mg extends OS versus anastrozole. This finding now awaits prospective confirmation in the larger phase III FALCON (Fulvestrant and Anastrozole Compared in Hormonal Therapy Naïve Advanced Breast Cancer) trial (ClinicalTrials.gov identifier: NCT01602380).

• MeSH
• anastrozol MeSH
• antagonisté estrogenového receptoru aplikace a dávkování   MeSH
• dospělí MeSH
• estradiol aplikace a dávkování   analogy a deriváty   MeSH
• fulvestrant MeSH
• hormonální protinádorové látky aplikace a dávkování   MeSH
• inhibitory aromatasy aplikace a dávkování   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu farmakoterapie   patologie   MeSH
• nitrily aplikace a dávkování   MeSH
• přežití bez známek nemoci MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• triazoly aplikace a dávkování   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• anastrozol MeSH
• antagonisté estrogenového receptoru MeSH
• estradiol MeSH
• fulvestrant MeSH
• hormonální protinádorové látky MeSH
• inhibitory aromatasy MeSH
• nitrily MeSH
• triazoly MeSH

BACKGROUND: At the time of the initial analysis of overall survival (OS) for the Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) randomized, double-blind, phase III trial, approximately 50% of patients had died. A final analysis of OS was subsequently planned for when 75% of patients had died. METHODS: Patients were randomly assigned 1:1 to fulvestrant 500 mg administered as two 5-mL intramuscular injections on days 0, 14, and 28 and every 28 (±3) days thereafter or fulvestrant 250 mg administered as two 5-mL intramuscular injections (one fulvestrant and one placebo [identical in appearance to study drug]) on days 0, 14 (two placebo injections only), and 28 and every 28 (±3) days thereafter. OS was analyzed using an unadjusted log-rank test. No adjustments were made for multiplicity. Serious adverse events (SAEs) and best response to subsequent therapy were also reported. All statistical tests were two-sided. RESULTS: In total, 736 women (median age = 61.0 years) were randomly assigned to fulvestrant 500 mg (n = 362) or 250 mg (n = 374). At the final survival analysis, 554 of 736 (75.3%) patients had died. Median OS was 26.4 months for fulvestrant 500 mg and 22.3 months for 250 mg (hazard ratio = 0.81; 95% confidence interval = 0.69-0.96; nominal P = .02). There were no clinically important differences in SAE profiles between the treatment groups; no clustering of SAEs could be detected in either treatment group. Type of first subsequent therapy and objective responses to first subsequent therapy were well balanced between the two treatment groups. CONCLUSIONS: In patients with locally advanced or metastatic estrogen receptor-positive breast cancer, fulvestrant 500 mg is associated with a 19% reduction in risk of death and a 4.1-month difference in median OS compared with fulvestrant 250 mg. Fulvestrant 500 mg was well tolerated, and no new safety concerns were identified.

• MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• estradiol aplikace a dávkování   analogy a deriváty   MeSH
• fulvestrant MeSH
• hormonální protinádorové látky aplikace a dávkování   MeSH
• injekce intramuskulární MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• modulátory estrogenních receptorů aplikace a dávkování   MeSH
• nádory prsu farmakoterapie   metabolismus   mortalita   patologie   MeSH
• odds ratio MeSH
• přežití bez známek nemoci MeSH
• receptory pro estrogeny metabolismus   MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• estradiol MeSH
• fulvestrant MeSH
• hormonální protinádorové látky MeSH
• modulátory estrogenních receptorů MeSH
• receptory pro estrogeny MeSH