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.