Fulvestrant and Buparlisib

Researchers investigated the safety and efficacy of combined fulvestrant and buparlisib therapy for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer, and explored PI3K activity as an indicator of treatment response. The study found that combined fulvestrant and buparlisib therapy improves progression-free survival.


Though hormone receptor (HR)-positive tumours are the most common type of breast cancer, their diverse makeup can make conventional HR-targeting therapies insufficient. Certain mutations in the PIK3CA gene –responsible for over-activation of the cellular pathway PI3K, implicated in cell growth, division, and survival – have been associated with cancer progression and resistance to HR therapies. As such, co-administration of HR-targeting drugs, such as fulvestrant, and PI3K-targeting drugs, such as buparlisib, has been proposed to improve treatment in patients for whom HR-targeting therapies alone have been ineffective.

Results of a clinical trial published in Lancet Oncology describes the safety and efficacy of a combined buparlisib and fulvestrant regimen for the treatment of advanced aromatase inhibitor-resistant, hormone receptor-positive, HER2-negative breast cancer, and the utility of PI3K activity as an indicator of responsiveness to treatment. Postmenopausal women with worsening HR-positive, HER2-negative breast cancer for whom aromatase inhibitors were ineffective were recruited for the study. Those undergoing PI3K-targeting therapies, on immuno-suppressants or blood thinners, for whom the disease had metastasized to the brain or spinal cord, or who suffered from mental illness were excluded.PI3K status – active, inactive, or unknown – and PIK3CA genotype – mutant or non-mutant – were determined through analysis of existing tissue samples and of circulating tumor DNA (ctDNA) in current tumours.

Subjects were grouped based on PI3K activity and the presence or absence of metastases to major internal organs, and were randomly assigned to receive either fulvestrant and buparlisib or fulvestrant and a placebo. The regimens were administered over the course of 28-day cycles until April 29, 2015, remission, withdrawal from the trial, or patient death. Cycle 1 was split into an introductory phase, in which all patients received an intramuscular injection of 500mg of fulvestrant on day 1, and a randomization phase, in which patients received another dose of fulvestrant and daily oral 100mg doses of buparlisib or a placebo starting on day 15. In subsequent cycles, patients received 1 dose of fulvestrant on day 1 and buparlisib for the full 28 days. Disease progression was analyzed by CT or MRI at the beginning of the study, at 6 weeks, and every 8 weeks afterward. Blood samples were collected at the beginning of the study, on days 1 and 22 of cycles 1 and 2, and on day 1 of subsequent cycles.

Safety was assessed with respect to adverse events until 30 days after a patient’s cycles had concluded. Survival was assessed up to 3 months after. Mood questionnaires were filled out at the beginning of the trial, on days 1 and 15 of cycles 1 through 3, and on day 1 of subsequent cycles. Efficacy was assessed with respect to progression-free survival, overall survival, and response to treatment.

Patients entered into the trial between September 2012 and September 2014. In total, 1,147 patients were included in the analysis. Metastases to internal organs was present in 678 (59%) patients. PI3K was active in 372 (32%), inactive in 479 (42%), and of unknown status in 296 (26%)pateints. Of the 576 patients allocated to the fulvestrant + buparlisib group, 474 (82.2%) discontinued treatment and there were 7 deaths. Of the 571 allocated to the fulvestrant + placebo group, 470 (82.3%) discontinued treatment and there were 5 deaths. For both groups, most who discontinued treatment – 313 (67%) in the buparlisib group and 417 (88.7%) in the placebo group – did so due to the worsening conditions of the disease.Treatment lasted around 4.2 months in the buparlisib group and 5.0 months in the placebo group – the difference was due in part to a higher number of withdrawals in the buparlisib group. On April 29, 2015, 187 (16%) were still receiving treatment.

Agreement on PIK3CA genotype between tissue samples and ctDNA was 77%. Of the 307 patients who started with non-mutant PIK3CA tissue, 243 (79%) remained non-mutant and 64 (21%) became mutated. Of the 286 in the buparlisib group with PIK3CA-positive ctDNA, 87 (30%) had a mutant copy compared to 113 of 301 (38%) in the placebo group.

Progression-free survival was around 6.9 months for the buparlisib group and 5.0 months in the placebo group. For buparlisib patients with known PI3K status, progression-free survival was around 6.8 months compared to 4.5 months in the placebo group, although there was no significant difference between buparlisib and placebo patients with active PI3K pathways. A response to treatment was seen in 11.8% of the buparlisib group, of which 43.8% obtained a clinical benefit, compared to 7.7% in the placebo group with 42.0% obtaining clinical benefit. Progression-free survival and the proportion of patients who experienced a response to treatment or clinical benefit were significantly higher in PIK3CA mutant buparlisib patients compared to mutant placebo patients.

Very high levels of alanine aminotransferase (indicative of liver damage), aspartate aminotransferase (indicative of heart or liver damage), and sugar in the blood were more common in the bulparlisib group than in the placebo group: 25% vs. 1%, 18% vs. 3%, and 15% vs. 0.18%, respectively. Rashes were present in 8% of buparlisib patients but no placebo patients. Mild and severe depression were reported for 22% and 5% of buparlisib patients, respectively, compared to 9% and 0.35% of placebo patients. Mild and severe anxiety was reported for 17% and 5% of bupasrlisib patients compared to 7% and 1% for placebo patients. Of the 12 deaths that occurred, none were ascribed to treatment.

Overall, the results suggest combined fulvestrant and buparlisib therapy improves progression-free survival in advanced HR-positive, HER2-negative breast cancer. Further, ctDNA screening for PIK3CA mutations may be useful in identifying patients likely to receive clinical benefit from PI3K-targeting therapies such as buparlisib. The majority of tissue samples were from archived sources, and as such the PI3K activity status observed may not fully reflect that of the tumours during the study. As buparlisib is a broad PI3K blocker, research into more selective PI3K blockers, which may produce fewer adverse effects than buparlisib, may be warranted.


Written By: Raishard Haynes, MBS


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