Capivasertib (AZD5363) plus fulvestrant versus placebo plus fulvestrant after relapse or progression on an aromatase inhibitor in metastatic ER-positive breast cancer (FAKTION): A randomized, double-blind, placebo-controlled, phase II trial.

Abstract

1005 Background: The PI3K/AKT signalling pathway is frequently activated in patients (pts) with estrogen receptor (ER) positive breast cancer (ER+BC) and has been implicated in endocrine therapy resistance. Capivasertib (AZD5363) is a highly-selective, oral, small molecule AKT inhibitor. The FAKTION trial investigated the addition of capivasertib to fulvestrant for postmenopausal women with ER+ and HER2 negative BC after relapse or disease progression on an aromatase inhibitor (AI). Methods: FAKTION is an investigator-led, double-blind, placebo-controlled, randomised phase II trial. Patients were recruited from 21 UK sites and randomly assigned (1:1) to fulvestrant 500mg (day 1 and 15 of cycle 1 and day 1 only of subsequent 28 day cycles) with either capivasertib 400mg bd or placebo (4 days on/3 days off starting C1D15) until disease progression, unacceptable toxicity or withdrawal of consent. Allocation was balanced by minimisation according to PIK3CA mutation and PTEN expression status, measurable/non-measurable disease, and primary/secondary endocrine resistance. The primary endpoint was progression-free survival (PFS). The trial had 90% power to detect a hazard ratio of 0.65 at the one-sided 20% significance level. Secondary endpoints included overall survival (OS), objective response and clinical benefit rates, safety and the effect of PI3K/Akt pathway activation on PFS. Results: Between Mar 2015 and Mar 2018, 140 pts were randomised to fulvestrant + capivasertib (n = 69) or fulvestrant + placebo (n = 71). In the Intention-to-treat analysis, after 112 events, median PFS was 10.3 months (m) for capivasertib compared to 4.8m for placebo (Hazard Ratio (HR) 0.57; 95% CI: 0.39 to 0.84; one-sided p = 0.0017; two-sided 0.0035). Fifty-two deaths were reported. Median OS was 26.0m for capivasertib compared to 20.0m for placebo, with a survival difference starting to emerge after 12m (HR = 0.59; 95% CI: 0.34 to 1.05; two-sided p = 0.071). Toxicity data and subgroup analyses including relative capivasertib benefit by PI3K/Akt pathway alteration will be presented at the conference. Conclusions: The trial met its primary endpoint. Addition of capivasertib to fulvestrant for patients with endocrine resistant advanced breast cancer resulted in significantly longer PFS and an improvement in OS. The FAKTION results warrant further investigation of capivasertib for the treatment of ER positive breast cancer. Clinical trial information: NCT01992952.

Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT)

“…More recently, in a phase II, randomized, double-blind, placebocontrolled study (FAKTION: NCT01992952; ref. 20), capivasertib in combination with fulvestrant significantly improved PFS in patients with advanced ER þ HER2 À breast cancer previously treated with aromatase inhibitors, with an observed OS improvement of approximately 6 months, although this was not statistically significant (37% OS data maturity). The successful development of a targeted AKT inhibitor such as capivasertib, either as monotherapy or in combination, may provide a new treatment option in breast cancer that helps circumvent endocrine therapy resistance from aberrant activation of the pathway (21).…”

Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients withAKT1E17K-Mutant, ER-Positive Metastatic Breast Cancer

“…More broadly, the role for co-targeting ER and PI3K pathway alterations has been demonstrated in multiple randomized, Phase III studies of PI3K inhibitors (17,49). Furthermore, in the recently reported randomized Phase II FAKTION study, the addition of capivasertib to fulvestrant showed a significant improvement in PFS in a molecularly unselected, aromatase-inhibitor-pretreated but fulvestrant-naïve ER+ MBC population (50).…”

“…A treatment cycle was defined as 3 weeks. In the combination cohorts, capivasertib was administered at the previously determined recommended Phase II combination therapy dose of 400 mg bid, 4 days on, 3 days off, repeated weekly, in addition to fulvestrant at the labeled dose (37).…”

Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non–BRCA1/2-Mutant Cancers

“…In addition, the FAKTION phase II trial showed that the addition of capivasertib to fulvestrant in patients with endocrine-resistant, advanced estrogen receptor-positive breast cancer also resulted in significantly longer PFS and an observed OS improvement of approximately 6 months, although this was not statistically significant (37% OS data maturity; ref. 25). Phase III trials of capivasertib-based combinations are planned or ongoing.…”