Fulvestrant Plus Capivasertib Improves PFS in ER+ Breast Cancer

The combination of fulvestrant and capivasertib prolonged progression-free survival compared with placebo in patients with estrogen receptor-positive breast cancer who were previously treated with aromatase inhibition, according to results from the phase II FAKTION trial, published in The Lancet Oncology.

The combination of fulvestrant (Faslodex) and capivasertib (AZD5363) prolonged progression-free survival (PFS) compared with placebo in patients with estrogen receptor (ER)—positive breast cancer who were previously treated with aromatase inhibition, according to results from the phase II FAKTION trial, published inThe Lancet Oncology.

"The FAKTION trial forms another important part of the jigsaw of which therapeutic strategy is likely to advantage patients with ER-positive breast cancer. It showed that the addition of capivasertib to fulvestrant produced a clinically and statistically significant improvement in PFS and response rates in this patient group. It also showed a trend to an improvement in overall survival and this may become statistically important as the data matures. Interestingly we have not yet found the advantage is limited to a particular patient subgroup, although a full biomarker analysis is in progress. The toxicity profile was also manageable meaning capivasertib appears to be a promising drug in combination with hormone therapy and warrants further investigation in a Phase 3 trial, Robert H. Jones, MD, reader and comnsultant in Medical Oncology, Cardiff University/Velindre Cancer Centre toldTargeted Oncology.

A total of 140 patients were divided between the fulvestrant plus capivasertib arm (n = 69) or the fulvestrant plus placebo arm (n = 71). At a median follow-up of 4.9 months (range, 1.6-11.6), 112 events were evaluable across arms at the time of the primary analysis for PFS. In the combination arm, 71% of patients experienced a PFS event (n = 49) and in the placebo arm, 89% of patients had a PFS event (n = 63).The data were first presented at the 2019 ASCO annual meeting. The median PFS was 10.3 months (95% CI, 5.0-13.2) in the combination group versus 4.8 months (95% CI, 3.1-7.7) in the placebo group (HR, 0.58; 95% CI, 0.39-0.84). Fulvestrant plus capivasertib demonstrated a favorable PFS (2-sidedP= .0044; one-sided log-rank test P= .0018).

Among the 99 patients who had measurable disease, a significantly longer median PFS of 7.6 months was observed with fulvestrant plus capivasertib compared with fulvestrant plus placebo, which demonstrated a median PFS of 3.2 months (HR, 0.61; 95% CI, 0.39-0.95,P= .030). In patients with non-measurable disease, the median PFS in the combination arm was 13.4 months (95% CI ,7.7-30.1) versus 7.9 months (95% CI, 4.4—10.8) in the placebo arm (HR, 0.47; 95% CI, 0.22-0.99; 2-sided P= .046).

Objective responses were observed in 29% of the fulvestrant-plus-capivasertib patient population (n = 20) versus 8% of the fulvestrant-plus-placebo participants (n = 6; odds ratio, 4.42; 95% CI, 1.65-11.84; 2-sidedP= .0031). Additionally, 55% of patients who received the combination therapy had a clinical benefit (n = 38) compared with 41% of those given fulvestrant plus placebo (n = 29; odds ratio, 1.78; 95% CI, 0.91-3.47, 2-sided P= .093).

For participants with measurable disease, objective responses were seen in 41% of the population (n = 20) in the combination group versus in 12% of patients on placebo (n = 6; odd ratio, 5.06; 95% CI, 1.81-14.11; 2-sidedP= .0020). The median duration of response among patients with measurable disease observed during a post-hoc analysis was 7.1 months (95% CI, 3.8-9.9) in the combination group versus 5.0 months (95% CI, 2.7-not reached) in the placebo group.

The efficacy of the combination was also investigated in a subgroup of participants with and without alterations of the PI3K and PTEN pathways. The median PFS observed among patients with no alterations inPI3KorPTENwas 10.3 months (95% CI, 3.2-13.2) in the capivasertib group and 4.8 months (95% CI, 3.0-8.6) in the placebo group. Among patients withPI3K/PTENalterations, the median PFS was 9.5 months (95% CI, 6.6-13.7) in the capivasertib group versus 5.2 months (95% CI, 3.1-8.4) in the placebo group.

Median overall survival (OS), while still immature after a median of 12 months of follow-up, was 26.0 months (95% CI, 18.4-32.3) with added capivasertib versus 20.0 months (95% CI, 15.1-21.2) without (HR, 0.59; 95% CI, 0.34-1.05; 2-sidedP= .071).

Fulvestrant treatment was administered for a median duration of 9.2 months (range, 3.0-14.1) to patients in the capivasertib group and a median duration of 4.6 months (range, 2.8-10.5) in the placebo group. Capivasertib treatment lasted for a median duration of 7.7 months (range, 1.5-13.5) in the combination group and 4.9 months (range, 2.3-10.6) in the placebo group.

Dose reductions were carried out in 41% of the patients who received the combination and 1% of those given placebo. Treatment discontinuation due to adverse events (AEs) occurred in 12% of patients in the combination arm (n = 8), which were attributed to rash, diarrhea, hypoglycemia, nausea, vomiting, mouth ulcers, and sweating. The most common toxicities that resulted in dose reduction were rash (20%), diarrhea (12%), and nausea or vomiting (4%). A post-hoc analysis showed that PFS was not compromised by dose reduction or treatment discontinuations.

The most common grade 3/4 AEs in the combination group versus the placebo group, respectively were hypertension (32% vs 24%), diarrhea (14% vs 4%), rash (20% vs 0%), infection (6% vs 3%), and fatigue (1% vs 4%). Overall, 65% of the capivasertib group and 50% of the placebo group experienced grade 3-5 AEs. Serious AEs were only seen with fulvestrant plus capivasertib and they included diarrhea (n = 3), acute kidney injury (n = 2), rash (n = 2), hyperglycemia (n = 1), loss of consciousness (n = 1), sepsis (n = 1), and vomiting (n = 1).

One patient in the study died as a result of atypical pulmonary infection, which was potentially related to treatment with capivasertib. Another death in the combination group had an unknown cause. All other deaths in both groups were disease-related and occurred in 19 patients in the capivasertib group and in 31 patients in the placebo group.

The multi-center, randomized, controlled FAKTION trial (NCT01992952) evaluated the safety and efficacy of fulvestrant plus capivasertib in postmenopausal women with aromatase inhibitor-resistant, ER-positive, HER2-negative advanced or metastatic breast cancer. Patients were randomized to receive either capivasertib 480 mg twice daily taken 4 days on and 3 days off plus fulvestrant 500 mg injections separated into 250 mg each, on days 1 and 15 of cycle 1 and on day 1 of each subsequent 28-day cycle, or an equal dose of fulvestrant with placebo.

The primary end point of FAKTION was PFS and the secondary end point included the number of participants with AEs, objective response rate, overall survival, the influence of mutational status ofPIK3CAand the presence of complete loss ofPTENon outcomes in both arms, the pharmacokinetics of fulvestrant, and the number of participants who required dose modifications.

To be eligible to enroll, patients were required to of post-menopausal age with a life expectancy of 3 months; histologically confirmed ER-positive breast cancer; metastatic or locally advanced disease not amenable to surgical resection; adequate bone marrow, renal, and hepatic function; and have an ECOG performance status of 2 or lower. Patients could have measurable or non-measurable disease.

In meeting its primary end point, this study is the first to show the efficacy of an AKT inhibitor combined with fulvestrant in this setting, study authors Jones et al noted.


Jones RH, Casbard A, Carucci M, et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial.Lancet Oncol. 2020;21:345-357. doi: 10.1016/S1470-2045(19)30817-4.

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