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CHICAGO -- Adding investigational capivasertib to fulvestrant extended survival in patients with aromatase inhibitor-resistant estrogen receptor (ER)-positive, HER2-negative advanced breast cancer, according to updated results from the .

In the phase II study, 140 patients were randomized 1:1 to capivasertib-fulvestrant or placebo-fulvestrant, and median overall survival (OS) was improved by almost 6 months (29.3 vs 23.4 months, adjusted hazard ratio 0.66, 95% CI 0.45-0.97, P=0.035) for patients getting the novel AKT inhibitor-based regimen, reported Robert H. Jones, PhD, of the Velindre Cancer Centre and School of Medicine, Cardiff University in Wales.

Updated median progression-free survival (PFS) was 10.3 months in the group receiving capivasertib-fulvestrant versus 4.8 months for fulvestrant plus placebo (adjusted HR 0.56, 95% CI 0.38–0.81, P=0.0023), he said in a presentation at the American Society of Clinical Oncology (ASCO) annual meeting. Trial results were published simultaneously in the.

This follow-up analysis of FAKTION, "is the first demonstration that the addition of a PI3K/AKT/PTEN pathway inhibitor to endocrine therapy results in significantly longer overall survival in patients with aromatase inhibitor-resistant ER-positive, HER2-negative advanced breast cancer compared with endocrine therapy alone," stated Jones and colleagues.

Thus, "the data supports further development of capivasertib," Jones said in the ASCO presentation.

He also reported that expanded genetic testing of the patients in the trial identified PIK3CA, AKT1, and PTEN alterations in 25% of the tumors that were classified as pathway non-altered in the , and that a subsequent subgroup analysis suggests that capivasertib predominantly benefited patients (n=76) with PI3K/AKT/PTEN pathway-altered tumors. Specifically:

• Pathway-altered tumors: PFS 12.8 months with capivasertib vs 4.6 months with placebo (P=0.0014); OS 38.9 months vs 20 months (P=0.005)
• Pathway non-altered tumors: PFS 7.7 months vs 4.3 months (P=0.23); OS 26 months vs 25.2 months (P=0.6)

ASCO discussant Claudine Isaacs, MD, of Georgetown University Medical Center in Washington, said that the "investigators should be commended for re-evaluating their original findings with contemporary technology. Their updated findings underscore the importance of having the right biomarker assay to predict who will respond to a targeted therapy, and are in keeping with the recently published findings from the And trials evaluating the role of AKT inhibitors in triple-negative breast cancer."

The updated safety analysis "showed no new safety signals compared to the primary analysis," Jones reported, adding that the adverse events that were observed most frequently in patients receiving capivasertib -- diarrhea, rash, hyperglycemia, infections, and oral mucositis -- "are recognized for this class of drug."

FAKTION was a multicenter, double-blind trial that included postmenopausal women (median age around 61) who had relapsed or whose disease had progressed on an aromatase inhibitor, from 19 hospitals across the U.K. They were assigned to receive intramuscular fulvestrant at 500 mg on day 1 every 28 days (with a loading dose on day 15 of cycle 1) plus either oral capivasertib at 400 mg or placebo twice daily on an intermittent weekly schedule of 4 days on and 3 days off, starting on day 15 of cycle 1. Treatment continued until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent.

Key eligibility requirements included a maximum of one line of cytotoxic chemotherapy and three lines of endocrine therapy for metastatic breast cancer, and measurable or non-measurable disease according to RECIST version 1:1. Patients were excluded if they had previous treatment with fulvestrant or inhibitors of the PI3K/AKT pathway.

Due to the recruitment period of the trial (2015-2016), no patients who had received prior treatment with CDK 4/6 inhibitors were included.

Based on these data, results from the phase III, with a planned enrollment of more than 800 patients with locally advanced or metastatic hormone receptor–positive/HER2-negative breast cancer in the study, are "eagerly awaited," Jones said.