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SAN ANTONIO -- Addition of an investigational AKT inhibitor to standard fulvestrant (Faslodex) doubled median progression-free survival (PFS) in the second-line setting for patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer, according to findings from a phase III study.

Among the roughly 700 patients in the trial, median PFS reached 7.2 months with capivasertib plus fulvestrant, as compared with 3.6 months with fulvestrant plus placebo (adjusted HR 0.60, 95% CI 0.51-0.71, P<0.001), said lead investigator Nicholas Turner, MD, PhD, of the Institute of Cancer Research, London, during a press conference at the San Antonio Breast Cancer Symposium.

The PFS advantage was similar in patients who had AKT pathway altered-tumors, defined as presence of at least one qualifying mutation in PIK3CA, AKT1, or PTEN (a co-primary endpoint), as well as in patients without these alterations or where the status was unknown (an exploratory analysis):

• With alterations: 7.3 vs 3.1 months (adjusted HR 0.50, 95% CI 0.38-0.65, P<0.001)
• Without alterations: 7.2 vs 3.7 months (HR 0.70, 95% CI 0.56-0.88)

"AKT pathway activation is very frequent in HR-positive/HER2-negative advanced breast cancer, through genetic alteration in the pathway, but may also occur in cancers without genetic alterations," said Turner. "AKT signaling is also implicated in the development of endocrine resistance."

He noted that capivasertib was developed as a potent and selective inhibitor of all three AKT isoforms, AKT 1/2/3.

In a previous phase II placebo-controlled trial, FAKTION, capivasertib added to fulvestrant significantly increased PFS and overall survival (OS), with more pronounced benefit in patients with tumors that had AKT pathway alterations.

CAPItello-291, the phase III study presented here, recruited 708 patients who had progressed on a prior aromatase inhibitor. Up to two prior lines of endocrine therapy and one prior line of chemotherapy for advanced breast cancer was allowed. Prior CDK4/6 inhibitor therapy was also allowed, and constituted 69% of the overall study cohort.

Patients with diabetes that did not require insulin were eligible for enrollment. Patients were randomized 1:1 to fulvestrant plus capivasertib or fulvestrant plus placebo. Capivasertib was given 4 days on, 3 days off. Overall, 41% of patients assigned to treatment had tumors with AKT pathway mutations.

Prespecified subgroup analyses showed that capivasertib had consistent PFS benefits across all subgroups, including those with and without liver metastases and those who had prior CDK4/6 inhibitors or not.

An OS analysis performed at 28% maturity showed HRs of 0.74 (95% CI 0.56-0.98) in the overall population and 0.69 (95% CI 0.45-1.05) in the AKT pathway-altered population, both favoring capivasertib. Overall survival follow-up is ongoing.

The most common grade ≥3 adverse events in the capivasertib plus fulvestrant arm were rash (12.1%), diarrhea (9.3%), and hyperglycemia (2.3%). The rate of discontinuation due to adverse events was 13% in the capivasertib arm versus 2.3% in the placebo arm. The adverse event profile was comparable in the AKT-altered population.

"I believe that these study results support this treatment regimen for advanced [estrogen receptor]-positive/HER-2 negative breast cancer following progression on CDK inhibitors," Douglas Marks, MD, of the Perlmutter Cancer Center at NYU Langone, told 名媛直播 by email.

"Importantly, the benefit for the combination was seen in the overall patient population and not specifically in patients with known PI3KCA/Akt pathway alterations," said Marks, a potentially "unexpected" outcome given the findings from FAKTION or studies underlying the approval of alpelisib (Piqray).

"However," he continued, "it is important to note that capivasertib targets AKT, a hub of this pathway, and may not require patients' tumors to have alterations in this pathway to have efficacy. Alternatively, in the patients without PI3KCA/AKT/PTEN pathway alterations who respond, there may be a specific, not-yet-identified biomarker which can help identify these patients."

Marks said he expects that the results from CAPItello-291 will ultimately lead to approval of a new combinatorial agent, with activity in a large subset of women with metastatic breast cancer.

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