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Capivasertib Plus Paclitaxel Versus Placebo Plus Paclitaxel As First-Line Therapy for Metastatic Triple-Negative Breast Cancer: The PAKT Trial.

Schmid, Peter; Abraham, Jacinta; Chan, Stephen; Wheatley, Duncan; Brunt, Adrian Murray; Nemsadze, Gia; Baird, Richard D.; Hee Park, Yeon; Hall, Peter S.; Perren, Timothy; Stein, Robert C.; Mangel, László; Ferrero, Jean-Marc; Phillips, Melissa; Conibear, John; Cortes, Javier; Foxley, Andrew; de Bruin, Elza C.; McEwen, Robert; Stetson, Daniel; Dougherty, Brian; Sarker, Shah-Jalal; Prendergast, Aaron; McLaughlin-Callan, Max; Burgess, Matthew; BPharm, Cheryl Lawrence; Cartwright, Hayley; Mousa, Kelly; Turner, Nicholas C.

Capivasertib Plus Paclitaxel Versus Placebo Plus Paclitaxel As First-Line Therapy for Metastatic Triple-Negative Breast Cancer: The PAKT Trial. Thumbnail


Authors

Peter Schmid

Jacinta Abraham

Stephen Chan

Duncan Wheatley

Gia Nemsadze

Richard D. Baird

Yeon Hee Park

Peter S. Hall

Timothy Perren

Robert C. Stein

László Mangel

Jean-Marc Ferrero

Melissa Phillips

John Conibear

Javier Cortes

Andrew Foxley

Elza C. de Bruin

Robert McEwen

Daniel Stetson

Brian Dougherty

Shah-Jalal Sarker

Aaron Prendergast

Max McLaughlin-Callan

Matthew Burgess

Cheryl Lawrence BPharm

Hayley Cartwright

Kelly Mousa

Nicholas C. Turner



Abstract

PURPOSE: The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is frequently activated in triple-negative breast cancer (TNBC). The AKT inhibitor capivasertib has shown preclinical activity in TNBC models, and drug sensitivity has been associated with activation of PI3K or AKT and/or deletions of PTEN. The PAKT trial was designed to evaluate the safety and efficacy of adding capivasertib to paclitaxel as first-line therapy for TNBC. PATIENTS AND METHODS: This double-blind, placebo-controlled, randomized phase II trial recruited women with untreated metastatic TNBC. A total of 140 patients were randomly assigned (1:1) to paclitaxel 90 mg/m2 (days 1, 8, 15) with either capivasertib (400 mg twice daily) or placebo (days 2-5, 9-12, 16-19) every 28 days until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), PFS and OS in the subgroup with PIK3CA/AKT1/PTEN alterations, tumor response, and safety. RESULTS: Median PFS was 5.9 months with capivasertib plus paclitaxel and 4.2 months with placebo plus paclitaxel (hazard ratio [HR], 0.74; 95% CI, 0.50 to 1.08; 1-sided P = .06 [predefined significance level, 1-sided P = .10]). Median OS was 19.1 months with capivasertib plus paclitaxel and 12.6 months with placebo plus paclitaxel (HR, 0.61; 95% CI, 0.37 to 0.99; 2-sided P = .04). In patients with PIK3CA/AKT1/PTEN-altered tumors (n = 28), median PFS was 9.3 months with capivasertib plus paclitaxel and 3.7 months with placebo plus paclitaxel (HR, 0.30; 95% CI, 0.11 to 0.79; 2-sided P = .01). The most common grade = 3 adverse events in those treated with capivasertib plus paclitaxel versus placebo plus paclitaxel, respectively, were diarrhea (13% v 1%), infection (4% v 1%), neutropenia (3% v 3%), rash (4% v 0%), and fatigue (4% v 0%). CONCLUSION: Addition of the AKT inhibitor capivasertib to first-line paclitaxel therapy for TNBC resulted in significantly longer PFS and OS. Benefits were more pronounced in patients with PIK3CA/AKT1/PTEN-altered tumors. Capivasertib warrants further investigation for treatment of TNBC.

Acceptance Date Sep 25, 2019
Online Publication Date Dec 16, 2019
Publication Date Feb 10, 2020
Publicly Available Date May 26, 2023
Journal Journal of Clinical Oncology
Print ISSN 0732-183X
Electronic ISSN 1527-7755
Publisher American Society of Clinical Oncology
Peer Reviewed Peer Reviewed
Volume 38
Issue 5
Pages 423 - 433
DOI https://doi.org/10.1200/JCO.19.00368
Publisher URL https://ascopubs.org/doi/pdf/10.1200/JCO.19.00368