AZD5363 plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (PAKT): A randomised, double-blind, placebo-controlled, phase II trial.

Schmid, Peter; Abraham, Jacinta; Chan, Stephen; Wheatley, Duncan; Brunt, Murray; Nemsadze, Gia; Baird, Richard D.; Park, Yeon Hee; Hall, Peter; Perren, Timothy; Stein, Robert; Mangel, László; Ferrero, Jean-­Marc; Phillips, Melissa; Conibear, John; Sarker, Shah-Jalal; Prendergast, Aaron; Cartwright, Hayley; Mousa, Kelly; Turner, Nicholas C.

doi:10.1200/jco.2018.36.15_suppl.1007

Cited by 55 publications

(36 citation statements)

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“…Since the STAKT trial was completed, the phase II study (PAKT: NCT02423603) has reported improved progression-free survival (PFS) and overall survival (OS) from the combination of capivasertib and paclitaxel as first-line therapy in patients with triplenegative breast cancer; an enhanced effect on PFS was observed in patients with mutations in the PIK3CA, AKT1, or PTEN genes (19). More recently, in a phase II, randomized, double-blind, placebocontrolled study (FAKTION: NCT01992952; ref.…”

Section: Discussionmentioning

confidence: 99%

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

Robertson

Coleman

Cheung

et al. 2019

Clinical Cancer Research

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◥ Purpose: The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation.Methods: STAKT was a two-stage, double-blind, randomized, placebo-controlled, "window-of-opportunity" study in patients with newly diagnosed ER þ invasive breast cancer. Stage 1 assessed capivasertib 480 mg b.i.d. (recommended monotherapy dose) and placebo, and stage 2 assessed capivasertib 360 and 240 mg b.i.d. Primary endpoints were changes from baseline in AKT pathway markers pPRAS40, pGSK3b, and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverseevent monitoring.Results: After 4.5 days' exposure, capivasertib 480 mg b.i.d. (n ¼ 17) produced significant decreases from baseline versus placebo (n ¼ 11) in pGSK3b (H-score absolute change: À55.3, P ¼ 0.006) and pPRAS40 (À83.8, P < 0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: À9.6%, P ¼ 0.031). Significant changes also occurred in secondary signaling biomarker pS6 (À42.3, P ¼ 0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P ¼ 0.005). At doses of 360 mg b.i.d. (n ¼ 5) and 240 mg b.i.d. (n ¼ 6), changes in primary and secondary biomarkers were also observed, albeit of smaller magnitude. Biomarker modulation was dose and concentration dependent, and no new safety signals were evident.Conclusions: Capivasertib 480 mg b.i.d. rapidly modulates key biomarkers of the AKT pathway and decreases proliferation marker Ki67, suggesting future potential as an effective therapy in AKTdependent breast cancers.

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Section: Discussionmentioning

confidence: 99%

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

Robertson

Coleman

Cheung

et al. 2019

Clinical Cancer Research

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“…For therapeutic strategies involving AKT inhibitors, currently tested in TNBC, it might be promising to combine PIK3CA mutations with other alterations, such as AKT and PTEN, the combination of these 3 genes has been linked to response to AKT inhibitors in the Lotus and Manta studies (29,30), and a similar approach was investigated in the neoadjuvant Fairlane study (31). The rate of PIK3/AKT pathway alterations ranged from 23% to 43%, which was higher than the 8% in our study, which did not include PTEN loss.…”

Section: Discussionmentioning

confidence: 99%

Mutational Diversity and Therapy Response in Breast Cancer: A Sequencing Analysis in the Neoadjuvant GeparSepto Trial

Loibl

Treue

Budczies

et al. 2019

Clinical Cancer Research

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Purpose: Next-generation sequencing (NGS) can be used for comprehensive investigation of molecular events in breast cancer. We evaluated the relevance of genomic alterations for response to neoadjuvant chemotherapy (NACT) in the GeparSepto trial. Experimental Design: Eight hundred fifty-one pretherapeutic formalin-fixed paraffin-embedded (FFPE) core biopsies from GeparSepto study were sequenced. The panel included 16 genes for mutational (AKT1,

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“…Interestingly, in these models coadministration of AKT inhibitors and taxanes resulted in increased tumor cell death compared to their monotherapy use. Ipatasertib and capivasertib are two highly selective oral pan‐AKT inhibitors, which were recently tested in combination with paclitaxel phase II trials [PAKT and LOTUS ]. The two studies had a similar design that randomized treatment naïve mTNBC patients to receive either weekly paclitaxel monotherapy, or the combination of weekly paclitaxel with an AKT inhibitor.…”

Section: Exploring Genetic Events To Tailor Therapy Of Mtnbcmentioning

confidence: 99%

“…The two studies had a similar design that randomized treatment naïve mTNBC patients to receive either weekly paclitaxel monotherapy, or the combination of weekly paclitaxel with an AKT inhibitor. The PAKT is a placebo‐controlled study, that investigated paclitaxel with or without capivasertib (400 mg twice daily on days 2‐5, 9‐12 and 16‐19) every 28 days, in 140 patients while the LOTUS investigated paclitaxel with or without ipatasertib (400 mg on days 1‐21) every 28 days in 124 patients . In the ITT analysis, the two studies did not meet all of their primary endpoints.…”

Section: Exploring Genetic Events To Tailor Therapy Of Mtnbcmentioning

confidence: 99%

Personalized treatment in metastatic triple‐negative breast cancer: The outlook in 2020

et al. 2019

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Compared with other breast cancer subtypes, patients with triple‐negative breast cancer (TNBC), and irrespective to their disease stage, were always recognized to have the worst overall survival data. Although this does not seem different at the present time, yet the last few years have witnessed many breakthrough genomic and molecular findings, that could dramatically improve our understanding of the biological complexity of TNBC. Based on genomic analyses, it was consistently evident that TNBC comprises a heterogeneous group of cancers, which have numerous diverse molecular aberrations. This—in return—has provided a platform for a new generation of clinical trials using many innovative therapies, directed against such novel targets. At the present time, two PARP inhibitors and one anti‐PD‐L1 monoclonal antibody (in combination with chemotherapy) have been approved in certain subpopulations of metastatic TNBC (mTNBC) patients, which have finally brought this disease into the era of personalized medicine. In the current review, we will explore the genomic landscape of TNBC, through which many actionable targets were graduated. We will also discuss the results of the key—practice changing—clinical studies, and some upcoming personalized treatment options for patients with mTNBC, that may be clinically adopted in the near future.

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AZD5363 plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (PAKT): A randomised, double-blind, placebo-controlled, phase II trial.

Cited by 55 publications

References 0 publications

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

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

Mutational Diversity and Therapy Response in Breast Cancer: A Sequencing Analysis in the Neoadjuvant GeparSepto Trial

Personalized treatment in metastatic triple‐negative breast cancer: The outlook in 2020

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