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BACKGROUND: Capivasertib, an AKT inhibitor, added to fulvestrant, was previously reported to improve progression-free survival in women with aromatase inhibitor-resistant oestrogen receptor (ER)-positive, HER2-negative advanced breast cancer. The benefit appeared to be independent of the phosphoinositide 3-kinase (PI3K)/AKT/phosphatase and tensin homologue (PTEN) pathway alteration status of tumours, as ascertained using assays available at the time. Here, we report updated progression-free survival and overall survival results, and a prespecified examination of the effect of PI3K/AKT/PTEN pathway alterations identified by an expanded genetic testing panel on treatment outcomes.METHODS: This randomised, multicentre, double-blind, placebo-controlled, phase 2 trial recruited postmenopausal adult women aged at least 18 years with ER-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2, who had relapsed or progressed on an aromatase inhibitor, from across 19 hospitals in the UK. Participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a 500 mg loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off, starting on cycle 1 day 15. Treatment continued until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment was allocated by an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival in the intention-to-treat population. Secondary endpoints shown in this Article were overall survival and safety in the intention-to-treat population, and the effect of tumour PI3K/AKT/PTEN pathway status identified by an expanded testing panel that included next-generation sequencing assays. Recruitment is complete. The trial is registered with ClinicalTrials.gov, number NCT01992952.FINDINGS: Between March 16, 2015, and March 6, 2018, 183 participants were screened for eligibility and 140 (77%) were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up at the data cut-off of Nov 25, 2021, was 58·5 months (IQR 45·9-64·1) for participants treated with fulvestrant plus capivasertib and 62·3 months (IQR 62·1-70·3) for fulvestrant plus placebo. Updated median progression-free survival was 10·3 months (95% CI 5·0-13·4) in the group receiving fulvestrant plus capivasertib compared with 4·8 months (3·1-7·9) for fulvestrant plus placebo (adjusted hazard ratio [HR] 0·56 [95% CI 0·38-0·81]; two-sided p=0·0023). Median overall survival in the capivasertib versus placebo groups was 29·3 months (95% CI 23·7-39·0) versus 23·4 months (18·7-32·7; adjusted HR 0·66 [95% CI 0·45-0·97]; two-sided p=0·035). The expanded biomarker panel identified an expanded pathway-altered subgroup that contained 76 participants (54% of the intention-to-treat population). Median progression-free survival in the expanded pathway-altered subgroup for participants receiving capivasertib (n=39) was 12·8 months (95% CI 6·6-18·8) compared with 4·6 months (2·8-7·9) in the placebo group (n=37; adjusted HR 0·44 [95% CI 0·26-0·72]; two-sided p=0·0014). Median overall survival for the expanded pathway-altered subgroup receiving capivasertib was 38·9 months (95% CI 23·3-50·7) compared with 20·0 months (14·8-31·4) for those receiving placebo (adjusted HR 0·46 [95% CI 0·27-0·79]; two-sided p=0·0047). By contrast, there were no statistically significant differences in progression-free or overall survival in the expanded pathway non-altered subgroup treated with capivasertib (n=30) versus placebo (n=34). One additional serious adverse event (pneumonia) in the capivasertib group had occurred subsequent to the primary analysis. One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment.INTERPRETATION: Updated FAKTION data showed that capivasertib addition to fulvestrant extends the survival of participants with aromatase inhibitor-resistant ER-positive, HER2-negative advanced breast cancer. The expanded biomarker testing suggested that capivasertib predominantly benefits patients with PI3K/AKT/PTEN pathway-altered tumours. Phase 3 data are needed to substantiate the results, including in patients with previous CDK4/6 inhibitor exposure who were not included in the FAKTION trial.FUNDING: AstraZeneca and Cancer Research UK.

Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)–deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K–AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off. Pharmacokinetics were dose proportional. Pharmacodynamic studies confirmed phosphorylated (p) GSK3β suppression, increased pERK, and decreased BRCA1 expression. Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without DDR and PI3K–AKT pathway alterations.Significance:In the first trial to combine PARP and AKT inhibitors, a prospective intrapatient dose- escalation design demonstrated safety, tolerability, and pharmacokinetic–pharmacodynamic activity and assessed predictive biomarkers of response/resistance. Antitumor activity was observed in patients harboring tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DDR and/or PI3K–AKT pathway alterations.This article is highlighted in the In This Issue feature, p. 1426

Supplementary Tables 1-7; Supplementary Figures 1-2; Supplementary Methods

Supplementary Figure 1. Participant Flow Diagram

Purpose:The activating mutation AKT1E17K occurs in approximately 7% of estrogen receptor–positive (ER+) metastatic breast cancer (MBC). We report, from a multipart, first-in-human, phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of patients with AKT1E17K-mutant ER+ MBC.Patients and Methods:Patients with an AKT1E17K mutation, detected by local (next-generation sequencing) or central (plasma-based BEAMing) testing, received capivasertib 480 mg twice daily, 4 days on, 3 days off, weekly or 400 mg twice daily combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS), and clinical benefit rate at 24 weeks (CBR24). Biomarker analyses were conducted in the combination cohort.Results:From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although the latter group may have had more aggressive disease at baseline. AKT1E17K mutations were detectable in plasma by BEAMing (95%, 41/43), droplet digital PCR (80%, 33/41), and next-generation sequencing (76%, 31/41). A ≥50% decrease in AKT1E17K at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy [most frequent grade ≥3 adverse events: rash (9% vs. 20%), hyperglycemia (5% vs. 30%), diarrhea (5% vs. 10%)].Conclusions:Capivasertib demonstrated clinically meaningful activity in heavily pretreated patients with AKT1E17K-mutant ER+ MBC, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination.

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.Patients and Methods:STAKT was a two-stage, double-blind, randomized, placebo-controlled, “window-of-opportunity” study in patients with newly diagnosed ER+ 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, pGSK3β, and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverse-event monitoring.Results:After 4.5 days' exposure, capivasertib 480 mg b.i.d. (n = 17) produced significant decreases from baseline versus placebo (n = 11) in pGSK3β (H-score absolute change: −55.3, P = 0.006) and pPRAS40 (−83.8, P < 0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: −9.6%, P = 0.031). Significant changes also occurred in secondary signaling biomarker pS6 (−42.3, P = 0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P = 0.005). At doses of 360 mg b.i.d. (n = 5) and 240 mg b.i.d. (n = 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 AKT-dependent breast cancers.

Supplementary Figure 3. AKT1E17K Allele Frequency (AF) Distribution and Median AF for patients with available ctDNA NGS data

Supplementary tables

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

Supplementary methods and results Supplementary Figure 1. Study 1 (NCT01226316) design Supplementary Figure 2. Dose escalation and DLTs in Part A, with MTDs of the continuous, 4/7, and 2/7 schedules being 320, 480, and 640 mg bid, respectively Supplementary Figure 3. Exploratory mutation analyses (ddPCR) in archival tissue and plasma (ctDNA) samples from a breast cancer patient who had progressive disease as best response (Cb cohort) Supplementary Figure 4. A) Tumour growth inhibition in preclinical tumor xenograft models (BT474c, HGC-27, HCC1954 and 786.0) treated with AZD5363 bid po at the indicated doses. B) AZD5363 PD in BT474c tumor xenografts. C) AZD5363 PD at steady state in BT474c xenograft tumors. D) Time course of pPRAS40 and pAkt S473 in BT474c tumor xenograft tissue following the final dose of AZD5363 after 3 weeks' continuous (100 mg/kg bid) or intermittent dosing (130 mg/kg bid 4/7 and 170 mg/kg bid 2/7) Supplementary Figure 5. Glucose (non-fasting/random) values over time after 480 mg single-dose AZD5363 (all dosing schedules) Supplementary Table 1. Percentage change from baseline for PoM biomarkers for 12 evaluable patients Supplementary Table 2. Antibodies and conditions for IHC analysis Supplementary Table 3. ddPCR primers and probes Supplementary Table 4. Tables with results of molecular analyses of Part C patients (PIK3CA and ESR1 mutation status in tissue and ctDNA, PTEN status in archival tissue) Supplementary Table 5. AEs of CTCAE grade {greater than or equal to}3 (irrespective of causality) in Parts A and B (frequency >3% total) and Part C (frequency >5% total)

Purpose: This phase I, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The objectives were to investigate the safety, tolerability, and pharmacokinetics of AZD5363, define a recommended dosing schedule, and evaluate preliminary clinical activity.Experimental Design: Patients were aged ≥18 years with World Health Organization (WHO) performance status of 0 to 1. Dose escalation was conducted within separate continuous and intermittent [4 days/week (4/7) or 2 days/week (2/7)] schedules with safety, pharmacokinetic, and pharmacodynamic analyses. Expansion cohorts of approximately 20 patients each explored AZD5363 activity in PIK3CA-mutant breast and gynecologic cancers.Results: MTDs were 320, 480, and 640 mg for continuous (n = 47), 4/7 (n = 21), and 2/7 (n = 22) schedules, respectively. Dose-limiting toxicities were rash and diarrhea for continuous, hyperglycemia for 2/7, and none for 4/7. Common adverse events were diarrhea (78%) and nausea (49%) and, for Common Terminology Criteria for Adverse Events grade ≥3 events, hyperglycemia (20%). The recommended phase II dose (480 mg bid, 4/7 intermittent) was assessed in PIK3CA-mutant breast and gynecologic expansion cohorts: 46% and 56% of patients, respectively, showed a reduction in tumor size, with RECIST responses of 4% and 8%. These responses were less than the prespecified 20% response rate; therefore, the criteria to stop further recruitment to the PIK3CA-mutant cohort were met.Conclusions: At the recommended phase II dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. Proof-of-concept responses were observed in patients with PIK3CA-mutant cancers treated with AZD5363. Clin Cancer Res; 24(9); 2050–9. ©2017 AACR.See related commentary by Costa and Bosch, p. 2029

Five to ten percent of ER+ metastatic breast cancer (MBC) tumors harbor somatic PTEN mutations. Loss of function of this tumor-suppressor gene defines a highly aggressive, treatment-refractory disease for which new therapies are urgently needed. This Phase I multipart expansion study assessed oral capivasertib with fulvestrant in patients with PTEN-mutant ER+ MBC. Safety and tolerability were assessed by standard methods. Plasma and tumor were collected for NGS and immunohistochemistry analyses of PTEN protein expression. In 31 eligible patients (12 fulvestrant naive; 19 fulvestrant pretreated), the 24-week clinical benefit rate was 17% in fulvestrant-naive and 42% in fulvestrant-pretreated patients, with objective response rate of 8% and 21%, respectively. Non-functional PTEN was centrally confirmed in all cases by NGS or immunohistochemistry. Co­mutations occurred in PIK3CA (32%), with less ESR1 (10% vs 72%) and more TP53 (40% vs 28%) alterations in fulvestrant-naive versus fulvestrant-pretreated patients, respectively. PTEN was clonally dominant in most patients. Treatment-related grade ≥3 adverse events occurred in 32% of patients, most frequently diarrhea and maculopapular rash (both n = 2). In this clinical study, which selectively targeted the aggressive PTEN-mutant ER+ MBC, capivasertib plus fulvestrant was tolerable and clinically active. Phenotypic and genomic differences were apparent between fulvestrant-naive and -pretreated patients.Trial registration number for the study is NCT01226316.

Background: In the PAKT study, addition of the oral AKT inhibitor capivasertib to 1st-line paclitaxel therapy for metastatic TNBC resulted in significantly longer progression-free survival (PFS; primary endpoint; Schmid, J Clin Oncol 2020). The stratified PFS hazard ratio was 0.74 (95% CI, 0.50-1.08; one-sided P=0.06; predefined significance level of 0.10, one-sided; median PFS 5.9 vs 4.2 months with capivasertib vs placebo). Overall survival (OS) results were immature at the primary analysis with 53% of events but suggested long OS with capivasertib (HR, 0.61; 95% CI, 0.37-0.99; two-sided P=0.04). Here we report final results. Methods: This double-blind, placebo-controlled, randomised phase II trial, recruited women with untreated, metastatic TNBC. Total of 140 patients were randomly assigned (1:1) to paclitaxel 90mg/m2 (days 1, 8, 15) with either capivasertib (400mg twice daily) or placebo (days 2-5, 9-12, 16-19) every 28 days until disease progression or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included OS in the ITT population and in patients with and without PIK3CA/AKT1/PTEN-alterations. Results: With a median F/U of 40.0 months, median OS was longer in the capivasertib arm (19.1 vs 13.5 months, stratified HR 0.70, 95% CI 0.47-1.05, p=0.085). In contrast to the earlier analysis, no meaningful differences were seen in terms of benefit with capivasertib between patients with or without alterations of PIK3CA/AKT1/PTEN. Median OS numerically favoured capivasertib vs placebo both in the PIK3CA/AKT1/PTEN-altered (stratified HR 0.58, 95% CI 0.21-1.58, p=0.290) and PIK3CA/AKT1/PTEN non-altered subgroup (stratified HR 0.74, 95% CI 0.47-1.18, p=0.207). The safety profile of capivasertib plus paclitaxel was unchanged. Conclusions: Final OS results show a numerical trend favouring capivasertib; effects were observed regardless of PIK3CA/AKT1/PTEN alterations. Consistent with the previously observed PFS benefit, these findings support further evaluation of first-line Capivasertib plus paclitaxel for metastatic TNBC in the ongoing Capitello290 randomised phase III trial in patients with and without PIK3CA/AKT1/PTEN alterations. Citation Format: Peter Schmid, Jacinta Abraham, Stephen Chan, Adrian Murray Brunt, Gia Nemsadze, Richard D Baird, Yeon Hee Park, Peter Hall, Timothy Perren, Robert C Stein, László Mangel, Jean-Marc Ferrero, Melissa Phillips, John Conibear, Javier Cortes, Andrew Foxley, Elza de Bruin, Robert McEwen, Myria Nikolaou, Daniel Stetson, Brian Dougherty, Aaron Prendergast, Max McLaughlin-Callan, Matthew Burgess, Cheryl Lawrence, Hayley Cartwright, Kelly Mousa, Nicholas Turner, Duncan Wheatley. Mature survival update of the double-blind placebo-controlled randomised phase II PAKT trial of first-line capivasertib plus paclitaxel for metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-11.

Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)–deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K–AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off. Pharmacokinetics were dose proportional. Pharmacodynamic studies confirmed phosphorylated (p) GSK3β suppression, increased pERK, and decreased BRCA1 expression. Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without DDR and PI3K–AKT pathway alterations. Significance: In the first trial to combine PARP and AKT inhibitors, a prospective intrapatient dose- escalation design demonstrated safety, tolerability, and pharmacokinetic–pharmacodynamic activity and assessed predictive biomarkers of response/resistance. Antitumor activity was observed in patients harboring tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DDR and/or PI3K–AKT pathway alterations. This article is highlighted in the In This Issue feature, p. 1426

Purpose:The activating mutation AKT1E17K occurs in approximately 7% of estrogen receptor–positive (ER+) metastatic breast cancer (MBC). We report, from a multipart, first-in-human, phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of patients with AKT1E17K-mutant ER+ MBC.Patients and Methods:Patients with an AKT1E17K mutation, detected by local (next-generation sequencing) or central (plasma-based BEAMing) testing, received capivasertib 480 mg twice daily, 4 days on, 3 days off, weekly or 400 mg twice daily combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS), and clinical benefit rate at 24 weeks (CBR24). Biomarker analyses were conducted in the combination cohort.Results:From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although the latter group may have had more aggressive disease at baseline. AKT1E17K mutations were detectable in plasma by BEAMing (95%, 41/43), droplet digital PCR (80%, 33/41), and next-generation sequencing (76%, 31/41). A ≥50% decrease in AKT1E17K at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy [most frequent grade ≥3 adverse events: rash (9% vs. 20%), hyperglycemia (5% vs. 30%), diarrhea (5% vs. 10%)].Conclusions:Capivasertib demonstrated clinically meaningful activity in heavily pretreated patients with AKT1E17K-mutant ER+ MBC, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination.

Background: Loss of function in the tumor suppressor gene, PTEN, activates PI3K/AKT signaling, driving tumor growth. Somatic mutations in PTEN occur in 5-10% of estrogen-receptor-positive (ER+) breast cancer (BC), and PTEN loss/inactivation is associated with an aggressive BC phenotype and poor outcome. Capivasertib, a pan-AKT kinase inhibitor, has shown antitumor activity in solid tumors. In ER+ BC, suppression of PI3K/AKT signaling results in a compensatory increase in ER-dependent transcription, potentially limiting the efficacy of AKT inhibitors when given as monotherapy. We therefore investigated concurrent inhibition of AKT and ER with combination therapy of capivasertib and fulvestrant in PTEN-mutant ER+ metastatic BC (MBC). Methods: In an expansion cohort (part F) of a Phase I study (NCT01226316), oral capivasertib 400 mg twice daily, 4 days on 3 days off, and fulvestrant at labeled dose, was administered to ER+ MBC patients (pts) with tumors harboring a deleterious PTEN alteration (identified in tissue/plasma by local next-generation sequencing [NGS], with central NGS and immunohistochemistry [IHC] performed retrospectively). Pts were enrolled in fulvestrant-naïve (FN) or fulvestrant-resistant (FR) cohorts (max 24 pts/cohort). Key objectives included safety and efficacy based on 24-week clinical benefit rate (CBR). Results: At data cut-off, 31 pts (12 FN; 19 FR) received treatment. Median number of prior metastatic regimens was 7. FN pts had higher rates of visceral disease (100%) and prior chemotherapy receipt (median 4 [range 0-8]) than FR pts (84%; median 2 [1-7]), respectively]. CBR and median progression-free survival (PFS) were 17% and 2.6 months in FN pts, and 37% and 4.1 months in FR pts, respectively (Table). Twenty-four patients (77%) had PTEN mutations and 7 (23%) had PTEN gene deletions determined by local NGS. Central plasma NGS confirmed 79% (19/24) of the PTEN mutations, and IHC confirmed complete loss of the PTENprotein in 85% (22/26) of cases. Treatment-related grade ≥3 adverse events (AEs) occurred in 32%, most frequently diarrhea and maculopapular rash (both n=2 pts). Treatment-related AEs resulted in dose reduction in 2 pts. Table. Clinical efficacyFN, n=12FR, n=19ORR, % (95% CI)8 (0.2, 39)21 (6, 46)CBR, % (95% CI)17 (2, 48)37 (16, 62)Confirmed response, n (%)1 (8)4 (21)Stable disease ≥24 weeks, n (%)2 (17)3 (16)Median PFS, months (95% CI)2.6 (1.2–4.2)4.1 (1.5–6.7)Median duration of response, months (95% CI)5.5 (NC–NC)6.9 (1.4–NC)Data cut-off was 21 March 2019. Median time from last fulvestrant administration to study entry in FR pts (n=19) was 13.8 months (range 0.7–28.2). CBR was defined as confirmed responders and those with stable disease ≥24 weeks. NC, not calculable (because of limited pt numbers); ORR, objective response rate Conclusions: Capivasertib plus fulvestrant is clinically active in heavily pretreated PTEN-mutated ER+ MBC, including in pts with prior resistance to fulvestrant. Efficacy appeared marginally better in FR than FN pts, possibly due to enrichment of pts with more aggressive disease in the FN cohort. Further analyses of the relationship between genomic features, such as concurrent mutations with drug activity, will be reported. Citation Format: Lillian M Smyth, Gerald Batist, Funda Meric-Bernstam, Peter Kabos, Iben Spanggaard, Ana Lluch, Alison Schram, Andrea Varga, Andrea Wong, Helen Ambrose, Alan Barnicle, T. Hedley Carr, Elza C de Bruin, Carolina Salinas-Souza, Andrew Foxley, Joana Hauser, Justin PO Lindemann, Rhiannon Maudsley, Robert McEwen, Michele Moschetta, Martine Roudier, Gaia Schiavon, Pedram Razavi, Udai Banerji, Sarat Chandarlapaty, José Baselga, David M Hyman. Capivasertib (AZD5363) in combination with fulvestrant in PTEN-mutant ER+ metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-05.

Background: Triple-negative breast cancer (TNBC) generally has an aggressive clinical course, including distant metastases and increased likelihood of death within 5 years of diagnosis compared with non-TNBCs. Therapeutic options for metastatic TNBC patients are limited to sequential chemotherapy, although recent advances with novel agents have been made for specific subgroups (PD-L1 inhibitor atezolizumab in combination with nab-paclitaxel in patients with PD-L1-positive tumors and PARP inhibitors in germline BRCA-mutant patients). However, improvements in progression-free survival (PFS) derived from immune-oncology and PARP inhibitors are still insufficient in terms of informing patient selection and overall magnitude of benefit. Developing novel treatments in both early and advanced TNBC settings remains a significant unmet need in the management of advanced breast cancer. The PI3K/AKT/PTEN signaling pathway is often activated in TNBC, mainly through activating mutations in PIK3CA or AKT1 and/or inactivating alterations in PTEN. The Phase II PAKT study (NCT02423603) demonstrated that addition of the oral AKT inhibitor capivasertib to first-line paclitaxel resulted in significantly longer PFS and overall survival (OS) in patients with advanced TNBC, especially in patients with PIK3CA/AKT1/PTEN-altered tumors (Schmid, 2018). The Phase III trial we report (NCT03997123) will further evaluate the efficacy and safety of capivasertib in combination with paclitaxel in first-line treatment of patients with metastatic TNBC in an unselected population and will also explore potential predictive markers of sensitivity to the combination of paclitaxel and capivasertib. Methods: Eligible patients for this double-blind, randomized, placebo-controlled trial must have metastatic TNBC or locally advanced disease not amenable to resection with curative intent. Patients must be candidates for single-agent taxane therapy and have received no prior systemic therapy for locally advanced inoperable or metastatic disease. Prior chemotherapy in the (neo)adjuvant setting must be completed ≥12 months prior to enrollment. Patients will be randomized 1:1 to paclitaxel 80 mg/m2 (days 1, 8 and 15) with either capivasertib 400 mg twice daily or placebo (days 2-5, 9-12, 16-19) every 28 days until objective radiologic disease progression as defined by RECIST 1.1, unacceptable toxicity, or death. Stratification factors will be prior adjuvant chemotherapy, visceral vs non-visceral disease, and geographic region. Post-randomization central testing of tumor tissue (collected prior to enrollment) will be carried out to identify predictive markers of sensitivity to treatment. The primary endpoints of this study are PFS and OS. Secondary endpoints include safety and tolerability, time to second progression or death, objective response rate, duration of response, and clinical benefit rate. Enrollment for this study opened in May 2019. Citation Format: Peter Schmid, Javier Cortes, Mark Robson, Hiroji Iwata, Roberto Hegg, Sunil Verma, Marina Nechaeva, Binghe Xu, Vincent Haddad, Esteban Rodrigo Imedio, Gaia Schiavon, Andrew Foxley, Yeon Hee Park. Capivasertib and paclitaxel in first-line treatment of patients with metastatic triple-negative breast cancer: A phase III trial (CAPItello-290) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-08-02.

TPS287 Background: Docetaxel is the standard first-line chemotherapy for patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease progressed on an androgen receptor-targeted agent (ARTA; typically, abiraterone, enzalutamide, apalutamide, or darolutamide). However, most patients develop chemotherapy resistance, and median overall survival (OS) remains under 3 years. Preclinical studies have associated phosphoinositide 3-kinase (PI3K)/protein kinase (AKT)/phosphatase and tensin homolog (PTEN) pathway signaling with the development of mCRPC and with resistance to taxane chemotherapy. The ProCAID Phase II trial (NCT02121639) examined whether adding capivasertib, a potent, selective inhibitor of all three AKT isoforms (AKT1/2/3), to docetaxel chemotherapy improved clinical outcomes. Although no difference in the primary endpoint (composite progression-free survival [PFS]) was detected, OS, a secondary endpoint, was extended in the capivasertib plus docetaxel treatment group. A subsequent follow-up analysis at advanced maturity suggested that the OS benefit in ProCAID was restricted to patients who had received prior treatment with an ARTA. Methods: CAPItello-280 is a Phase III study to confirm the efficacy and safety of capivasertib in combination with docetaxel compared with placebo and docetaxel in patients with mCRPC who have not previously received chemotherapy for mCRPC, but whose disease has progressed despite treatment with an ARTA in any setting. Approximately 790 patients will be randomized 1:1 to receive either capivasertib or matching placebo (320 mg orally, twice daily [BD], 4 days on, 3 days off) plus docetaxel (75 mg/m2 on day 1 of each 21-day cycle for 6–10 cycles, with prednisone or prednisolone 5 mg BD or 10 mg once daily) with a background of continued androgen deprivation therapy until disease progression, unacceptable toxicity, death, or withdrawal of consent. The primary endpoint is OS; secondary endpoints include radiographic PFS, time to pain progression, symptomatic skeletal events, safety, and tolerability. Recruitment began in March 2022 and is planned at 207 study sites in 20 countries, including the USA, Canada, Europe, South America, and Asia-Pacific. Clinical trial information: NCT05348577 .

Background: Capivasertib (AZD5363), an AKT1,2,3 inhibitor, significantly improved progression-free and overall survival when added to paclitaxel in triple negative breast cancer (BC) patients (Schmid et al. ASCO 2018). We have previously reported in STAKT, robust target inhibition at 480mg BD versus placebo, including significant decreases in the primary biomarkers (PBs) - Ki67, pPRAS40 & pGSK3β - in primary BCs (Robertson et al. SABCS 2017). We now report the dose- and exposure-response relationship of capivasertib and the correlation between primary and secondary (pAKT, pS6, nuclear FOXO3a) tumor biomarkers. Design: STAKT was a two-stage, double blind, randomized, placebo controlled 'window-of-opportunity' trial in newly diagnosed ER+ BC patients. Stage 1 assessed capivasertib at a dose of 480mg BD p.o. versus placebo. Stage 2 assessed capivasertib at two lower doses 360mg and 240mg BD. Tumor biopsies were taken prior to 1st dose and after 4.5 days of dosing. Evaluable patients (who required pre-defined minimum baseline PD values for PBs) included placebo (n=11), capivasertib at 480mg (n=17), 360mg (n=5) and 240mg (n=6). Blood samples for pharmacokinetic (PK) studies were scheduled at pre-dose; 2, 4, optional 6 & 8 hrs post first dose on Day 1; ˜2-4 h post last dose on Day 5 (before biopsy). The % change from baseline for PBs were evaluated against the following exposure variables (placebo=0): i) Dose, ii) Observed Cmax Day 1 (˜2h post-dose), iii) Observed plasma concentration on Day 5, iv) Model-predicted plasma concentration Day 5 at time of biopsy, and v) Model-predicted AUC on Day 5. Spearman correlation coefficient measured the strength and direction of association between biomarkers. Results: · Significant mean reductions in % change from baseline were observed for the PBs pGSK3β (-39%; p · Dose-response relationships for individual % change from baseline could be described by an Emax model for all PBs. Overall, the correlation to PK exposure (observed or predicted) was similar to the correlation to dose. · Correlation coefficient analyses between biomarkers at capivasertib 480mg BD identified- i) Positive correlations for pGSK3β with Ki67 (ρ = 0.52, p-value < 0.05) & with pS6 (ρ = 0.54, p-value Conclusions · Capivasertib caused dose- and concentration- dependent effects on biomarkers after only 4.5 days. · Significant changes in the PBs were demonstrated at 480 mg BD. Biomarker changes was observed at 360mg and 240mg BD, but statistical analysis was limited by the small sample size at lower doses. · Correlation between a number of tumor biomarkers (relative changes) were identified for capivasertib 480mg BD. Citation Format: Gee J, Coleman RE, Cheung KL, Evans A, Holcombe C, Skene A, Rea D, Ahmed S, Jahan A, Horgan K, Rauchhaus P, Littleford R, Finlay P, Cheung A, Cullberg M, de Bruin E, Foxley A, Koulai L, Pass M, Schiavon G, Rugman P, Deb R, Robertson JFR. Dose- and exposure-response relationship and biomarker correlation analysis in breast tumors from patients treated with capivasertib, an AKT inhibitor, in the STAKT randomized, placebo controlled pre-surgical study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-12-01.

1005 Background: Previous results from the Phase 2 FAKTION trial (NCT01992952) showed progression free survival (PFS) in patients with aromatase inhibitor (AI) resistant ER+/HER2− advanced breast cancer was significantly longer with fulvestrant plus capivasertib vs fulvestrant plus placebo. At the time of analysis, PFS benefit associated with capivasertib was not restricted to patients with activating mutations in PIK3CA (E542K, E545K, H1047R or H1047L) or PTEN protein null. We report now mature overall survival (OS) data with enhanced biomarker analysis. Methods: For the enhanced analysis, available tissue and plasma samples were sent for targeted next generation sequencing (NGS) with Foundation One CDx and GuardantOMNI assays. ‘Pathway altered’ (PA) was defined as any activating mutation in PIK3CA (exons 1,4,7,9,20) or AKT1 (E17K only) or inactivating alterations in PTEN. For samples not tested by targeted NGS, previously reported digital droplet PCR (ddPCR) results for PIK3CA were used, in addition to tissue AKT1 ddPCR analysis performed after the initial publication. Concordance between mutations identified by ddPCR and subsequent NGS was 97%. Results: In January 2022, 108 OS events were reported (77% maturity) in the intention to treat (ITT) population. The median OS was 29.3 vs 23.4 months (mo) in the capivasertib (n = 69) vs placebo (n = 71) arms respectively (HR 0.66, 95% CI 0.45–0.97; p = 0.035). In the enhanced biomarker analysis, 76 participants were classified as PA compared to 59 in the original analysis. In the PA group, OS was 39.0 vs 20.0 mo in the capivasertib vs placebo arms respectively (HR 0.46, 95% CI: 0.27–0.79; p = 0.005). Within the pathway non-altered (PNA) group, median OS was 26.0 vs 25.2 mo in the capivasertib vs placebo arms respectively (HR 0.86, 95% CI: 0.49–1.52; p = 0.60). In the updated PFS analysis, the advantage in the ITT population persisted with capivasertib vs placebo (median 10.3 vs 4.8 mo, HR 0.56, 95% CI: 0.38–0.81; p = 0.002). PFS analysis against the updated biomarker subgroups shows a significant improvement in PFS in the PA group: 12.8 vs 4.6 mo in the capivasertib vs placebo arms respectively (HR 0.44, 95% CI: 0.26–0.72; p = 0.001). In the PNA group, median PFS was 7.7 vs 4.9 mo in the capivasertib vs placebo arms respectively (HR 0.70, 95% CI: 0.40–1.25; p = 0.23). Conclusions: Updated analysis of the FAKTION trial data show a significant improvement in OS in the ITT population. Enhanced subgroup analysis suggests that the benefit of capivasertib in both PFS and OS may be predominantly in patients with PIK3CA/AKT1/PTEN pathway altered tumours, but further elucidation will be forthcoming from the ongoing Phase 3 CAPItello-291 study in which participants with PA and PNA tumours have been recruited. Clinical trial information: NCT01992952.

Preclinical studies have demonstrated synergy between poly(ADP-ribose) polymerase (PARP) and phosphatidylinositol-3-kinase (PI3K)/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)-deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose-escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2-wildtype cancers harboring somatic DNA damage response (DDR) or PI3K/AKT pathway alterations. The combination was well-tolerated. Recommended phase 2 doses for the two schedules were: olaparib 300mg BID with either capivasertib 400mg BID 4- days-on, 3-days-off, or capivasertib 640mg BID 2-days-on, 5-days-off. Pharmacokinetics were dose-proportional. Pharmacodynamic studies confirmed pGSK3β suppression, increased pERK and decreased BRCA1 expression. 25 (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST CR/PR or stable disease ≥4 months), including patients with tumors harboring germline BRCA1/2- mutations and BRCA1/2-wildtype cancers with or without DDR and PI3K/AKT pathway alterations.

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.

PURPOSE: The activating mutation AKT1(E17K) occurs in ~7% of ER+ metastatic breast cancer (MBC). We report, from a multipart, first-in-human, Phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of AKT1(E17K)-mutant ER+ MBC patients. PATIENTS AND METHODS: Patients with an AKT1(E17K) mutation, detected by local (NGS) or central (plasma-based BEAMing) testing, received capivasertib 480 mg bid, 4 days on, 3 days off, weekly or 400 mg bid combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS) and clinical benefit rate at 24 weeks (CBR(24)). Biomarker analyses were conducted in the combination cohort. RESULTS: From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although this latter group may have had more aggressive disease at baseline. AKT1(E17K) mutations were detectable in plasma by BEAMing (95%, 41/43), ddPCR (80%, 33/41) and NGS (76%, 31/41). A ≥50% decrease in AKT1(E17K) at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy (most frequent grade ≥3 adverse events: rash [9% vs 20%], hyperglycemia [5% vs 30%], diarrhea [5% vs 10%]). CONCLUSIONS: Capivasertib demonstrated clinically meaningful activity in heavily pretreated AKT1(E17K)-mutant ER+ MBC patients, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination.

PURPOSE: AZD5363 is a potent pan-AKT inhibitor originally formulated as a capsule; a tablet was developed for patient convenience and manufacturing ease. This study assessed the PK comparability of both formulations (Part A) and the effect of food (Part B) on the PK/safety of the tablet.METHODS: Adults with advanced solid tumours received AZD5363 480 mg bid in a partially fasted state by tablet (Week 1) and capsule (Week 2) in a '4-days-on/3-days-off' schedule (Part A). PK parameters were evaluated using pre-defined 90% CIs for AUCτ and Cmax ratios of 0.75-1.33 to assess comparability. In Part B, AZD5363 tablet was given to a new cohort of patients under the same conditions as Part A, except on the morning of PK assessment days, when it was administered after an overnight fast (Week 1) and standard meal (Week 2).RESULTS: In evaluable patients (N = 11), the geometric least-squares mean ratios (tablet:capsule) for AUCτ and Cmax were 0.90 (0.77-1.06) and 1.02 (0.86-1.20), respectively, demonstrating comparable PK in the partially fasted state. Tablet and capsule safety data were also comparable. Tablet PK profiles indicated later tmax and lower Cmax after food versus overnight fast. Fed and fasted AUCτ and Cmax ratios were 0.89 (0.76-1.05) and 0.67 (0.55-0.82), respectively (N = 9). The safety/tolerability profile of the tablet was comparable between fed and fasted states.CONCLUSIONS: PK and safety/tolerability of AZD5363 tablet and capsule were comparable. Food did not affect the bioavailability of AZD5363, but reduced the absorption rate without discernibly affecting safety/tolerability.

This abstract was withdrawn by the authors.

Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary activity of AKT inhibition in AKT-mutant cancers. Patients and Methods Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary end points were progression-free survival (PFS) and response according to Response Evaluation Criteria in Solid Tumors (RECIST). Tumor biopsies and plasma cell-free DNA (cfDNA) were collected in the majority of patients to identify predictive biomarkers of response. Results In patients with AKT1 E17K–mutant tumors (n = 52) and a median of five lines of prior therapy, the median PFS was 5.5 months (95% CI, 2.9 to 6.9 months), 6.6 months (95% CI, 1.5 to 8.3 months), and 4.2 months (95% CI, 2.1 to 12.8 months) in patients with estrogen receptor–positive breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K–mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS (hazard ratio [HR], 0.41; P = .04), as was the presence of coincident PI3K pathway hotspot mutations (HR, 0.21; P = .045). Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS (HR, 0.18; P = .004) and response ( P = .025). Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. The most common grade ≥ 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). Conclusion This study provides the first clinical data that AKT1 E17K is a therapeutic target in human cancer. The genomic context of the AKT1 E17K mutation further conditioned response to AZD5363.

This abstract was withdrawn by the authors.

Background Capivasertib (AZD5363) is a potent selective oral inhibitor of all three isoforms of, the serine/threonine kinase, Akt. Akt inhibitors are anticipated to have maximal efficacy in combination with chemotherapy, targeted, or anti-hormonal drugs. The FAKTION trial investigated whether the addition of capivasertib to fulvestrant improved progression-free survival in patients with aromatase inhibitor resistant advanced breast cancer.Methods In this randomised, phase 2, double-blind, placebo-controlled trial, postmenopausal women aged at least18 years with an Eastern Cooperative Oncology Group performance status of 0–2 and oestrogen receptor-positive,HER2-negative, metastatic or locally advanced inoperable breast cancer who had relapsed or progressed on an aromatase inhibitor were recruited from 19 UK centres. Enrolled participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a loading dose onday 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off (starting on cycle 1 day 15) until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment allocation was done using an interactive web-response system using a minimisation method (with a 20% random element) and the following stratification factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival with a one-sided alpha of 0·20. Analyses were done by intention to treat. All recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov, number NCT01992952.Findings Between March 16, 2015, and March 6, 2018, 183 patients were screened for eligibility, of whom 140 (76%) were eligible and were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up for progression-free survival was 4·9 months (IQR 1·6–11·6). At the time of primary analysis for progression-free survival, 112 progression-free survival events had occurred, 49 (71%) in 69 patients in the capivasertib group compared with 63 (89%) of 71 in the placebo group. Medianprogression-free survival was 10·3 months (95% CI 5·0–13·2) in the capivasertib group versus 4·8 months (95% CI 3·1–7·7) in the placebo group, giving an unadjusted hazard ratio (HR) of 0·58 (95% CI 0·39–0·84) in favour of thecapivasertib group (two-sided p=0·0044; one-sided log rank test p-0·0018). The most common grade 3–4 adverse events were hypertension (22 [32%] of 69 patients in the capivasertib group vs 17 [24%] of 71 in the placebo group), diarrhoea (10 [14%] vs 3 [4%]), rash (14 [20%] vs 0), infection (4 [5%] vs 2 [3%]), and fatigue (1 [1%] vs 3 [4%]). Serious adverse reactions occurred only in the capivasertib group, and were acute kidney injury (2), diarrhoea (3), rash (2), hyperglycaemia (1), loss of consciousness (1), sepsis (1), and vomiting (1). One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. One further death in the capivasertib group had an unknown cause; all remaining deaths in both groups were disease related.Interpretation Progression-free survival was significantly longer in participants who received capivasertib than in those who received placebo. The combination of capivasertib and fulvestrant warrants further investigation in phase 3 trials.

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.STAKT was a two-stage, double-blind, randomized, placebo-controlled, "window-of-opportunity" study in patients with newly diagnosed ERAfter 4.5 days' exposure, capivasertib 480 mg b.i.d. (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 AKT-dependent breast cancers.

Inhibidor de l'AKT; PIK3CA; Capivasertib Inhibidor de AKT; PIK3CA; Capivasertib AKT inhibitor; PIK3CA; Capivasertib Background BEECH investigated the efficacy of capivasertib (AZD5363), an oral inhibitor of AKT isoforms 1–3, in combination with the first-line weekly paclitaxel for advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer, and in a phosphoinositide 3-kinase, catalytic, alpha polypeptide mutation sub-population (PIK3CA+). Patients and methods BEECH consisted of an open-label, phase Ib safety run-in (part A) in 38 patients with advanced breast cancer, and a randomised, placebo-controlled, double-blind, phase II expansion (part B) in 110 women with ER+/HER2− metastatic breast cancer. In part A, patients received paclitaxel 90 mg/m2 (days 1, 8 and 15 of a 28-day cycle) with capivasertib taken twice daily (b.i.d.) at two intermittent ascending dosing schedules. In part B, patients were randomly assigned, stratified by PIK3CA mutation status, to receive paclitaxel with either capivasertib or placebo. The primary end point for part A was safety to recommend a dose and schedule for part B; primary end points for part B were progression-free survival (PFS) in the overall and PIK3CA+ sub-population. Results Capivasertib was well tolerated, with a 400 mg b.i.d. 4 days on/3 days off treatment schedule selected in part A. In part B, median PFS in the overall population was 10.9 months with capivasertib versus 8.4 months with placebo [hazard ratio (HR) 0.80; P = 0.308]. In the PIK3CA+ sub-population, median PFS was 10.9 months with capivasertib versus 10.8 months with placebo (HR 1.11; P = 0.760). Based on the Common Terminology Criteria for Adverse Event v4.0, the most common grade ≥3 adverse events in the capivasertib group were diarrhoea, hyperglycaemia, neutropoenia and maculopapular rash. Dose intensity of paclitaxel was similar in both groups. Conclusions Capivasertib had no apparent impact on the tolerability and dose intensity of paclitaxel. Adding capivasertib to weekly paclitaxel did not prolong PFS in the overall population or PIK3CA+ sub-population of ER+/HER2− advanced/metastatic breast cancer patients. This study was supported by AstraZeneca (no grant number applies).

TPS178 Background: In metastatic hormone-sensitive prostate cancer (mHSPC), abiraterone combined with androgen deprivation therapy (ADT) is highly effective in improving patient outcomes. However, around 20% of patients progress to castration-resistant disease within 12 months of treatment; these patients have shorter survival and limited treatment options. Aberrant activation of the PI3K/AKT pathway, predominately due to PTEN loss, is common in prostate cancer, especially in later-stage disease. The androgen receptor signaling and AKT pathway are reciprocally cross-regulated such as that inhibition of one leads to upregulation of the other. Therefore, combining abiraterone therapy with AKT inhibition may be beneficial in patients with mHSPC who have PTEN deficiency. In preclinical studies, capivasertib, a selective oral pan-AKT inhibitor, inhibited proliferation of models of hormone-sensitive and castration-resistant prostate cancer with PTEN loss. The results of the IPATential150 phase 3 study (NCT03072238) demonstrated that another oral AKT inhibitor, ipatasertib, prolonged radiographic progression-free survival (rPFS) when combined with abiraterone compared with placebo plus abiraterone in metastatic castration-resistant prostate cancer, particularly among patients with PTEN loss. CAPItello-281 (NCT04493853) is a global, multicenter, phase 3 trial to evaluate capivasertib in combination with abiraterone, on a background of ADT, as a treatment for de novo mHSPC patients with PTEN-deficient tumors. Methods: Eligible patients for this double-blind, randomized trial are men aged 18 years or older with confirmed newly diagnosed previously untreated metastatic hormone-sensitive prostate adenocarcinoma with immunohistochemically confirmed PTEN deficiency and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Following screening, approximately 1000 patients will be randomized 1:1 to receive either capivasertib (400 mg) or placebo (twice daily; 4 days on, 3 days off) in combination with abiraterone (1000 mg once daily) and ADT until radiographic progression or intolerable toxicity. The primary endpoint is rPFS. Secondary endpoints include overall survival, time to start of first subsequent therapy or death, symptomatic skeletal event-free survival, time to pain progression and safety profile. Enrolment started in July 2020. Acknowledgments: We thank Julia Grigorieva, PhD, of Oxford PharmaGenesis, Philadelphia, USA, for providing medical writing assistance. Funding: The CAPItello-281 trial is funded and overseen by AstraZeneca. Clinical trial information: NCT04493853.

TPS1109 Background: Therapeutic options for patients with metastatic triple-negative breast cancer (TNBC) are limited to sequential chemotherapy, although recent advances with novel agents have been made for specific subgroups (PD-L1 inhibitor atezolizumab in combination with nab-paclitaxel in patients with PD-L1-positive tumors and PARP inhibitors in patients with germline BRCA mutations). The PI3K/AKT/PTEN signaling pathway is often activated in TNBC, mainly through activating mutations in PIK3CA or AKT1 and/or inactivating alterations in PTEN. The phase II PAKT study (NCT02423603) demonstrated that addition of the oral AKT inhibitor capivasertib to first-line paclitaxel resulted in significantly longer progression-free survival (PFS) and overall survival (OS) in patients with advanced TNBC, especially in patients with PIK3CA/AKT1/PTEN-altered tumors (Schmid et al, 2019). This phase III trial (NCT03997123) will further evaluate the efficacy and safety of capivasertib in combination with paclitaxel in first-line treatment of patients with metastatic TNBC in an unselected population and will also explore potential predictive markers of sensitivity to the combination of paclitaxel and capivasertib. Methods: Eligible patients for this double-blind, randomized, placebo-controlled trial must have metastatic TNBC or locally advanced disease not amenable to resection with curative intent. Patients must be candidates for single-agent taxane therapy and have received no prior systemic therapy for locally advanced inoperable or metastatic disease. Prior chemotherapy in the (neo)adjuvant setting must be completed ≥12 months prior to enrollment. Patients will be randomized 1:1 to paclitaxel 80 mg/m2 (days 1, 8 and 15) with either capivasertib 400 mg twice daily or placebo (days 2–5, 9–12 and 16–19) every 28 days, until objective radiologic disease progression as defined by RECIST 1.1, unacceptable toxicity or death. Stratification factors will be prior adjuvant chemotherapy, visceral versus non-visceral disease, and geographic region. Post-randomization central testing of tumor tissue (collected prior to enrollment) will be carried out to identify predictive markers of sensitivity to treatment. The primary endpoints of this study are PFS and OS. Secondary endpoints include safety and tolerability, time to second progression or death, objective response rate, duration of response, and clinical benefit rate. Enrollment for this study started in May 2019. Clinical trial information: NCT03997123 .

Background: AKT is an important intracellular control point through which Type 1 growth factors and IGFR signal. Mutations in PIK3CA, AKT and PTEN are prevalent in estrogen receptor positive (ER+) breast cancer (BC) and have been implicated in resistance to endocrine therapies. AZD5363 is an inhibitor of AKT 1, 2 and 3 currently in Phase 2 trials for BC and other solid cancers. Design: The study examined whether AZD5363 impacts on key biomarkers within the AKT pathway and their subsequent effects on Ki67, a marker of tumor proliferation. STAKT is a multi-center, two-stage, double blind, randomized, placebo controlled, biomarker 'window-of-opportunity' trial in women with newly diagnosed, previously untreated ER+ BC who were deemed would require chemotherapy as part of their primary treatment regimen. Stage 1 assessed AZD5363 at a dose of 480mg bd p.o. versus matching placebo. Up to 30 patients per arm were permitted, to allow 12 subjects per arm with evaluable paired biopsies - obtained at baseline, and after 4.5 days of AZD5363 / placebo. Primary endpoint markers were pPRAS40, pGSK3β and Ki67 assessed by immunohistochemistry. pPRAS40 and pGSK3β were assessed by H-scores and measured separately for cytoplasmic (cyto), nuclear (nuc) and total (cyto+nuc) staining. Ki67 was assessed as % positive staining of 500 tumor nuclei. Laboratory staff were blinded to treatment arm and whether the biopsies were taken before or after AZD5363/placebo. Changes in marker expression (both absolute and %) between biopsies were calculated, and compared between the two groups. An ANOVA test was applied for normally distributed data and Wilcoxon Mann-Whitney used if not normally distributed. Results: 28/36 patients were evaluable with patient & tumor characteristics as follows: 17 received AZD5363 and 11 placebo; the median ages were 48 & 49 years respectively. 27 patients were Caucasian and 1 African-American. Tumors were all ER+. For HER2 status 8 were positive & 9 negative in the AZD5363 treated group compared to 2 & 9 respectively in the placebo group. For pPRAS40 and pGSK3β cyto was the predominant staining while for Ki67 staining was nuclear. Changes in each marker with associated p-values are shown in the table. MarkerType of change vs baselineDegree of change in AZD5363 arm (n=17)p-value versus placebo arm (n=11)pPRAS40 (H-score)TotalAbsolute-83.8 Conclusions• AZD5363 for 4.5 days caused highly significant falls in pGSK3β and pPRAS40, key markers of AKT pathway activation • AZD53643 also caused a significant decline in Ki67 even after only 4.5 days of drug. This is one of the shortest 'window'-studies to report such an early effect on proliferation. • Placebo controlled 'window' studies of this short duration can provide important evidence of the therapeutic potential early in a drug's development. Citation Format: Robertson JFR, Coleman RE, Cheung KL, Evans A, Holcombe C, Skene A, Rea D, Ahmed S, Jahan A, Kelly S, Horgan K, Rauchhaus P, Littleford R, Foxley A, Lindemann JPO, Pass M, Rugman P, Deb R, Finlay P, Gee JMW. AZD5363, an AKT inhibitor, significantly inhibits key biomarkers of the AKT pathway and Ki67, in a randomized, placebo, controlled study (STAKT) in human breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-06.

Background: Preclinical synergy between PARP and PI3K pathway inhibition in BRCA m and sporadic cancers provided rationale for this trial. Methods: Ola 300mg BID was combined with 2 schedules of AZD BID: 4 days on 3 days off (4/7) and 2 days on 5 days off (2/7) using a novel intrapatient dose escalation design (Michalarea et al, AACR 2015). Cohort expansion of pts with gBRCA m tumors and sporadic tumors with relevant somatic mutations or BRCAness phenotype, assessed 2 regimens: (1) 300mg BID Ola + 400mg BID 4/7 AZD and (2) 300mg BID Ola + 640mg BID 2/7 AZD. Targeted next generation sequencing (NGS) of tumor and cell-free (cf)DNA from 3-weekly plasma samples with a 113 gene panel was undertaken in all pts. Results: 53 pts with advanced cancers (21 gBRCA m) were enrolled (20 in dose escalation; 33 in dose expansion), including ovarian (9/19 with BRCA m), breast (8/16 with BRCA m), prostate (3/4 with BRCA m) and bile duct (1/2 with BRCA m) cancers. Common G1-2 toxicities were nausea, fatigue, anemia, diarrhea, anorexia, mucositis and vomiting on both schedules. 1 dose limiting toxicity (DLT) of G3 rash was seen at 300mg BID Ola + 480mg BID 4/7 AZD. In 4/7 schedule (n = 23), non-DLT G3 toxicities were anemia (n = 3), diarrhea, vomiting and proteinuria (all n = 1). In 2/7 schedule (n = 30), non-DLT G3 toxicities were transaminitis, nausea, fatigue, anemia (all n = 2), rash, hyperglycemia and diarrhea (all n = 1). There were 10 RECIST complete or partial responses (CR/PR) out of 37 (15 BRCA m) evaluable pts, including gBRCA m breast (n = 4), platinum-resistant gBRCA m ovarian (n = 2), BRCA wildtype (WT) triple negative breast (n = 1), BRCA WT ovarian (n = 2) and BRCA unknown prostate (n = 1) cancer pts. A BRCA1 m prostate cancer pt has MRI and PSA responses for 21mths+. A PI3K/mTOR inhibitor resistant peritoneal mesothelioma pt had CA125 response and RECIST stable disease (SD) for 21m. Of 5 ovarian cancer pts who had prior PARP inhibitors, 1 pt had RECIST PR at 13wks+ and 2 pts had SD with tumor shrinkage (18 and 24 wks). 160 cfDNA samples from 38 pts underwent NGS (minimum coverage 500X). Driver mutations were detected and tracked from baseline in 28 (76%) pts. Concordance in mutation status between tumor and cfDNA was 100% in 24/28 (86%) pts. 70% of pts had DNA repair gene mutations, most frequently BRCA. TP53 (40%) and KRAS (25%) were the most commonly detected somatic mutations. Changes in cfDNA concentrations appeared to correlate with treatment response in 72% of pts, while tracking of mutation allele frequency in serial cfDNA samples during treatment showed potential clonal responses. Conclusion: The combination of Ola and AZD is well tolerated with multiple responses in both gBRCA and non-BRCA m tumors, and prior PARP inhibitor treated cancers. The recommended phase 2 doses are 300mg BID Ola + 400mg BID 4/7 AZD and 300mg BID Ola + 640mg BID 2/7 AZD. Citation Format: Vasiliki Michalarea, Desam Roda, Yvette Drew, Suzanne Carreira, Brent S. O’Carrigan, Heather Shaw, Rene Roux, Sanjeev Kumar, Sarah Ward, Mona Parmar, Alison Turner, Emma Hall, Sonia Serrano Fandos, Raquel Perez, Nina Tunariu, Florence Raynaud, Marie Cullberg, Andrew Foxley, Justin PO Lindemann, Martin Pass, Paul Rugman, Juanita S. Lopez, Udai Banerji, Bristi Basu, Ruth Plummer, Rebecca Kristeleit, Johann S. de Bono, Timothy A. Yap. Phase I trial combining the PARP inhibitor olaparib (Ola) and AKT inhibitor AZD5363 (AZD) in germline (g)BRCA and non-BRCA mutant (m) advanced cancer patients (pts) incorporating noninvasive monitoring of cancer mutations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT010.

This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 10:00 AM ET Saturday, November 7. Citation Format: David M. Hyman, Lillian Smyth, Philippe L. Bedard, Amit Oza, Emma Dean, Anne Armstrong, Joao Lima, Hideaki Bando, Peter Kabos, J. Alejandro Perez-Fidalgo, Kathleen Moore, Shannon N. Westin, Benoit You, Sarat Chandarlapaty, Leila Alland, Helen Ambrose, Andrew Foxley, Justin Lindemann, Martin Pass, Paul Rugman, Shaista Salim, Gaia Schiavon, Kenji Tamura, Jose Baselga, Udai Banerji. AZD5363, a catalytic pan-Akt inhibitor, in Akt1 E17K mutation positive advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B109.

Background: The PI3K/AKT/MTOR pathway is frequently de-regulated in breast cancer. AZD5363 (AZD) is a potent selective inhibitor of AKT1-3. We report the dose-finding phase assessing the safety/tolerability of two intermittent weekly dosing schedules of AZD combined with paclitaxel (P) in HER2 negative breast cancer. The study incorporates prospective assessment of whether circulating tumour DNA (ctDNA) analysis can predict response/resistance earlier than conventional RECIST. Design: AZD capsules were dosed p.o. in one of two schedules: “4/3” (4 days on-treatment followed by 3 days off, starting 360 mg twice daily (bd)) or “2/5” (2 days on-5 days off, starting 560 mg bd). Both schedules comprised 3 weeks P 90 mg/m2 IV on Day 1 with AZD started on Day 2, and 1 week off-treatment. Patients who stopped P were able to continue AZD alone at investigators’ discretion. Escalating doses of AZD were evaluated in cohorts of 3-6 evaluable patients treated until disease progression, unacceptable toxicity, or withdrawal of consent. A safety review committee reviewed safety data and dose limiting toxicities (DLTs) prior to dose modification. Plasma samples for ctDNA extraction were collected at baseline, weekly in cycle 1, day 1 of all subsequent cycles, and were analysed by digital PCR. Female patients aged ≥18 years with HER2 negative MBC and up to two prior chemotherapy courses for advanced cancer were recruited. Results: 37 patients have received AZD. DLTs in 2/6 patients at 480 mg 4/3 comprised one patient with maculo-papular rash, and another with immune allergic reaction (both CTCAE grade 3). No DLT was observed in the 400 mg 4/3 cohort, which was defined as the maximum tolerated dose (MTD) in combination with P. DLTs in 2/6 patients at 640 mg 2/5 comprised one patient with prolonged neutropaenia (grade 4), and another with diarrhoea (grade 3). No DLTs were observed in 11 patients on the 560 mg 2/5 cohort. In all patients median progression free survival was 8.2 months, despite pre-treatment with taxane chemotherapy in 62% patients and a median of 2 prior lines of chemotherapy. A patient with Cowden's syndrome (PTEN germline mutation) had a partial response maintained for 18 months, including 12 months on AZD5363 alone. ctDNA assessment suggests that lack of a fall in ctDNA abundance may predict for early progression. Conclusions: AZD5363 400mg bd 4/3 in combination with paclitaxel was determined to be well tolerated in patients with MBC, with investigation of the 2/5 schedule continuing. Two international double-blind randomised studies have commenced to assess AZD5363 400 mg bd 4/3 schedule combined with paclitaxel versus paclitaxel plus placebo in ER positive HER2 negative MBC stratified by PIK3CA mutation status (BEECH Part B), and in triple negative breast cancer (PAKT). Citation Format: Nicholas C. Turner, Mafalda Oliveira, Anne Armstrong, Marie-Paule Sablin, José A. Perez-Fidalgo, Sarah Herebien, Isaac Garcia-Murillas, Stan Johnson, Andrew Foxley, Adnan Mahmood, Justin P. Lindemann. “BEECH”, a phase I/II study of the AKT inhibitor AZD5363 combined with paclitaxel in patients with advanced or metastatic breast cancer: results from the dose-finding study, including quantitative assessment of circulating tumor DNA as a s [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT331. doi:10.1158/1538-7445.AM2015-CT331

2577 Background: AZD5363 is a potent pan-Akt inhibitor and acts on cancers by blocking a cell survival pathway. AZD5363, administered to patients in the fasted state, was originally formulated as a...

Background: AZD5363 is a novel potent pan-AKT inhibitor (IC50of AKT1, AKT2 and AKT3 of 3, 7 and 7nM respectively) with preclinical activity across a range of models. Methods: The trial had an adaptive design that allowed changes in schedule based on toxicity, PK, and PD findings. AZD5363 was administered orally (PO) twice a day (BID). Three schedules were explored: continuous dosing (7/7), four days a week, (4/7) and two days a week (2/7). PD biomarkers including pAKT, pGSK3?, and pPRAS40 were measured by IHC in pre- and post-treatment tumor biopsies. Once a RP2D was established, two expansion cohorts of PIK3CA-mutant ER+ve breast (B) and gynecological (G) cancers were explored. Results: 47, 21 and 22 patients were treated on the 7/7, 4/7 and 2/7 schedules respectively, with a further 27 and 18 patients recruited to the B and G cohorts to date. The MTDs of 7/7, 4/7 and 2/7 were 320mg BID, 480mg BID and 640mg BID respectively. The dose limiting toxicities (DLTs) were rash and diarrhea for 7/7, and hyperglycemia for 2/7. No DLTs were identified for 4/7. The most common causally-related adverse events CTC Grade 3 were hyperglycemia (20%), diarrhea (10%), rash (10%), nausea (3%) and fatigue (1%). PK profiles at the RP2D of 480mg BID (4/7) showed a multi-dose Css,max of 1426ng/mL and AUCssof 7952ng.hr/mL, which were consistent with exposures that gave tumor regression in preclinical models. Pre- and post-treatment biopsies confirmed target engagement in tumor tissue, with an increase in pAKT and reductions in pGSK3? and pPRAS40. Based on toxicity, PK and PD profiles 480mg BID (4/7) was chosen as the R2PD for single agent AZD5363, with the option of using 640mg BID (2/7) as a pharmacologically active dose for future combination studies. Target lesion shrinkage was observed in 7/15 and 4/14 in the B and G cohorts respectively to date, and with RECIST responses in evaluable patients of 3/15 (20%) and 1/14 (7%). Conclusions: Based on toxicity, PK and PD data two intermittent schedules of AZD5363 have been identified for further exploration. Promising single agent activity has been seen in PIK3CA-mutant breast cancer providing support for ongoing combination studies. Clinical trial information: NCT01226316.

2541 Background: AZD5363 is an ATP competitive small molecule inhibitor of AKT1, AKT2 and AKT3 and is currently in phase 1 and 2 clinical trials in breast, gynaecological and prostate cancer. In pr...