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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.

Background: Estrogen receptor positive (ER+) breast cancer is routinely treated with endocrine therapies targeting the ER axis. However, primary and secondary resistance ultimately limits the use of these agents. Fulvestrant (FULV) is the first-in-class selective ER degrader (SERD) clinically effective in patients with ER+ breast cancer, both naïve and resistant to tamoxifen and aromatase inhibitors. FULV has low oral bioavailability, and its dose-dependent pharmacodynamic (PD) activity and clinical efficacy is limited by the currently approved maximal feasible dose (MFD) of 500 mg, which is administered monthly as two intramuscular injections. AZD9496 is an orally bioavailable, nonsteroidal, selective and potent degrader and antagonist of ER in preclinical models. This pre-surgical, window of opportunity study (NCT03236974) compared PD changes and the PD/pharmacokinetic (PK) relationships of AZD9496 with FULV in patients with newly diagnosed ER+ HER2- breast cancer awaiting curative intent surgery.Methods: In this open-label, multicenter study, patients were randomized 1:1 to receive oral AZD9496 250 mg BID from Day 1 for 5-14 days or FULV 500 mg administered intramuscularly on Day 1 only. On-treatment image-guided core tumor biopsies were taken between Days 5 and 14. The primary objective was to compare the effects of AZD9496 and FULV on ER expression in tumor tissue using pre-dose biopsies as baseline. Secondary objectives were changes in progesterone receptor (PR) and Ki-67 biomarkers, AZD9496 and FULV plasma concentrations during treatment, and safety. Immunohistochemistry was used to determine ER and PR H-scores, and Ki-67 index, and treatment effects were compared using an analysis of covariance model. Blood samples for PK analysis were taken at on-treatment biopsy and 1-2 hours afterwards. Adverse events (AEs) were monitored from screening through to a follow-up visit 28 days after the last study dose.Results: Of the 49 women enrolled, 46 received treatment (AZD9496 n=22; FULV n=24) and of these, 35 paired biopsies were evaluable (AZD9496 n=15; FULV n=20). The least square mean estimate for the reduction in ER H-score after AZD9496 treatment was 24% (80% CI: 34.4, 14.3), and after FULV treatment was 36% (44.9, 27.7), with a least square mean difference between AZD9496 and FULV of 12% (p=0.86). AZD9496 was not superior to FULV in terms of ER modulation at the tested dose. AZD9496 also reduced PR H-scores and Ki-67 levels from baseline (by 33.3% and 39.9%, respectively). These effects were not statistically superior to FULV at the tested dose (PR: -68.7%, p=0.97; Ki 67: 75.4%, p=0.98).Plasma exposure of AZD9496 (AUC -40%, Cmax -25%) was lower than predicted based on PK data from the previous phase 1 study, whereas FULV exposure was consistent with historical data. No clear exposure-response relationship for plasma concentration at biopsy and PD markers for AZD9496 or FULV were observed.The median treatment duration of AZD9496 was 9.5 days (range: 6-15), and the relative dose intensity was 100% (range: 90-125); no patients discontinued AZD9496. AZD9496 and FULV were both well tolerated, and no new safety findings were identified. No grade ≥3 toxicities or serious AEs occurred. Conclusion: AZD9496 250 mg BID reduced ER, PR and Ki-67 expression, and as such, is the first pre surgical study to demonstrate an oral SERD impacting its key biological targets. These reductions were not superior to the FULV clinically approved dose, which performed as expected based on historical data. Pre-surgical studies represent an important method to test the proof of mechanism of novel SERDs early in clinical development. Citation Format: John FR Robertson, Abigail Evans, Stephan Henschen, Cliona Kirwan, Ali Jahan, Laura Kenny, J. Michael Dixon, Peter Schmid, Ashutosh Kothari, Omar Mohamed, Peter A Fasching, Kwok-Leung Cheung, Rachel Wuerstlein, Danielle Carroll, Teresa Klinowska, Justin PO Lindemann, Alexander MacDonald, Richard Mather, Rhiannon Maudsley, Michele Moschetta, Myria Nikolaou, Martine P Roudier, Tinnu Sarvotham, Gaia Schiavon, Diansong Zhou, Li Zhou, Nadia Harbeck. A pre-surgical, window of opportunity study comparing the novel oral SERD AZD9496 with fulvestrant in patients with newly diagnosed ER+ HER2- primary 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 P6-04-01.