Abstract OT2-14-01: CAPItello-292: A phase Ib/III study of capivasertib, palbociclib and fulvestrant, versus placebo, palbociclib and fulvestrant, for endocrine therapy-resistant HR+/HER2− advanced breast cancer

Background: More than two-thirds of advanced breast cancer (ABC) is hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-). Endocrine therapy (ET) is the core treatment for patients with HR+/HER2- ABC, most commonly an aromatase inhibitor (AI), tamoxifen, or the selective estrogen receptor degrader (SERD), fulvestrant. ET is increasingly also combined with a cyclin-dependent kinase (CDK) 4/6 inhibitor, and this has become the first-line standard of care for HR+/HER2- ABC in many countries. However, despite the fact that combination therapy prolongs life compared with ET alone, most patients eventually develop therapy resistance and HR+/HER2- ABC is considered incurable. Overcoming therapy resistance is a major challenge, partially because it is associated with several different mechanisms. The phosphoinositide 3-kinase/protein kinase/phosphatase and tensin homologue (PI3K/AKT/PTEN) pathway regulates cell growth, proliferation and survival. Increased PI3K/AKT/PTEN pathway activity has been observed as one of the key mechanisms driving resistance to the combination therapy of ET and CDK4/6 inhibitors. Capivasertib is a potent selective inhibitor of all three AKT isoforms that suppresses PI3K/AKT/PTEN pathway activity. Capivasertib has demonstrated synergistic anticancer activity with standard ET agents in in vitro and in vivo experimental models. Moreover, the Phase II FAKTION trial found that patients with AI-resistant HR+/HER2- ABC had longer progression-free survival (PFS) when capivasertib was added to fulvestrant therapy, compared with fulvestrant alone. CAPItello-292 is a Phase Ib/III trial examining the safety, tolerability and clinical benefit of adding AKT inhibition (with capivasertib) to combined CDK4/6 inhibition (with palbociclib) and ET (with fulvestrant) for patients with ET-resistant HR+/HER2- ABC. Trial design: CAPItello-292 (NCT04862663) is enrolling patients with HR+/HER2- locally advanced or metastatic breast cancer whose disease progressed or recurred while receiving ET or within 12 months of completing an ET (neo)adjuvant regimen. The Phase Ib trial will identify the recommended Phase III dose (RP3D) for combined capivasertib, palbociclib and fulvestrant therapy. Up to 72 patients will be enrolled for the Phase Ib part. The initial regimen will be capivasertib (320 mg twice daily; 4 days on, 3 days off through each 28-day cycle), palbociclib (125 mg once daily for 21 days of each 28-day cycle) and fulvestrant (500 mg once every 28 days, plus a loading dose on day 15 of the first cycle). In the Phase III part, approximately 628 patients will be randomized 1:1 to receive either the RP3D of the triplet or placebo plus palbociclib and fulvestrant until disease progression, unacceptable toxicity or withdrawal of consent. The Phase III primary endpoint is PFS. Secondary endpoints include safety, tolerability and overall survival, as well as PFS of patients whose tumors have PIK3CA/AKT1/PTEN alterations. The first site for the study was activated in mid-May 2021. As of July 2021, two patients have been dosed in the first cohort. Funding and acknowledgements: CAPItello-292 is funded and overseen by AstraZeneca. AstraZeneca funded medical writing support provided by Rose Goodchild, PhD, of Oxford PharmaGenesis, Oxford, UK. This abstract was previously presented at the 2021 European Society for Medical Oncology (ESMO) Annual Meeting, 3019TiP, Erika Hamilton et al. - Reused with permission. Citation Format: Hope S Rugo, Gaia Schiavon, Lynda M Grinsted, Elza C De Bruin, Maria Teresa Catanese, Erika Hamilton. CAPItello-292: A phase Ib/III study of capivasertib, palbociclib and fulvestrant, versus placebo, palbociclib and fulvestrant, for endocrine therapy-resistant HR+/HER2− advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-14-01.