Abstract 350TiP
Background
Endocrine therapies (ET) targeting the oestrogen receptor (ER) are integral to the treatment of hormone receptor-positive (HR+) breast cancer (BC). However, resistance develops in most patients with advanced BC. Studies show increased PI3K/AKT signalling upon development of ET resistance and increased dependency on the PI3K/AKT pathway for cell survival. In BC models, endocrine resistance was overcome synergistically by treatment with the AKT inhibitor capivasertib combined with fulvestrant, a selective ER degrader. Therefore, a rationale exists for simultaneously targeting the ER and PI3K/AKT pathway in patients with BC. In the phase II FAKTION study (NCT01992952), adding capivasertib to fulvestrant significantly prolonged progression-free survival (PFS) in patients with aromatase inhibitor (AI)-resistant HR+/HER2− locally advanced or metastatic BC. The phase III CAPItello-291 trial (NCT04305496) will further evaluate this combination.
Trial design
Eligible patients for this double-blind randomized trial are pre-/post-menopausal women or men with locally advanced (inoperable) or metastatic HR+/HER2− BC with recurrence or progression while receiving, or within 12 months of the end of, (neo)adjuvant AI therapy, or progression during treatment with AI. Patients must provide a tumour sample for central testing to determine PIK3CA/AKT1/PTEN mutation status and identify predictive markers of sensitivity to treatment. Up to 2 prior lines of ET and/or ≤1 line of chemotherapy for locally advanced or metastatic BC are allowed. Patients are randomized 1:1 to fulvestrant (500 mg intramuscularly on days 1 and 15 of cycle 1 and day 1 of subsequent 28-day treatment cycles) with either oral capivasertib or placebo (400 mg twice daily, 4 days on and 3 days off) until objective radiological disease progression (defined by RECIST 1.1), unacceptable toxicity or patient withdrawal. The primary endpoint is PFS. Secondary endpoints include PFS in the PIK3CA/AKT1/PTEN-altered subgroup, overall survival, safety and tolerability, time to second progression or death, overall response rate, duration of response and clinical benefit rate. Enrolment started in April 2020.
Clinical trial identification
NCT04305496.
Editorial acknowledgement
Medical writing assistance was provided by Adam Errington, PhD, of Oxford PharmaGenesis.
Legal entity responsible for the study
AstraZeneca.
Funding
The CAPItello-291 trial is funded and overseen by AstraZeneca.
Disclosure
N. Turner: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Merck Sharpe and Dohme; Honoraria (self), Advisory/Consultancy: Novartis ; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Roche/Genetech; Honoraria (self), Advisory/Consultancy: Bicycle Therapeutics ; Honoraria (self), Advisory/Consultancy: Taiho; Honoraria (self), Advisory/Consultancy: Zeno Pharmaceuticals ; Honoraria (self), Advisory/Consultancy: Repare Therapeutics ; Research grant/Funding (self): BioRad; Research grant/Funding (self): Clovis; Research grant/Funding (self): Guardant health. S. Howell: Honoraria (self): Eisai; Advisory/Consultancy: Genomic health; Speaker Bureau/Expert testimony: Pfizer ; Advisory/Consultancy: AbbVie; Advisory/Consultancy: Novartis ; Research grant/Funding (institution): Evgen Pharma PLC. K. Jhaveri: Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Pfizer ; Advisory/Consultancy, Research grant/Funding (institution): Genetech; Advisory/Consultancy, Research grant/Funding (institution): Lilly Pharmaceutical; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): ADC Therapeutics ; Advisory/Consultancy: Taiho Oncology; Advisory/Consultancy: Jounce Therapeutics ; Advisory/Consultancy: AbbVie; Advisory/Consultancy: Synthon; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Puma Biotechnology ; Research grant/Funding (institution): Zymeworks; Research grant/Funding (institution): Debio Pharmaceuticals ; Research grant/Funding (institution): Clovis Oncology; Research grant/Funding (institution): Novita Pharmaceuticals. H. Gomez: Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Speaker Bureau/Expert testimony, Research grant/Funding (self), Principle investigator : MSD; Speaker Bureau/Expert testimony: Novartis ; Leadership role, Non-remunerated activity/ies, Previous President : Sociedad Peruana De Cancerología; Leadership role, Non-remunerated activity/ies, Current president : Oncology Latinoamercia Association . M. Toi: Honoraria (self), Research grant/Funding (institution), Honoraria for lectures -20,000E for 5 years; Research Fund 50,000E- for 5 years: Taiho; Honoraria (self), Research grant/Funding (institution), Honoraria for lectures -20,000E for 5 years; Research Fund 50,000E- for 5 years: Chugai; Honoraria (self), Research grant/Funding (institution), Honoraria for lectures -20,000E for 5 years; Research Fund 20,000E-50,000E for 5 years: Takeda; Honoraria (self), Honoraria for lectures -20,000E for 5 years: Shimadzu; Honoraria (self), Research grant/Funding (institution), Honoraria for lectures -20,000E for 5 years; Research Fund 50,000E- for 5 years: Daiichi-Sankyo; Honoraria (self), Research grant/Funding (institution), Honoraria for lectures -20,000E for 5 years; Research Fund 50,000E- for 5 years: Eisai; Honoraria (self), Honoraria for lectures -20,000E for 5 years: Yakult; Honoraria (self), Research grant/Funding (institution), Honoraria for lectures -20,000E for 5 years; Research Fund 20,000E-50,000E for 5 years: Kyowa Kirin; Honoraria (self), Research grant/Funding (institution), Honoraria for lectures -20,000E for 5 years; Research Fund 20,000E-50,000E for 5 years: Pfizer; Honoraria (self), Honoraria for lectures -20,000E for 5 years: Eli Lilly; Honoraria (self), Honoraria for lectures -20,000E for 5 years: MSD; Honoraria (self), Advisory/Consultancy, Honoraria for attending an advisory meeting -20,000E for 5 years: Genomic Health; Honoraria (self), Research grant/Funding (institution), Honoraria for lectures -20,000E for 5 years; Research Fund 50,000E- for 5 years: AstraZeneca; Honoraria (self), Honoraria for lectures -20,000E for 5 years: Novartis; Honoraria (self), Honoraria for lectures -20,000E for 5 years: Bayer; Honoraria (self), Honoraria for lectures -20,000E for 5 years: Terumo; Honoraria (self), Research grant/Funding (institution), Honoraria for lectures -20,000E for 5 years; Research Fund 50,000E- for 5 years: C&C Res Lab; Honoraria (self), Advisory/Consultancy, Honoraria for an advisory meeting -20,000E for 5 year: Konica-Minolta; Honoraria (self), Advisory/Consultancy, Honoraria for an advisory meeting -20,000E for 5 year: Bristol-Myers Squibb; Honoraria (self), Research grant/Funding (institution), Honoraria for lectures -20,000E for 5 years: Nippon Kayaku; Research grant/Funding (institution), Research Fund 20,000E-50,000E for 5 years: Bizcom Japan; Research grant/Funding (institution), Research Fund 20,000E-50,000E for 5 years: GL science; Research grant/Funding (institution), Research Fund 20,000E-50,000E for 5 years: Luxonus; Research grant/Funding (institution), Research Fund 50,000E- for 5 years: A&T; Research grant/Funding (institution), Research Fund 50,000E- for 5 years: JBCRG Associate ; Research grant/Funding (institution), Research Fund 50,000E- for 5 years: Shimadzu Group; Research grant/Funding (institution), Research Fund 50,000E- for 5 years: Astellas; Research grant/Funding (institution), Research Fund 50,000E- for 5 years: Ono; Research grant/Funding (institution), Research Fund 50,000E- for 5 years: DSK; Research grant/Funding (institution), Research Fund 50,000E- for 5 years: AFI technology; Non-remunerated activity/ies, Board of directors: Japan Society Clinical Oncology; Non-remunerated activity/ies, Board of directors: Japan Surgical Society; Non-remunerated activity/ies, Board of directors: Japan Breast Cancer Society; Non-remunerated activity/ies, Board of directors: Japan Society Molecular Targeting Therapy; Non-remunerated activity/ies, Board of directors: Japan Breast Cancer Research Group organization; Non-remunerated activity/ies, Board of directors: Japan Breast Cancer Research Group association; Non-remunerated activity/ies, Board of directors: Ogranisation for Oncology and Translational Research; Non-remunerated activity/ies, Board of directors: Kyoto Breast Cancer Research Network. S. Loibl: Honoraria (institution), Research grant/Funding (institution): AbbVie; Honoraria (institution): Ipsen; Honoraria (institution): Pierre-Fabre ; Honoraria (institution), Research grant/Funding (institution): AstraZeneca ; Honoraria (institution), Research grant/Funding (institution): Pfizer; Honoraria (institution), Research grant/Funding (institution): Novartis ; Honoraria (institution), Research grant/Funding (institution): Roche; Honoraria (institution): GH Pharma; Honoraria (institution), Research grant/Funding (institution): Celgene; Honoraria (institution): PRIME; Honoraria (institution): PEER; Honoraria (institution): Evate; Honoraria (institution): Celtrion; Honoraria (institution): SeaGen; Honoraria (institution): Puma; Honoraria (institution): Eirgenix; Honoraria (institution): MedScape; Leadership role, CEO and Chair: German Breast Group; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Teva; Research grant/Funding (institution): Vifor; Research grant/Funding (institution): Cepheid; Research grant/Funding (institution): Sividon; Research grant/Funding (institution): Myriad; Research grant/Funding (institution): Daiichi-Sankyo; Research grant/Funding (institution): Immunomedics; Officer/Board of Directors, Non-remunerated activity/ies: Breast International Group; Non-remunerated activity/ies, Congress chair: ESMO Breast Conference . H.S. Rugo: Advisory/Consultancy: Samsung; Advisory/Consultancy: Celtrion; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Genetech; Research grant/Funding (institution): Lilly; Research grant/Funding (institution), Travel/Accommodation/Expenses: MarcoGenics; Research grant/Funding (institution): Merck; Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis ; Research grant/Funding (institution): OBI Pharma; Research grant/Funding (institution): Odonate Therapeutics; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution), Travel/Accommodation/Expenses: Daiichi-Sankyo; Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Mylan; Travel/Accommodation/Expenses: AstraZeneca. P. Ni: Shareholder/Stockholder/Stock options: GSK; Shareholder/Stockholder/Stock options: AstraZeneca. E. De Bruin: Full/Part-time employment: AstraZeneca. C.M.A.A. Orbegoso: Leadership role, Shareholder/Stockholder/Stock options: AstraZeneca. G. Schiavon: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. A. Foxley: Leadership role, Shareholder/Stockholder/Stock options: AstraZeneca; Non-remunerated activity/ies, Honorary Advisory Board member,: LIF Nanotherapeutics; Non-remunerated activity/ies, Chair: UK Clinical Pharmacology Trailblazer Apprenticeship Group; Non-remunerated activity/ies, Co-Chair: UK Clinical Pharmacology Skills Alliance; Non-remunerated activity/ies, Chair: New Medicines and Data Strategic Leadership Group at the Association of the British Pharmaceutical Industry. M. Oliveira: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Roche; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): GSK; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy, Research grant/Funding (institution): PUMA Biotechnology; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Philips; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Zenith Epigenetics; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Boehringer-Ingelheim. All other authors have declared no conflicts of interest.