Capivasertib (C) and fulvestrant (F) for patients (pts) with aromatase inhibitor (AI)-resistant HR+/HER2– advanced breast cancer (ABC): Characterization and management of common adverse events (AEs) from the phase 3 CAPItello-291 trial.

person Hope S. Rugo University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA info_outline Hope S. Rugo, Mafalda Oliveira, Sacha Jon Howell, Florence Dalenc, Javier Cortes, Henry Leonidas Gomez, Xichun Hu, Hiroji Iwata, Komal L. Jhaveri, Sibylle Loibl, Serafin Morales Murillo, Meena Okera, Yeon Hee Park, Joohyuk Sohn, Lyudmila Zhukova, Jill Logan, Ken Twomey, Mahmuda Khatun, Celina M. D'Cruz, Nicholas C. Turner

Authors person Hope S. Rugo University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA info_outline Hope S. Rugo, Mafalda Oliveira, Sacha Jon Howell, Florence Dalenc, Javier Cortes, Henry Leonidas Gomez, Xichun Hu, Hiroji Iwata, Komal L. Jhaveri, Sibylle Loibl, Serafin Morales Murillo, Meena Okera, Yeon Hee Park, Joohyuk Sohn, Lyudmila Zhukova, Jill Logan, Ken Twomey, Mahmuda Khatun, Celina M. D'Cruz, Nicholas C. Turner Organizations University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, Medical Oncology Department and Breast Cancer Group, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain, The University of Manchester, Manchester, United Kingdom and The Christie NHS Foundation Trust, Manchester, United Kingdom, Institut Claudius Regaud, Institut Universitaire du Cancer – Oncopole, Toulouse, France, International Breast Cancer Center (IBCC), Pangaea Oncology, Quiron Group, Barcelona, Spain, Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain, Universidad Europea de Madrid, Faculty of Biomedical and Health Sciences, Department of Medicine, Madrid, Spain, Instituto Nacional de Enfermedades Neoplásicas (INEN), Departamento de Oncología Médica and Universidad Ricardo Palma, Lima, Peru, Fudan University Shanghai Cancer Center, Shanghai, China, Aichi Cancer Center Hospital, Aichi, Japan, Memorial Sloan Kettering Cancer Center New York, NY, USA and Weill Cornell Medical College, New York, NY, GBG Forschungs GmbH, Neu-Isenburg, Germany and Centre for Haematology and Oncology, Bethanien, Frankfurt, Germany, Institut de Recerca Biomèdica, Barcelona, Spain, ICON Cancer Centre, Adelaide, Australia, Sungkyunkwan University School of Medicine, Samsung Medical Centre, Seoul, South Korea, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, Loginov Moscow Clinical Scientific Center, Moscow, Russian Federation, Oncology R&D, AstraZeneca, Cambridge, United Kingdom, Oncology R&D, AstraZeneca, Waltham, MA, Royal Marsden Hospital, Institute of Cancer Research, London, United Kingdom Abstract Disclosures Research Funding Pharmaceutical/Biotech Company AstraZeneca Background: In the CAPItello-291 trial in eligible pts with AI-resistant HR+/HER2– ABC, the addition of C (a potent, selective pan-AKT inhibitor) to F significantly improved PFS (primary endpoint) compared with placebo (P) in the overall (HR 0.60; 95% CI 0.51–0.71; p<0.001) and AKT pathway-altered population (HR 0.50; 95% CI 0.38–0.65; p<0.001). We report a detailed analysis of AEs. Methods: Pts were randomized 1:1 to receive F (500 mg IM on days 1 and 15 of cycle 1, and day 1 of each subsequent 28-day cycle) with either P or C (400 mg BID; 4 days on, 3 days off). Pts with HbA1c <8.0% and diabetes not requiring insulin were eligible. Incidence, management, and time to onset were summarized for common AEs (>10% any grade and >2.0% grade ≥3; CTCAE v5.0). Results: Overall, 708 pts were randomized to C+F (n=355) vs P+F (n=353); safety population C+F (n=355) vs P+F (n=350). Baseline risk factors potentially associated with hyperglycemia were a history of diabetes in 34 pts (10%) in the C+F arm vs 20 pts (6%) in the P+F arm (baseline median [range] HbA1c 5.4% [4.0–8.3] vs 5.4% [3.9–7.7]), median weight 65.0 kg (34–150) vs 66.5 kg (37–147) and 54% vs 53% of pts overweight/obese in the C+F vs P+F arms, respectively. Common AEs were diarrhea, rash, and hyperglycemia; maximum AE grade was mostly 1/2 and led to low rates of discontinuation. In the C+F arm, medications for the management of AEs were used in 151/257 pts (59%) with diarrhea (mostly loperamide; n=135), 109/135 pts (81%) with rash (mostly antihistamines; n=75/topical corticosteroids; n=64), and 28/60 pts (47%) with hyperglycemia (mostly metformin; n=18). Conclusions: Diarrhea, rash, and hyperglycemia, the most commonly reported AEs associated with AKT pathway inhibition, occur early in treatment with C+F, are generally low grade and manageable, and are associated with low rates of dose modifications/discontinuations. Clinical trial information: NCT04305496. Diarrhea a Rash a Hyperglycemia a C+F P+F C+F P+F C+F P+F Any grade; n (%) 257 (72.4) 71 (20.3) 135 (38.0) 25 (7.1) 60 (16.9) 14 (4.0) Maximum grade; n (%) 1 164 (46.2) 61 (17.4) 57 (16.1) 19 (5.4) 26 (7.3) 8 (2.3) 2 60 (16.9) 9 (2.6) 35 (9.9) 5 (1.4) 26 (7.3) 5 (1.4) 3 33 (9.3) 1 (0.3) 43 (12.1) 1 (0.3) 7 (2.0) b 1 (0.3) Median (interquartile range) time to onset, days 8.0 (2.0–22.0) 22.0 (10.0–57.0) 12.0 (10.0–15.0) 48.0 (22.0–108) 15.0 (1.0–51.0) 47.5 (28.0–120.0) AE leading to dose change; n (%) Reduction 28 (7.9) 0 16 (4.5) 0 2 (0.6) 0 Interruption 35 (9.9) 3 (0.9) 42 (11.8) 0 9 (2.5) 3 (0.9) Discontinuation 7 (2.0) 0 16 (4.5) 0 1 (0.3) 1 (0.3) a Group terms (preferred terms): diarrhea (diarrhea, frequent bowel movements, gastrointestinal hypermotility); rash (rash, rash macular, maculopapular rash, rash papular, rash pruritic) and hyperglycemia (blood glucose increased, hyperglycemia). b One additional pt (0.3%) had grade 4 hyperglycemia.

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