Detailed results from the Phase 3 CAPItello-291 study shows that capivasertib, a potent, first-in-class, selective adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3), in combination a with fulvestrant (Faslodex®; AstraZeneca), an estrogen receptor antagonist, versus placebo plus fulvestrant in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-low or negative, locally advanced or metastatic breast cancer, following recurrence or progression on, or after, endocrine therapy (with or without a CDK4/6 inhibitor), reduced the risk of disease progression or death in advanced HR-positive breast cancer. [1]

The results of the study were presented in an oral presentation at the 2022 San Antonio Breast Cancer Symposium (SABCS), held December 6 – 10, in San Antonio, Tx.

Capivasertib, an investigational oral treatment, discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology), is currently in Phase 3 trials for the treatment of multiple subtypes of breast cancer, prostate cancer and a Phase 2 trial for hematologic malignancies and is being evaluated as a monotherapy and in combination with existing therapies in tumors harboring alterations in the AKT pathway (PI3K/AKT/PTEN), as well as tumors reliant on signaling via this pathway for survival.

The CAPItello-291 study
The CAPItello-291 trial, an industry-supported, phase 3 clinical trial, enrolled 708 adult patients with histologically confirmed HR-positive, HER2-low or negative breast cancer whose disease has recurred or progressed during or after aromatase inhibitor therapy, with or without a CDK4/6 inhibitor, and up to one line of chemotherapy for advanced disease. In the study patients were randomized to either receive fulvestrant with either capivasertib (400 mg twice daily; 4 days on, 3 days off) or placebo.

The CAPItello-291 study has dual primary endpoints of PFS in the overall patient population and in a population of patients whose tumors have qualifying alterations in the AKT pathway (PIK3CA, AKT1 or PTEN genes). In the study, approximately 40% of tumors had these alterations.

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Study outcome
The outcomes of the study demonstrated that capivasertib in combination with fulvestrant demonstrated a 40% reduction in the risk of disease progression or death versus placebo plus fulvestrant in the overall trial population (based on a hazard ratio [HR] of 0.60, 95% confidence interval [CI] 0.51-0.71; p=<0.001; median 7.2 versus 3.6 months). [1]

In the AKT pathway biomarker-altered population, capivasertib plus fulvestrant reduced the risk of disease progression or death by 50% versus placebo plus fulvestrant (HR of 0.50, 95% CI 0.38-0.65; p=<0.001; median 7.3 versus 3.1 months). [1] Alterations within the AKT pathway (PI3K/AKT/PTEN) occur frequently in breast cancer, affecting up to 50% of patients with advanced HR-positive breast cancer. [2][3][4]

The confirmed objective response rate (ORR) was 22.9% for the capivasertib plus fulvestrant arm versus 12.2% for the placebo plus fulvestrant arm in the overall trial population, and 28.8% versus 9.7%, respectively, in the biomarker-altered population. [1] Although the overall survival (OS) data were immature at the time of the analysis, early data are encouraging. [1] The trial will continue to assess OS as a key secondary endpoint.

The safety profile of capivasertib plus fulvestrant was similar to that observed in previous trials evaluating this combination. [1] In the overall trial population, the most frequent any grade adverse events (AEs) with capivasertib plus fulvestrant occurring in 20% or more of patients were diarrhea (72.4%), nausea (34.6%), rash (group term including rash, rash macular, maculo-papular rash, rash papular and rash pruritic; 38%) fatigue (20.8%) and vomiting (20.6%). [1] The most frequent Grade 3 or higher AEs occurring in 5% or more of patients were diarrhea (9.3%) and rash (12.1%). [1]

Most common cancer
Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.[5] More than two million patients were diagnosed with breast cancer in 2020, with nearly 685,000 deaths globally.[5]

HR-positive breast cancer (expressing estrogen or progesterone receptors, or both), is the most common subtype of breast cancer with approximately 70% of breast cancer tumors considered HR-positive and HER2-low or negative.[6]

The growth of HR-positive breast cancer cells is often driven by estrogen receptors (ER),[7] and endocrine therapies that target ER-driven disease are widely used as 1st-line treatment in the advanced setting, and often paired with cyclin-dependent kinase (CDK) 4/6 inhibitors.[8][9] However, resistance to CDK4/6 inhibitors and current endocrine therapies develops in many patients with advanced disease.[9] Once this occurs, treatment options are limited – with chemotherapy being the current standard of care [9][10] – and survival rates are low with 30% of patients anticipated to live beyond five years after diagnosis.[6]

Because standard endocrine agents are showing poor activity, new endocrine strategies following endocrine therapy or treatment with CDK4/6 inhibitors remains a major unmet medical need. Optimizing endocrine therapy and overcoming resistance for patients with ER-driven disease at all stages of treatment as well as identifying new therapies for those who no longer have ER-driven disease are active areas of focus for breast cancer research.

Professor Nicholas Turner, MD, Ph.D, Professor of Molecular Oncology at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, London, UK, and principal investigator in the CAPItello-291 Phase 3 trial.

Practice-changing potential
The results of the CAPItello-291 show that by partnering endocrine therapy with targeted therapy improved clinical outcomes for patients with metastatic, ER+/HER2-negative breast cancer. In may cases, after disease progression on a CDK4/6 inhibitor, doctors will determine if a PIK3CA-mutation is present, which allows the use of alpelisib (Piqray®; Novartis), which is is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. 

“These data demonstrate the practice-changing potential of capivasertib as a new treatment option for patients with advanced HR-positive breast cancer. Critically, this potentially first-in-class treatment has shown it delays disease progression for those who have progressed on, or become resistant to, endocrine therapies and CDK4/6 inhibitors,” explained Nicholas Turner, MD, Ph.D, Professor of Molecular Oncology at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, London, UK, and principal investigator in the CAPItello-291 Phase 3 trial.

“Capivasertib brings important progress to an area with persistent treatment gaps as the first therapy of its kind shown to be effective in a Phase 3 trial in patients with advanced HR-positive, HER2-low or negative breast cancer,” noted Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca.

“We believe these results which showed benefit in all-comers and biomarker positive populations can reshape HR-positive breast cancer treatment, and that capivasertib can become an important new option for patients,” Galbraith added.

The results from the CAPItello-291 study may offer another targeted treatment option for patients with pathway-altered mutations, extending the time until chemotherapy is required.

Summary of results: CAPItello-291

Capivasertib plus fulvestrant (n=355)Placebo plus fulvestrant (n=353)
Median PFS in overall population (months)7.23.6
HR (95% CI)0.60 (0.51-0.71)
Median PFS in the biomarker-altered population (months)7.33.1
HR (95% CI)0.50 (0.38-0.65)
ORR in overall population22.9%12.2%
ORR in biomarker-altered population28.8%9.7%

HR, hazard ratio; CI, confidence interval; PFS, progression-free survival; ORR, objective response rate

Clinical trials
Capivasertib+Fulvestrant vs Placebo+Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic HR+/HER2- Breast Cancer (CAPItello-291) – NCT04305496

Highlights of Prescription Information
Fulvestrant (Faslodex®; AstraZeneca) [Prescribing Information]
Alpelisib (Piqray®; Novartis)[Prescribing Information]

[1] Turner, et al. Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the Phase III CAPItello-291 trial. Presented at: San Antonio Breast Cancer Symposium, 6-10 December 2022, San Antonio, Texas, USA.
[2] Howell S J, et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION). J Clin Oncol. 2022; 23:851-64.
[3] Hortobagyi G N, et al. Correlative Analysis of Genetic Alterations and Everolimus Benefit in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From BOLERO-2. J Clin Oncol.2016; 34:419-26.
[4] Millis S Z, et al. Landscape of phosphatidylinositol-3-kinase pathway alterations across 19784 diverse solid tumors. JAMA Oncol. 2016;2(12):1565-73.
[5] Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 10.3322/caac.21660.
[6] National Cancer Institute. Surveillance, Epidemiology and End Results Program. Online. Last accessed December, 7 2022.
[7] Scabia V, et al. Estrogen receptor positive breast cancers have patient specific hormone sensitivities and rely on progesterone receptor. Nat Commun. 2022; 10.1038/s41467-022-30898-0.
[8] Lin M, et al. Comparative Overall Survival of CDK4/6 Inhibitors Plus Endocrine Therapy vs. Endocrine Therapy Alone for Hormone receptor-positive, HER2-negative metastatic breast cancer. J Cancer. 2020; 10.7150/jca.48944.
[9] Lloyd M R, et al. Mechanisms of Resistance to CDK4/6 Blockade in Advanced Hormone Receptor-positive, HER2-negative Breast Cancer and Emerging Therapeutic Opportunities. Clin Cancer Res. 2022;28(5):821-30.
[10] National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology (NCCN Guidelines). Online. Last accessed December 7, 2022.

Featured image: 2022 San Antonio Breast Cancer Symposium (SABCS) being held at the Henry B. Gonzalez Convention Center in San Antonio, TX. Photo courtesy: © 2022 AACR/SABCS MedMeetingImages/Todd Buchanan. Used with permission.



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