Update on the CAPItello-290 Phase III trial for TRUQAP® (capivasertib) plus chemotherapy in advanced or metastatic triple-negative breast cancer

The CAPItello-290 Phase III trial for TRUQAP® (capivasertib) in combination with paclitaxel in patients with locally advanced (inoperable) or metastatic triple-negative breast cancer (TNBC) did not meet the dual primary endpoints of improvement in overall survival (OS) versus paclitaxel in combination with placebo in either the overall trial population or in a subgroup of patients with tumors harboring specific biomarker alterations (PIK3CA, AKT1 or PTEN).

Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.1 While some breast cancers may test positive for estrogen receptors, progesterone receptors or overexpression of human epidermal growth factor receptor 2 (HER2), TNBC is defined as negative for all three.2 In the 1st-line setting, approximately 59,000 patients with TNBC are treated with a medicine.3 Collectively, mutations in PIK3CA, AKT1 and alterations in PTEN affect approximately 35% of patients with TNBC.4

Peter Schmid, MD, Barts Cancer Institute, London, UK, and principal investigator for the trial said: “Despite modest advances, triple-negative breast cancer remains one of the most challenging forms of disease to treat due to the lack of known actionable biomarker targets, and chemotherapy-based regimens continue to be the mainstay of treatment. While the CAPItello-290 trial results have not shown what we hoped, they provide important information to further understand this aggressive form of breast cancer where patients are in urgent need of new treatments.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “We are committed to advancing science for patients in some of the most challenging cancers, including this heterogeneous subtype of breast cancer. While we are disappointed in the CAPItello-290 outcome, these results will further our understanding of the role of the PI3K/AKT/PTEN pathway in breast cancer as we continue our clinical research across the TRUQAP clinical development program and across our pipeline.”

The safety profile of TRUQAP in combination with paclitaxel in CAPItello-290 was broadly consistent with the known safety profile of each medicine with no new safety concerns identified. Data will be shared in due course.

TRUQAP is currently being evaluated in Phase III trials for the treatment of breast cancer (CAPItello-292) and prostate cancer (CAPItello-280 and CAPItello-281) in combination with established treatments.

IMPORTANT SAFETY INFORMATION ABOUT TRUQAP® (capivasertib) tablets

TRUQAP is contraindicated in patients with severe hypersensitivity to TRUQAP or any of its components.

Hyperglycemia

Severe hyperglycemia, associated with ketoacidosis, has occurred in patients treated with TRUQAP. The safety of TRUQAP has not been established in patients with Type I diabetes or diabetes requiring insulin. Patients with insulin-dependent diabetes were excluded from CAPItello-291.

Hyperglycemia occurred in 18% of patients treated with TRUQAP (n=355).  Grade 3 (insulin therapy initiated; hospitalization indicated) or Grade 4 (life-threatening consequences; urgent intervention indicated) hyperglycemia occurred in 2.8% of patients. Diabetic ketoacidosis occurred in 0.3% of patients and diabetic metabolic decompensation in 0.6% of patients. Dose reduction for hyperglycemia was required in 0.6% and permanent discontinuation was required in 0.6% of patients. The median time to first occurrence of hyperglycemia was 15 days (range: 1 to 367).

In the 65 patients with hyperglycemia, 45% required treatment with anti-hyperglycemic medication (insulin in 15% and metformin in 29%). Of the 29 patients who required anti-hyperglycemic medication during treatment with TRUQAP, 66% (19/29) remained on these medications at treatment discontinuation or last follow-up.

Evaluate fasting blood glucose (FG) and hemoglobin A1C (HbA1C) and optimize blood glucose prior to treatment. Before initiating TRUQAP, inform patients about TRUQAP’s potential to cause hyperglycemia and to immediately contact their healthcare professional if hyperglycemia symptoms occur (eg, excessive thirst, urinating more often than usual or greater amount of urine than usual, or increased appetite with weight loss).  Evaluate FG at least every two weeks during the first month and at least once a month starting from the second month, prior to the scheduled dose of TRUQAP. Monitor HbA1C every three months.  Monitor FG more frequently during treatment with TRUQAP in patients with a medical history of diabetes mellitus and in patients with risk factors for hyperglycemia such as obesity (BMI ≥ 30), elevated FG of >160 mg/dL (>8.9 mmol/L), HbA1C at or above the upper limit of normal, use of concomitant systemic corticosteroids, or intercurrent infections. 

If a patient experiences hyperglycemia after initiating treatment with TRUQAP, monitor FG as clinically indicated, and at least twice weekly until FG decreases to normal levels. During treatment with anti-hyperglycemic medication, continue monitoring FG at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated. Consider consultation with a healthcare practitioner with expertise in the treatment of hyperglycemia and counsel patients on lifestyle changes.  Withhold, dose reduce, or permanently discontinue TRUQAP based on severity.

Diarrhea

Severe diarrhea associated with dehydration occurred in patients who received TRUQAP (n=355).

Diarrhea occurred in 72% of patients.  Grade 3 or 4 diarrhea occurred in 9% of patients. The median time to first occurrence was 8 days (range: 1 to 519).  In the 257 patients with diarrhea, 59% required antidiarrheal medications to manage symptoms. Dose reductions were required in 8% of patients and 2% of patients permanently discontinued TRUQAP due to diarrhea.  In patients with Grade ≥ 2 diarrhea (n=93) with at least 1 grade improvement (n=89), median time to improvement from the first event was 4 days (range: 1 to 154). 

Monitor patients for signs and symptoms of diarrhea. Advise patients to increase oral fluids and start antidiarrheal treatment at the first sign of diarrhea while taking TRUQAP. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity.

Cutaneous Adverse Reactions

Cutaneous adverse reactions, which can be severe, including erythema multiforme (EM), palmar-plantar erythrodysesthesia, and drug reaction with eosinophilia and systemic symptoms (DRESS), occurred in patients who received TRUQAP (n=355).

Cutaneous adverse reactions occurred in 58% of patients. Grade 3 or 4 cutaneous adverse reactions occurred in 17% of patients receiving TRUQAP. EM occurred in 1.7% of patients and DRESS occurred in 0.3% of patients. Dose reduction was required in 7% of patients and 7% of patients permanently discontinued TRUQAP due to cutaneous adverse reactions. 

Monitor patients for signs and symptoms of cutaneous adverse reactions. Early consultation with a dermatologist is recommended. Withhold, dose reduce, or permanently discontinue TRUQAP based on severity.

Embryo-Fetal Toxicity

Based on findings from animals and mechanism of action, TRUQAP can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRUQAP and for 1 month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRUQAP and for 4 months after the last dose.

TRUQAP is used in combination with fulvestrant. Refer to the full Prescribing Information of fulvestrant for pregnancy and contraception information.

ADVERSE REACTIONS

Among the 355 patients who received TRUQAP in CAPItello-291, the most common (≥20%) adverse reactions, including laboratory abnormalities, were diarrhea (72%), cutaneous adverse reactions (58%), increased random glucose (57%), decreased lymphocytes (47%), decreased hemoglobin (45%), increased fasting glucose (37%), nausea and fatigue (35% each), decreased leukocytes (32%), increased triglycerides (27%), decreased neutrophils (23%), increased creatinine (22%), vomiting (21%), and stomatitis (20%).

In the 155 patients with PIK3CA/AKT1/PTEN alterations treated with TRUQAP + fulvestrant, dose reductions due to adverse reactions were reported in 21% of patients. Permanent TRUQAP discontinuation due to an adverse reaction occurred in 10% of patients. Dose interruptions of TRUQAP occurred in 39% of patients.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid concomitant use with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce the dose of TRUQAP and monitor patients for adverse reactions.

Moderate CYP3A Inhibitors: When concomitantly used with a moderate CYP3A inhibitor, reduce the dose of TRUQAP and monitor patients for adverse reactions.

Strong or Moderate CYP3A Inducers: Avoid concomitant use of TRUQAP with strong or moderate CYP3A inducers.

INDICATION AND USAGE

TRUQAP in combination with fulvestrant is indicated for the treatment of adult patients with hormone receptor (HR)‑positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN alteration as detected by an FDA-approved test following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.

Please see full Prescribing Information, including Patient Information for TRUQAP.

Notes

Triple-negative breast cancer

1st-line treatment for advanced or metastatic TNBC usually consists of chemotherapy alone or in combination with an immunotherapy – options generally associated with response rates between 30 to 50%.2,5,6 Among patients with tumors that do respond to initial treatment, disease progression is common and rapid, often occurring within two years.2,6-8 The average overall survival of patients living with advanced or metastatic TNBC is 12 to 18 months, with only about 14% of patients living five years following diagnosis.9,10

CAPItello-290

CAPItello-290 is a Phase III, double-blind, randomized trial evaluating the efficacy and safety of TRUQAP in combination with paclitaxel versus placebo in combination with paclitaxel in the 1st-line treatment of patients with locally advanced (inoperable) or metastatic TNBC.

The global trial enrolled 923 adult patients with histologically confirmed locally advanced or metastatic TNBC. The trial has dual primary endpoints of OS in the overall patient population and in a population of patients whose tumors have qualifying alterations in the PI3K/AKT/PTEN pathway (PIK3CA, AKT1 or PTEN genes). 

TRUQAP

TRUQAP is a first-in-class, potent, adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3). TRUQAP 400mg is administered twice daily according to an intermittent dosing schedule of four days on and three days off. This was chosen in early phase trials based on tolerability and the degree of target inhibition.

TRUQAP is approved in the US, Japan and several other countries for the treatment of adult patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer with one or more biomarker alterations (PIK3CA, AKT1 or PTEN) following recurrence or progression on or after an endocrine-based regimen based on the results from the CAPItello-291 trial. TRUQAP is also approved in Australia for the treatment of adult patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer following recurrence or progression on or after an endocrine based regimen based on these trial results.

TRUQAP is currently being evaluated in Phase III trials for the treatment of breast cancer (CAPItello-292) and prostate cancer (CAPItello-280 and CAPItello-281) in combination with established treatments.

TRUQAP was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited).

AstraZeneca in breast cancer

Driven by a growing understanding of breast cancer biology, AstraZeneca is starting to challenge, and redefine, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need – with the bold ambition to one day eliminate breast cancer as a cause of death.

AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumor environment.

With fam-trastuzumab deruxtecan-nxki, a HER2-directed antibody drug conjugate (ADC), AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in previously treated HER2-positive and HER2-low metastatic breast cancer and are exploring its potential in earlier lines of treatment and in new breast cancer settings.

In HR-positive breast cancer, AstraZeneca continues to improve outcomes with foundational medicines fulvestrant and goserelin and aims to reshape the HR-positive space with first-in-class AKT inhibitor, TRUQAP, and next-generation SERD and potential new medicine camizestrant. AstraZeneca is also collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan, in this setting.

PARP inhibitor olaparib is a targeted treatment option that has been studied in early and metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with Merck & Co., Inc. (MSD outside the US and Canada) continue to research olaparib in these settings and to explore its potential in earlier disease.

To bring much-needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is evaluating the potential of datopotamab deruxtecan alone and in combination with immunotherapy durvalumab, and durvalumab in combination with other oncology medicines, including olaparib and fam-trastuzumab deruxtecan-nxki.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on social media @AstraZeneca.

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References

  1. Bray F, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 Apr 4. doi: 10.3322/caac.21834.
  2. O’Reilly D, et al. Overview of recent advances in metastatic triple negative breast cancer. World J Clin Oncol. 2021; 12(3):164-182.
  3. Cerner CancerMPact database. Accessed May 2024.
  4. Cocco S, et al. Biomarkers in Triple-Negative Breast Cancer: State-of-the-Art and Future Perspectives. Int J Mol Sci. 2020; 21(13): 4579.
  5. Bergin A, et al. Triple-negative breast cancer: recent treatment advances. F1000Res. 2019; 8:10.12688/f1000research.18888.1.
  6. Zhang Y, et al. Genomic features of rapid versus late relapse in triple negative breast cancer. BMC Cancer. 2021; 21(568).
  7. Cortes J, et al. Pembrolizumab plus Chemotherapy in Advanced Triple -Negative Breast.
  8. Cancer. N Engl J Med. 2022; 387:217-226. 10.1056/NEJMoa2202809.
  9. Emans L, et al. Atezolizumab and nab-Paclitaxel in Advanced Triple-Negative Breast Cancer: Biomarker Evaluation of the IMpassion130 Study. J Natl Cancer Inst. 2021; 113(8): Djab004.
  10. National Cancer Institute. Surveillance, Epidemiology and End Results Program. Available.
  11. at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed June 2024.
  12. Sharma P, et al. Biology and Management of Patients with Triple-Negative Breast Cancer. Oncologist. 2016; 21(9);1050-62. 10.1634/theoncologist.2016-0067.

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TRUQAP is a registered trademark of the AstraZeneca group of companies.