TRUQAP™ (capivasertib) plus fulvestrant approved in the US for patients with advanced HR-positive breast cancer

First-in-class AKT inhibitor has potential to reshape treatment for breast cancer patients with specific biomarker alterations (PIK3CA, AKT1 or PTEN)

Approval based on CAPItello-291 results which showed this combination reduced the risk of disease progression or death by 50% vs. fulvestrant alone in the biomarker-altered population

AstraZeneca’s TRUQAP™ (capivasertib) in combination with fulvestrant has been approved in the US for the treatment of adult patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer with one or more biomarker alterations (PIK3CA, AKT1 or PTEN). Eligible patients will have progressed on at least one endocrine-based regimen in the metastatic setting or experienced recurrence on or within 12 months of completing adjuvant therapy.

The approval by the Food and Drug Administration (FDA) was based on the results from the CAPItello-291 Phase III trial published earlier this year in The New England Journal of Medicine.¹ In the trial, TRUQAP in combination with fulvestrant reduced the risk of disease progression or death by 50% versus fulvestrant alone in patients with tumors harboring PI3K/AKT/PTEN pathway biomarker alterations (based on hazard ratio of 0.50, 95% confidence interval 0.38-0.65; p=<0.001; median progression-free survival (PFS) 7.3 versus 3.1 months).

Breast cancer is the most common cancer and one of the leading causes of cancer-related death worldwide.² HR-positive breast cancer (expressing estrogen or progesterone receptors, or both), is the most common subtype, with more than 65% of tumors considered HR-positive and HER2-low or HER2-negative.³ Collectively, mutations in PIK3CA and AKT1 and alterations in PTEN occur frequently, affecting up to 50% of patients with advanced HR-positive breast cancer.^4-6 Endocrine therapies are widely used in this setting, but many patients develop resistance to first-line cyclin-dependent kinase (CDK) 4/6 inhibitors and estrogen receptor-targeting therapies, underscoring the need for additional endocrine therapy-based options.⁷

Komal Jhaveri, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center (MSK), US, said: “Patients with advanced HR-positive breast cancer typically experience tumor progression or resistance with widely used first-line endocrine therapies and there is an urgent need to extend the effectiveness of these approaches. The combination of capivasertib and fulvestrant, a first-of-its-kind combination, provides a much-needed new treatment option for up to half of patients in this setting with these specific biomarkers, offering the potential to delay disease progression and provide more time with their disease under control.”

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: “The rapid US approval of TRUQAP reinforces the important role of the PI3K/AKT/PTEN pathway in HR-positive breast cancer and the critical need to test patients at the time of diagnosis, as up to fifty percent have tumors with these alterations. As a first-in-class medicine, this approval provides a critical new option for patients in the US with this specific type of disease and we look forward to bringing TRUQAP to the many breast cancer patients who can benefit across the globe.”

In the CAPItello-291 trial, the safety profile of TRUQAP plus fulvestrant was similar to that observed in previous trials evaluating this combination.¹

Concurrently with this approval, the FDA also approved a companion diagnostic test to detect relevant alterations (PIK3CA, AKT1 and PTEN).

The US regulatory submission was granted Priority Review and reviewed under Project Orbis, which provides a framework for concurrent submission and review of oncology medicines among participating international partners. As part of Project Orbis, TRUQAP plus fulvestrant is also under review by regulatory authorities in Australia, Brazil, Canada, Israel, Singapore, Switzerland and the UK.

Regulatory applications for TRUQAP in combination with fulvestrant are also currently under review in China, the European Union, Japan and several other countries.

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

Financial considerations

Following this approval in the US, Astex Therapeutics is eligible to receive a milestone payment from AstraZeneca on first commercial sale of the drug in the US as well as royalties on future sales in line with the agreement between the two companies.

HR-positive breast cancer

Breast cancer is the most common cancer and one of the leading causes of cancer-related death worldwide.² More than two million patients were diagnosed with breast cancer in 2020, with nearly 685,000 deaths globally.² In the US, more than 290,000 patients are expected to be diagnosed in 2023, with more than 43,000 deaths.⁸

HR-positive breast cancer (expressing estrogen or progesterone receptors, or both), is the most common subtype of breast cancer with more than 65% of tumors considered HR-positive and HER2-low or HER2-negative.³ Collectively, mutations in PIK3CA and AKT1 and alterations in PTEN occur frequently, affecting up to 50% of patients with advanced HR-positive breast cancer.^4-6

The growth of HR-positive breast cancer cells is often driven by estrogen receptors (ER), and endocrine therapies that target ER-driven disease are widely used as first-line treatment in the advanced setting, and often paired with CDK4/6 inhibitors.^7,9,10 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 – and survival rates are low with 30% of patients anticipated to live beyond five years after diagnosis.^3,9,11

The optimization of endocrine therapy and overcoming resistance to enable patients to continue benefiting from these treatments, as well as identifying new therapies for those who are less likely to benefit, are active areas of focus for breast cancer research.

CAPItello-291

CAPItello-291 is a Phase III, double-blind, randomized trial evaluating the efficacy of TRUQAP in combination with fulvestrant versus placebo plus fulvestrant for the treatment of locally advanced (inoperable) or metastatic HR-positive, HER2-low or negative (immunohistochemistry (IHC) 0 or 1+, or IHC 2+/in-situ hybridization (ISH)-negative) breast cancer.

The global 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. The trial has dual primary endpoints of PFS 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). In the trial, approximately 40% of tumors had these alterations and approximately 70% of patients received a prior CDK4/6 inhibitor.

TRUQAP

TRUQAP™ (capivasertib) 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 currently being evaluated in Phase III trials for the treatment of multiple subtypes of breast cancer and in other tumor types either as monotherapy or in combination with established treatments. The ongoing clinical research program is focused on tumors reliant on signaling via the PI3K/AKT/PTEN pathway, and in tumors harboring biomarker alterations in this pathway.

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).

Fulvestrant

Fulvestrant is an endocrine therapy indicated for the treatment of estrogen receptor-positive, locally advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy, or with disease relapse on or after adjuvant anti-estrogen therapy, or disease progression on anti-estrogen therapy.

In the US, EU and Japan, fulvestrant is also approved in combination with CDK4/6 inhibitors for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer, whose cancer has progressed after endocrine medicine. Fulvestrant represents a hormonal treatment approach that helps to slow tumor growth by blocking and degrading the estrogen receptor – a key driver of disease progression.

Fulvestrant is approved as monotherapy or in combination with medicines from various drug classes including CDK4/6, PI3K and AKT inhibitors for the treatment of patients with HR-positive advanced breast cancer and is being evaluated in combination with medicines from other drug classes.

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., known as 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, TRUQAP in combination with chemotherapy, 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. Please visit www.astrazeneca-us.com and follow us on social media @AstraZeneca.

References

Dr. Jhaveri has financial interests related to AstraZeneca.

US-82368 Last Updated 11/23

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