TRUQAP® (capivasertib) combination in PTEN deficient metastatic hormone sensitive prostate cancer demonstrated statistically significant and clinically meaningful improvement[...]

First and only AKT inhibitor combination to demonstrate
benefit in this specific subtype of prostate cancer

Positive high-level results from the CAPItello-281 Phase III trial showed that AstraZeneca's TRUQAP^® (capivasertib) in combination with abiraterone and androgen deprivation therapy (ADT) demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of radiographic progression-free survival (rPFS) versus abiraterone and ADT with placebo in patients with PTEN-deficient de novo metastatic hormone-sensitive prostate cancer (mHSPC).

Overall survival (OS) data were immature at the time of this analysis; however, the TRUQAP combination showed an early trend towards an OS improvement versus abiraterone and ADT with placebo. The trial will continue as planned to further assess OS as a key secondary endpoint.

Prostate cancer is the second most prevalent cancer in men and the fifth leading cause of male cancer death globally.¹ Only one-third of patients with metastatic prostate cancer survive five years after diagnosis.² Newly diagnosed mHSPC is an aggressive form of the disease associated with poor outcomes and survival.^3,4 Approximately 200,000 patients are diagnosed with mHSPC each year, and one in four have PTEN-deficient tumors.⁵ Patients with a tumor biomarker of PTEN deficiency have a particularly poor prognosis.⁶

Karim Fizazi, MD, PhD, Institut Gustave Roussy, and University of Paris Saclay in Villejuif, France, and principal investigator for the trial said: "Patients with this aggressive form of prostate cancer with tumor PTEN deficiency currently face a particularly poor prognosis, and there is an urgent need for new treatments that improve upon current therapies. The results seen with capivasertib in combination with abiraterone-prednisone and androgen deprivation therapy in the CAPItello-281 trial represent a step forward for these patients."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "These results show for the first time, that adding an AKT inhibitor to a standard-of-care therapy can provide benefit to patients with a biomarker of PTEN-deficient metastatic hormone-sensitive prostate cancer. By targeting a key driver of the disease, we have been able to improve upon current therapies and demonstrate the potential role of this combination in an area of critical unmet need. It will be important to see greater maturity in key secondary endpoints including overall survival."

The safety profile of TRUQAP in combination with abiraterone and ADT in CAPItello-281 was broadly consistent with the known profile of each medicine.

Data will be presented at a forthcoming medical meeting and shared with global regulatory authorities.

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.

You may report side effects related to AstraZeneca products.

Notes

Prostate cancer
Prostate cancer is the second most commonly diagnosed cancer in men and the fifth leading cause of cancer death in men globally, with an incidence of more than 1.4 million and over 397,000 deaths in 2022.¹

Metastatic prostate cancer is associated with a significant mortality rate, with only a third of patients surviving five years after diagnosis.² Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.⁷

Metastatic hormone-sensitive prostate cancer
In patients with mHSPC, also known as metastatic castration-sensitive prostate cancer (mCSPC), prostate cancer cells need high levels of androgens to drive cancer growth.^4,7 Hormone therapies, such as ADT, are widely used to block the action of male sex hormones and lower the levels of androgens in the body.^4,8 However, resistance to these therapies is common and there is a need to extend their use to delay disease progression and castration resistance, where the prostate cancer grows and spreads to other parts of the body despite the use of these therapies.^3,4,8

In patients with de novo mHSPC, the cancer has spread to distant parts of the body at the time of first diagnosis.⁹

PTEN-loss or deficiency fuels the growth of cancer cells, leading to dysregulation of the PI3K/AKT pathway, and is associated with poor outcomes in patients with prostate cancer.^6,10

CAPItello-281
CAPItello-281 is a Phase III, double-blind, randomized trial evaluating the efficacy and safety of TRUQAP in combination with abiraterone and ADT versus abiraterone and ADT in combination with placebo in the treatment of patients with PTEN-deficient de novo mHSPC.

The global trial enrolled 1,012 adult patients with histologically confirmed de novo hormone-sensitive prostate adenocarcinoma and PTEN deficiency as confirmed by central testing. The primary endpoint of the CAPItello-281 trial is rPFS as assessed by investigator, with OS as a secondary endpoint.

TRUQAP^® (capivasertib)
TRUQAP^® (capivasertib) is a first-in-class, potent, adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3). TRUQAP 400 mg 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, EU, Japan and several other countries for the treatment of adult patients with HR-positive (or ER-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 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. Chowdhury S, et al. Real-World Outcomes in First-Line Treatment of Metastatic Castration-Resistant Prostate Cancer: The Prostate Cancer Registry. Target Oncol. 2020;15(3):301-315.

3. Hussain M, et al. Metastatic Hormone-Sensitive Prostate Cancer and Combination Treatment Outcomes A Review. JAMA Oncol. 2024;10(6):807-820.

4. American Society of Clinical Oncology Educational Book. Metastatic Hormone-Sensitive Prostate Cancer: Toward an Era of Adaptive and Personalized Treatment. Available at: https://ascopubs.org/doi/pdf/10.1200/EDBK_390166. Accessed November 2024.

5. Cerner CancerMPact database. Accessed November 2024.

6. Cuzick J et al. Prognostic value of PTEN loss in men with conservatively managed localised prostate cancer. Br J Cancer. 2013;108(12):2582-2589.

7. National Cancer Institute. Hormone Therapy for Prostate Cancer Fact Sheet. Available at: https://www.cancer.gov/types/prostate/prostate-hormone-therapy-fact-sheet. Accessed November 2024.

8. Cancer Research UK. Hormone therapy for metastatic prostate cancer. Available at: https://www.cancerresearchuk.org/about-cancer/prostate-cancer/metastatic-cancer/treatment/hormone-therapy-for-metastatic-prostate-cancer. Accessed November 2024.

9. McManus H et al. The Past, Present, and Future of Treatment Intensification for Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol 2023; 41:3576-3579.

10. Gasmi A et al. Overview of the Development and Use of Akt Inhibitors in Prostate Cancer. J Clin Med. 2021;11(1):160.