TRUQAP™ (capivasertib) Approval for Breast Cancer Treatment

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TRUQAP™ (capivasertib) Approval for Breast Cancer Treatment

Breast cancer, which is the most diagnosed cancer and the primary cause of cancer-related deaths in women globally, is predominantly characterized by hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+/HER2−) disease. In the United States alone, it was estimated that approximately 297,790 new cases of invasive breast cancer would be diagnosed among US women, and 43,700 women would die from breast cancer in 2023. Globally, the World Health Organization reported 2.3 million women diagnosed with breast cancer and 685,000 breast cancer-related deaths in 2020. Risk factors for HR-positive breast cancer encompass germline genetic mutations, family history, increased age, obesity, heavy alcohol intake, decreased physical activity, early menarche, late first full-term pregnancy, and late menopause. The use of hormone-replacement therapy also plays a role in breast cancer incidence.^1-3

The majority of breast cancer cases are diagnosed at a localized stage; however 3%–6% of patients present with de novo metastatic disease. Additionally, 20%–30% of patients with early-stage breast cancer later experience systemic recurrence, marked by the acquisition of new mutations, altered gene expression, increased proliferation, formation of metastases, and the development of treatment resistance. In addressing locally advanced or metastatic HR+/HER2− breast cancer, the primary approach for most patients is endocrine therapy. Recent years have witnessed the introduction of targeted therapies for metastatic HR+/HER2− breast cancer, including everolimus, palbociclib, ribociclib, abemaciclib, and alpelisib. Combining these targeted therapies with endocrine therapy has shown enhanced progression-free survival (PFS) and overall survival (OS) in clinical trials compared to endocrine therapy alone. Moreover, Poly(ADP‐ribose) polymerase (PARP) inhibitors such as olaparib and talazoparib, when used as monotherapy, have demonstrated significant improvements in PFS compared to chemotherapy in germline BRCA-mutated, HER2− metastatic breast cancer. However, variations in HR expression and HER2 status during the development of metastatic disease may impact treatment approaches. Ongoing research is dedicated to exploring innovative treatment strategies for HR+/HER2− metastatic breast cancer, with the aim of further enhancing patient outcomes.^3-6

Notably, on November 16, 2023, the Food and Drug Administration (FDA) approved TRUQAP™ (capivasertib) in combination with fulvestrant for adult patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer. This approval is for those with one or more PIK3CA/AKT1/PTEN-alterations, detected by an FDA-approved test (FoundationOne®CDx assay), who have experienced disease progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy. This approval represents a new treatment option for a specific subset of breast cancer patients, emphasizing the progress in precision medicine and the potential for improved outcomes in managing HR-positive, HER2-negative breast cancer with specific molecular alterations.⁷

Capivasertib acts as a potent inhibitor of all three isoforms of serine/threonine kinase AKT (AKT1, AKT2, and AKT3), disrupting the PI3K/AKT pathway crucial in breast cancer cells. Its mechanism involves inhibiting the phosphorylation of downstream AKT substrates, impacting cell growth, survival, and disease progression. In vitro studies demonstrate capivasertib's efficacy in reducing the growth of breast cancer cell lines, particularly those harboring relevant PIK3CA or AKT1 mutations or PTEN alterations. Furthermore, in vivo experiments showcase capivasertib's ability, both as a monotherapy and in combination with fulvestrant, to inhibit tumor growth in mouse models. This advancement highlights the focus on precision medicine, with the goal of enhancing patient outcomes and reshaping the treatment approach for HR+ /HER2− breast cancer.¹

The pivotal trial that led to the approval of capivasertib was the phase 3, randomized, double-blind trial known as CAPItello-291. This trial aimed to evaluate the efficacy of capivasertib in combination with fulvestrant for individuals with HR+ /HER2− advanced breast cancer who experienced disease relapse or progression while on aromatase inhibitor therapy, with or without prior cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor treatment.. Eligible pre-, peri-, and postmenopausal women and men with HR+ /HER2− participated.  A total of 708 patients were randomized (1:1), with 355 patients assigned to the capivasertib–fulvestrant group and 353 to the placebo–fulvestrant group. Both groups had comparable baseline characteristics in the trial. The median age was 58 years, with 77.3% being postmenopausal women. All patients had HER2-negative disease, 69.1% had prior CDK4/6 inhibitor treatment, and 18.2% had previously received chemotherapy for advanced cancer. Overall, the demographic characteristics closely represented patients with hormone receptor–positive, HER2-negative breast cancer.⁸

Results from the trial indicated that in the overall population, the median progression-free survival was 7.2 months in the capivasertib–fulvestrant group, compared to 3.6 months in the placebo–fulvestrant group (hazard ratio [HR] 0.60; 95% confidence interval [CI], 0.51 to 0.71; p<0.001). Among the AKT pathway–altered population, the median progression-free survival was 7.3 months in the capivasertib–fulvestrant group, in contrast to 3.1 months in the placebo–fulvestrant group (HR 0.50; 95% CI, 0.38 to 0.65; p<0.001). The most frequent grade 3 or higher adverse events in patients receiving capivasertib–fulvestrant were rash (12.1% vs. 0.3% with placebo–fulvestrant) and diarrhea (9.3% vs. 0.3%). Adverse events leading to discontinuation were reported in 13.0% of patients receiving capivasertib and 2.3% receiving placebo. These findings suggest that capivasertib–fulvestrant therapy demonstrated significantly longer progression-free survival compared to treatment with fulvestrant alone in patients with hormone receptor–positive advanced breast cancer whose disease had progressed during or after previous aromatase inhibitor therapy with or without a CDK4/6 inhibitor.⁸

The recommended dosage of capivasertib, in combination with fulvestrant, is 400 mg orally twice daily for 4 days followed by 3 days off, and continue until disease progression or unacceptable toxicity. Dosing schedule details are provided in Tables 1 and 2.¹

Table 1: Capivasertib Dosing Schedule
Day	Morning	Evening
1	2 x 200 mg	2 x 200 mg
2	2 x 200 mg	2 x 200 mg
3	2 x 200 mg	2 x 200 mg
4	2 x 200 mg	2 x 200 mg
5*	-	-
6*	-	-
7*	-	-
*No dosing on day 5, 6, and 7. Adapted from: TRUQAP ™ (capivasertib). Prescribing information. AstraZeneca Pharmaceuticals LP; 2023

 

 

Table 2: Recommended Dose Reductions of Capivasertib for Adverse Reactions
Dose Reduction	Dose and Schedule
First dose reduction	320 mg twice daily for 4 days followed by 3 days off
Second dose reduction	200 mg twice daily for 4 days followed by 3 days off
Adapted from: TRUQAP ™ (capivasertib). Prescribing information. AstraZeneca Pharmaceuticals LP; 2023

 

Adverse events associated with capivasertib include hyperglycemia, with severe cases of diabetic ketoacidosis and metabolic decompensation occurring in a minority of patients. Diarrhea is also common, with severe cases leading to dehydration. Cutaneous adverse reactions, such as erythema multiforme and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), are reported in a significant proportion of patients, some of which may require corticosteroid treatment. Additionally, capivasertib poses a risk of embryo-fetal toxicity, warranting caution in pregnant women and the need for effective contraception during treatment and for a specified period afterward. Monitoring for these adverse events and appropriate management strategies, including dose adjustments or discontinuation, are advised based on severity.¹

Overall, the recent approval of capivasertib in combination with fulvestrant by the FDA represents a significant step forward in expanding treatment options for HR+/HER2− locally advanced or metastatic breast cancer. This approval provides an alternative therapy approach for patients with specific molecular alterations, as determined by an FDA-approved test, who have experienced disease progression on prior endocrine-based regimens. Capivasertib's mechanism, targeting all three isoforms of AKT and disrupting the PI3K/AKT pathway crucial in breast cancer cells, holds promise for potentially improving treatment outcomes. Clinical trial data have shown an extension in progression-free survival compared to fulvestrant alone, particularly among patients with AKT pathway alterations. This advancement underscores the ongoing efforts to personalize treatment strategies and optimize care for patients with HR+/HER2− breast cancer.

References

1. TRUQAP ™ (capivasertib). Prescribing information. AstraZeneca Pharmaceuticals LP; 2023
2. American Cancer Society. Breast Cancer Facts & Figures 2022-2024. Atlanta: American Cancer Society, Inc. 2022. Updated January 17, 2024. Accessed February 20, 2024
3. Arnold M, Morgan E, Rumgay H, et al. Current and future burden of breast cancer: Global statistics for 2020 and 2040. Breast. 2022;66:15-23. doi:10.1016/j.breast.2022.08.010
4. Wang R, Zhu Y, Liu X, Liao X, He J, Niu L. The Clinicopathological features and survival outcomes of patients with different metastatic sites in stage IV breast cancer. BMC Cancer. 2019;19(1):1091. Published 2019 Nov 12. doi:10.1186/s12885-019-6311-z
5. Twelves C, Cheeseman S, Sopwith W, et al. Systemic treatment of hormone receptor positive, human epidermal growth factor 2 negative metastatic breast cancer: retrospective analysis from Leeds Cancer Centre. BMC Cancer. 2020;20(1):53. Published 2020 Jan 21. doi:10.1186/s12885-020-6527-y
6. Kay C, Martínez-Pérez C, Meehan J, et al. Current trends in the treatment of HR+/HER2+ breast cancer. Future Oncol. 2021;17(13):1665-1681. doi:10.2217/fon-2020-0504
7. The Food and Drug Administration (FDA). FDA approves capivasertib with fulvestrant for breast cancer. Updated November 16, 2023. Accessed February 20, 2024 https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer
8. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131

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