Capivasertib for Hormone-Positive Breast Cancer: For Whom and When?

Hormone receptor (HR)-positive, HER2-negative metastatic breast cancer is the most common subtype, representing 65-70% of all breast cancers. This article examines capivasertib's effectiveness, side effects, and place in treatment sequencing using clinical data following FDA approval.

It discusses the importance of molecular testing, capivasertib's role in patients with PI3K/AKT/PTEN pathway alterations, and effects on survival and quality of life.

Current Treatment Approaches for HR-Positive, HER2-Negative Metastatic Breast Cancer

First-line treatment generally combines endocrine therapy with CDK4/6 inhibitors. However, following progression, second-line treatment remains a matter of debate.

One recently developed targeted treatment that received FDA approval on November 16, 2023, is capivasertib (Truqap), a promising option for patients with PI3K/AKT/PTEN pathway alterations.

Capivasertib's Mechanism and the PI3K/AKT/PTEN Pathways

Alterations in PI3K/AKT/PTEN signaling occur in 50% of HR-positive breast cancers and play a critical role in progression. In the CAPItello-291 study published in 2023, capivasertib with fulvestrant was shown to improve progression-free survival (PFS) by 4.2 months in biomarker-positive patients. However, the PFS improvement in biomarker-negative patients did not reach statistical significance.

Dose and Clinical Use

Capivasertib is given orally at 400 mg daily on 4 days each week, with fulvestrant. Patient groups showing benefit in clinical studies include:

• Patients with PI3K/AKT/PTEN Alterations: Combination treatment with capivasertib significantly prolonged progression-free survival in biomarker-positive patients.

• Patients Progressing After Aromatase Inhibitors and CDK4/6 Inhibitors: Capivasertib may be considered as a second-line option after first-line treatment.

Quality of Life and Side Effects

In CAPItello-291, capivasertib maintained quality of life for longer. However, the following common side effects may impair adherence:

1. Diarrhea (77%): Early use of antidiarrheal medicines such as loperamide may control it.

2. Hyperglycemia (19%): Blood glucose requires careful monitoring in patients with diabetes.

3. Skin Rashes (56%): Severe skin reactions may require dose adjustment.

Multidisciplinary collaboration in managing side effects may improve treatment effectiveness.

Treatment Sequencing and Alternatives

Several options are available after progression on a CDK4/6 inhibitor in HR-positive, HER2-negative metastatic breast cancer. Selection depends on general health, previous response, and molecular tumor characteristics. Possible scenarios include:

1. Combining Endocrine Therapy with Targeted Agents:

   • PI3K Inhibitors: For PIK3CA-mutant disease, PI3K inhibitors such as alpelisib may be combined with fulvestrant. This combination prolongs progression-free survival.
   • AKT Inhibitors: For PI3K/AKT/PTEN pathway alterations, AKT inhibitors such as capivasertib may be used with fulvestrant. This combination shows promise for improving progression-free survival.

2. Selective Estrogen Receptor Degraders (SERDs):

   • Elacestrant: The oral SERD elacestrant may be used alone in ESR1-mutant disease. The EMERALD study demonstrated prolonged progression-free survival.

3. mTOR Inhibitors:

   • Everolimus: Everolimus plus exemestane may be used for patients without mutations or unsuitable for other targeted treatments. BOLERO-2 demonstrated its effectiveness.

4. PARP Inhibitors:

   • Olaparib or Talazoparib: PARP inhibitors may be used alone in BRCA1/2-mutant disease. They target DNA repair mechanisms, causing tumor-cell death.

5. Chemotherapy:

   • Single-agent or combination chemotherapy may be considered when targeted treatments fail or are unsuitable. Options include capecitabine, eribulin, vinorelbine, or taxanes.

6. Immunotherapy:

   • Immunotherapies such as pembrolizumab may be considered for high microsatellite instability (MSI-H) or high tumor mutational burden (TMB-H). However, immunotherapy effectiveness in HR-positive, HER2-negative breast cancer is limited.

7. Clinical Trials:

   • Trials evaluating new agents and combinations may be an option for eligible patients, providing access to innovative treatments.

Treatment selection should consider general health, previous responses, molecular tumor profile, and side-effect profiles. A multidisciplinary approach and detailed discussion with the patient are critical to identifying the most suitable strategy.

Conclusion

Capivasertib is an effective option that significantly improves progression-free survival in HR-positive, HER2-negative metastatic breast cancer with PI3K/AKT/PTEN pathway alterations. Biomarker testing is critical for treatment selection.