The Evolution of PI3K Inhibitors in the Treatment of Breast Cancer

Breast cancer remains one of the leading causes of cancer-related mortality in women worldwide. Over the years, advancements in molecular profiling and targeted therapies have significantly transformed treatment approaches. Among these advancements, inhibitors targeting the PIK3CA mutation have gained attention, particularly in hormone receptor positive (HR+), HER2 negative (HER2–) breast cancer.¹ This mutation is one of the most frequent genetic alterations in HR+/HER2– breast cancer and is associated with a worse prognosis, making it an important target for therapy.²

HR+/HER2- breast cancer is associated with a poor prognosis. | Image credit: © arcyto | stock.adobe.com

The PIK3CA mutation is found in approximately 40% of HR+/HER2– breast cancer cases.³ This mutation leads to hyperactivation of the PI3K/AKT/mTOR signaling pathway, which plays a key role in regulating cell growth, metabolism, and survival.⁴ When mutated, the pathway drives uncontrolled cell proliferation, contributing to tumor progression and treatment resistance.

PI3K inhibitors work by selectively targeting the alpha isoform of the PI3K enzyme, which is encoded by the PIK3CA gene. This selective inhibition reduces cancer cell growth by blocking the pathway that promotes tumor cell survival. By focusing specifically on the mutated isoform, these inhibitors minimize off-target effects on other isoforms of PI3K, such as β, γ, and δ, which are involved in normal physiological functions.⁴

Alpelisib

Alpelisib (Piqray; Novartis) was the first PI3K inhibitor approved for the treatment of HR+/HER2– breast cancer. The FDA approved alpelisib in 2019 in combination with the estrogen receptor antagonist fulvestrant (Faslodex; AstraZeneca) for postmenopausal women and men with HR+/HER2– advanced or metastatic breast cancer carrying PIK3CA mutations.⁵ This combination is recommended following progression on or after an endocrine-based regimen. The recommended dose of alpelisib is 300 mg taken orally once daily with food.

The pivotal SOLAR-1 trial, a phase 3 clinical study, established alpelisib’s efficacy. In the trial, patients with advanced or metastatic PIK3CA-mutated HR+/HER2– breast cancer were randomized 1:1 to receive alpelisib plus fulvestrant or placebo plus fulvestrant. The median progression-free survival (PFS) in the alpelisib arm was 11 months compared to 5.7 months for those receiving placebo.⁶ The most common adverse events (AEs) were hyperglycemia, diarrhea, nausea, decreased appetite, and rash. The significant improvement in PFS with alpelisib demonstrated the impact of targeting the PIK3CA mutation within this category of patients with breast cancer.

Capivasertib

Capivasertib (Truqap; AstraZeneca) is another oral kinase inhibitor approved in combination with fulvestrant for the treatment of HR+/HER2– advanced or metastatic breast cancer. Capivasertib is a novel AKT-inhibitor that is indicated for patients whose tumors have 1 or more PIK3CA/AKT1/PTEN-alterations. This combination is recommended for patients who have developed disease progression following at least 1 endocrine-based regimen in the metastatic setting or recurrence within 12 months of adjuvant therapy completion.⁷ The recommended dose of capivasertib is 400 mg taken orally twice daily, with or without food, for 4 consecutive days each week, followed by 3 days off.⁷

The CAPItello-291 trial demonstrated a significant improvement in PFS in patients with PIK3CA/AKT1/PTEN-altered HR+/HER2– advanced breast cancer, where the median PFS was 7.2 months for those receiving capivasertib and fulvestrant, compared to 3.6 months for the placebo group. The most common AEs of capivasertib included diarrhea, rash, nausea, and hyperglycemia.⁸ Of note, hyperglycemia was observed to a lesser degree compared to alpelisib.

Inavolisib

Investigators have been assessing the potential of combining PI3K inhibitors with other targeted therapies to further improve outcomes. For example, trials combining PI3K inhibitors, CDK4/6 inhibitors, and endocrine therapy have shown promise. Data has indicated that targeting the estrogen receptor, CDK4/6, and PI3K pathways has synergistic effects and greater activity than targeting only 2 of the pathways.⁹

Inavolisib (Genentech) is a highly selective inhibitor of PI3K alpha that has shown promise in the treatment of PIK3CA-mutated HR+/HER2– advanced breast cancer. Inavolisib has shown significant clinical activity in combination with endocrine therapy and a CDK4/6 inhibitor, such as palbociclib (Ibrance; Pfizer). In the phase 3 INAVO120 trial, patients with PIK3CA-mutated, HR+/HER2– advanced breast cancer were randomized 1 to 1 to receive inavolisib 9 mg orally once daily, palbociclib 125 mg orally once daily for 21 days on, 7 days off, and fulvestrant or placebo, palbociclib and fulvestrant. The combination of inavolisib, palbociclib, and fulvestrant demonstrated a 57% reduction in the risk of disease progression, relapse, or death vs placebo.¹⁰ The most common AEs were neutropenia, stomatitis, hyperglycemia, diarrhea, nausea, and rash.

Inavolisib was approved by the FDA on October 10, 2024.¹⁴ Following this approval, the triplet regimen could become an option for the treatment of PIK3CA-mutated, HR+/HER2–, locally advanced or metastatic breast cancer, following recurrence on or after completing adjuvant therapy or progression on an endocrine-based regimen in the metastatic setting.¹¹

Management of AEs

While PI3K inhibitors have shown significant promise, their use is associated with various AEs, which require close monitoring and management. The most common AEs include hyperglycemia, rash, diarrhea, and nausea.¹² Hyperglycemia is particularly notable due to the role of PI3K pathway in insulin signaling. Each drug carries different recommendations on identification and management of its toxicities, and it is recommended to refer to each individual package insert.

Overall, clinical pharmacists should ensure that patients receiving PI3K inhibitors are monitored regularly for blood glucose levels, especially those with pre-diabetes or other metabolic conditions. Preventive measures, such as starting the patient on metformin, can help manage hyperglycemia before it becomes severe. Another concern is skin toxicity, including maculopapular rashes, which can often be managed with antihistamines or corticosteroids if detected early.

Conclusion

NCCN guidelines highlight the value of genetic testing to identify the presence of PIK3CA mutations.¹³ The development of PIK3 inhibitors has provided a significant breakthrough in the treatment of HR+/HER2– advanced breast cancer. While challenges such as hyperglycemia and skin reactions exist, the benefits of PIK3CA inhibitors in delaying disease progression make them a valuable tool in the fight against breast cancer.

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