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PI3K/AKT Inhibitors in mBC
Novel Targeted Therapies for PIK3CA/AKT1/PTEN-Altered Metastatic Breast Cancer: Key Evidence and Real-world Insights to Optimize Patient Care

Released: September 29, 2025

Nadia Harbeck
Nadia Harbeck, MD, PhD
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Key Takeaways
  • Patients with HR-positive/HER2-negative locally advanced or metastatic breast cancer have several treatment options available to them based on their disease mutational profile which can include PIK3CA/AKT/PTEN alterations or ESR1 mutation in the setting of progression on endocrine therapy and CDK4/6 inhibitor.
  • Although testing PIK3CA/AKT/PTEN alterations is feasible across Europe through major laboratories, there can be significant delays with regard to reimbursement for genetic testing and the approved PI3K/AKT inhibitor(s).
  • Based on a global survey, most healthcare professionals are generally familiar with the recent indications for PI3K/AKT inhibitors in the metastatic disease setting, but education is still needed on whether to test for actionable biomarkers in the postadjuvant setting.

Background on PI3K/AKT Inhibitors
At present, there are 2 oral PI3K inhibitors (alpelisib and inavolisib) and 1 oral AKT inhibitor (capivasertib) available for patients with HR-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC).

The randomized phase III SOLAR-1 trial is evaluating alpelisib plus fulvestrant vs placebo plus fulvestrant in patients with HR+/HER2- advanced breast cancer who had previously received endocrine therapy (ET). Patients were enrolled into 2 cohorts based on PIK3CA mutation status. Addition of alpelisib to fulvestrant compared with fulvestrant plus placebo yielded improved median progression-free survival (PFS) in patients with PI3K-mutated advanced breast cancer (11.0 vs 5.7 months HR: 0.65; P <.001) but no statistically significant overall survival (OS) benefit was observed (39.3 vs 31.4 months; HR:0.86; P = .15). Similarly, the phase III CAPItello-291 trial compared capivasertib plus fulvestrant vs placebo plus fulvestrant in women with any menopausal status or men with HR+/HER2- locally advanced or mBC who had relapse or disease progression during or after treatment with an aromatase inhibitor (AI), with or without previous CDK4/6 inhibitor therapy. CAPItello-291 showed a median PFS benefit in the overall population (7.2 vs 3.6 months; HR: 0.60; 2-sided P <.001) and in the AKT pathway–alteration population (7.3 vs 3.1 months; adjusted HR: 0.50; 2-sided P <.001). We are still waiting for the OS analysis from CAPItello-291. More recently, the phase III INAVO120 trial evaluated the addition of inavolisib to palbociclib plus fulvestrant vs palbociclib plus fulvestrant alone in patients with PIK3CA-mutated HR+/HER2- locally advanced or mBC with disease progression during or within 12 months of completing adjuvant ET and who had not received prior systemic therapy for metastatic disease. At a median follow-up of 34.2 months, the median PFS benefit with inavolisib was 17.2 months compared with 7.3 months with placebo (HR: 0.42). Final OS analyses from INAVO120 also showed an OS benefit of approximately 7 months in the inavolisib arm (34.0 vs 27.0 months; HR: 0.67; P = .019).

I think having access to these 3 agents is a major step forward in the care of patients with HR+/HER2- mBC with PI3KCA/AKT/PTEN alterations. Overall, the above data show how important a role these PI3K/AKT inhibitors have in this space, particularly the endocrine-resistant population that was explored in those trials.

Frequently Asked Questions

What informs your decision on which targeted therapy to use in a patient with HR+/HER2- mBC with progression on AI plus CDK4/6 inhibitor and carrying multiple genetic PIK3CA/AKT/PTEN alterations?
In a patient with a tumor carrying an ESR1 mutation and PIK3CA or AKT pathway alteration, there are a few factors to consider. First, I consider the side effect profile for these agents and whether the patient is going to tolerate any of the treatments well. Second, if the patient is potentially a good candidate for ET continuation I might offer an oral SERD such as elacestrant, if they have an ESR1 mutation, particularly because it is an oral agent and it does not have many of the side effects that patients find bothersome. Third, if the tumor is progressing rapidly and is highly aggressive, I would think it may not be as ET sensitive and could be driven by the PIK3CA/AKT/PTEN pathway alteration. In that scenario, doublet therapy with an ET plus a PI3K inhibitor might be my preferred approach.

What is the best time to assess for tumor driver mutations (ie, ESR1, PIK3CA/AKT/PTEN alterations) in HR+/HER2- mBC?
We used to test for PIK3CA or AKT pathway alterations in patients after progression on first-line CDK4/6 inhibitor plus an AI. Now we also test patients with rapid disease progression while receiving an adjuvant ET or within 1 year after stopping it. This practice is supported by results from the INAVO120 phase III study mentioned earlier. I would also test in first-line mBC on rapid progressors where we feel there is ET resistance, and in second line on patients that had a good response to CDK4/6 inhibitor but then eventually progressed.

In the first-line setting, testing within 2-3 weeks is reasonable because at this stage we are also doing additional staging, potentially with a biopsy, to help the patient better understand their disease. Here we do have the time to wait for the results, and optimally we will get genetic testing results within 2 weeks.

Is there standardized/centralized testing across Europe to assess for PIK3CA/AKT/PTEN alterations?
In Europe, we do not currently use the concept of a “required” companion diagnostic. I do recognize that some indications require assessment of genetic biomarkers but the tests that are being used can vary widely, such as personalized genomic testing and/or use of immunohistochemistry. In Germany, where I practice, the testing laboratories follow standard procedures and good quality control systems. We know that PIK3CA mutations are not acquired, so we can test for these on the primary tumor tissue as well as on a liquid biopsy. Whether I want to test for other mutations as well also depends on the disease setting, and that gives me the choice of tissue I send for testing—whether it is liquid biopsy or the primary tumor tissue.

Current Indications/Market Authorization for PI3K/AKT Inhibitors in Europe
The following are the current indications for the agents we have covered—across Europe:

  • Alpelisib is indicated in combination with fulvestrant for the treatment of men and postmenopausal women with HR+/HER2-, locally advanced or mBC with a PIK3CA mutation after disease progression following ET monotherapy.
  • Capivasertib is indicated in combination with fulvestrant for the treatment of men and postmenopausal women with HR+/HER2- locally advanced or mBC with a PIK3CA mutation after disease progression following ET monotherapy.
  • Inavolisib is indicated in combination with palbociclib and fulvestrant for the treatment of adult patients with estrogen receptor–positive/HER2-negative, locally advanced or mBC with a PIK3CA mutation following recurrence on or within 12 months of completing adjuvant ET.

The recent inavolisib approval is quite exciting because it is an option we can immediately offer to our patients based on how the registration process works in Europe. However, getting reimbursed for the tests that we need to perform can take up to 6 months—which may or may not be limiting for the treating healthcare professional (HCP). We already have PIK3CA mutations built into the reimbursement system because of the alpelisib approval in 2020. This means there is not a big challenge for HCPs to start to prescribe inavolisib in the triplet combination. But to be clear, across Europe, reimbursement for the drug does not automatically follow the approval. Many colleagues have to wait until they have reimbursement in place and otherwise can only prescribe inavolisib in certain settings or some rapid access programs.

Expert’s Insights From a Global HCP Survey
As part of an upcoming educational program we polled physicians around the world (ie, Brazil, France, Germany, Italy, Portugal, Spain, Sweden/Switzerland, United States, and other countries) about their current practice and hands-on experience with and use of PI3K/AKT inhibitors for their patients with advanced breast cancer.

Overall, the survey results to date reflect what I would expect because we have used alpelisib for quite a while whereas capivasertib and inavolisib are relatively more recent to the market. In Germany, alpelisib is not marketed anymore and if we wanted to prescribe it we would have to apply for it on a case by case basis. Survey results on a 7-point confidence scale showed an intermediate level of confidence among survey respondents with regard to describing to patients the rationale for using PI3K/AKT inhibitors.  

Testing for PIK3CA/AKT/PTEN Alterations
In general, I think HCPs usually do not know much about the testing and thus might be unclear there. This explains why survey participants felt that there is a lack of standardized testing protocols. In my experience, major laboratories where testing is performed are quite proficient and competent and use all the appropriate controls.

Survey participants reiterated what I have experienced in my practice regarding cost and reimbursement issues with a little over half (53%) indicating this is a barrier for using these agents. Other common barriers included slow turnaround time (34%), uncertainty about the optimal sample source for testing (28%), and identifying which patients need testing (25%). Using or requesting liquid biopsy is something that we have only recently started to implement. Of note, I believe the elacestrant registration helped us there because it is an acquired mutation and the label did not specify to test the primary tumor. However, HCPs are not as confident with liquid biopsies as they are with ordering immunohistochemistry.

Indications
Regarding properly identifying patients to evaluate for PI3K/AKT inhibitors based on recent indications, fewer than 50% of survey participants understood that it was for “newly diagnosed mBC who were ET-resistant progressing within 1 year from end of adjuvant ET with or without CDK4/6 inhibitor” and for “mBC following progression on first-line ET with or without CDK4/6 inhibitor.” However, there were approximately 30% of survey responders who indicated they would test newly diagnosed early breast cancer for PIK3CA, AKT, or PTEN alterations. It could also be that in the process of testing for ESR1 mutations they may come across incidental cases with those alterations, but in the newly diagnosed early breast cancer we would still go with CDK4/6 inhibitor. Testing for these alterations in the setting of early breast cancer is not currently recommended. We will discuss these recommendations in our upcoming educational program and downloadable resources.

Adverse Event Challenges With PI3K/AKT Inhibitors
In our survey, we asked the community which adverse events (AEs) associated with these PI3K/AKT inhibitors are the most challenging to manage in clinical practice. A majority of respondents indicated that they had experience with alpelisib and that the biggest AE management challenge with this drug was hyperglycemia (57%). In the clinical trials of alpelisib, ≥30% of patients experienced grade 3/4 hyperglycemia. Stomatitis is also challenging with alpelisib. We just started to use inavolisib and I do not think people in Europe are as familiar with it compared with managing AEs with alpelisib and capivasertib. This is why I think most survey participants answered in a “neutral” manner. However, managing AEs with capivasertib is often easier than with alpelisib and this was reflected in the survey with most survey responders saying hyperglycemia, infections, itching/pruritus, and diarrhea are less challenging. Again, this is probably in comparison with alpelisib which is the 1 agent we have had more experience with. However, in general I think newer PI3K/AKT inhibitors have improved upon the AE profile from the earlier drugs. A final note of caution: although we refer to PI3K/AKT inhibitors interchangeably, we cannot really compare these 3 drugs as if they are all the same. We must remember they have slightly different indications, and they vary with regard to specificity/site for the target protein (alpelisib: the PI3Kα [p110α] isoform; capivasertib: pan-AKT inhibitor [isoforms AKT1, AKT2, and AKT3; and inavolisib more selective for PI3Kα[p110α]).

Your Thoughts
What are your thoughts on integrating PI3K/AKT inhibitor treatment options into everyday clinical practice for patients with HR+/HER2- locally advanced or mBC? Answer the poll and join the conversation by leaving a comment, visit the program page to register for an upcoming live webinar on this topic, and access free downloadable resources to continue your education and share with colleagues.

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Which of the following are your greatest challenges related to incorporating PI3K/AKT inhibitors into the care of patients with HR+/HER2- locally advanced or mBC? Please select all that apply.

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