Capivasertib/Fulvestrant Approval Expands Options in PIK3CA/AKT1/PTEN-Altered HR+/HER2– Breast Cancer

Sara M. Tolaney, MD, MPH

Capivasertib (Truqap) plus fulvestrant (Faslodex) provides another effective and safe treatment option for patients with hormone receptor (HR)–positive, HER2-negative, locally advanced or metastatic breast cancer after CDK4/6 inhibition. However, genomic information and a deeper understanding of toxicity management are necessary to navigate this expanding armamentarium, according to Sara M. Tolaney, MD, MPH.

Capivasertib/fulvestrant was evaluated in the phase 3 CAPItello-291 trial (NCT04305496), which met its primary end points of significantly improved progression-free survival (PFS) in the overall study population as well as those harboring PIK3CA/AKT1/PTEN alterations. In the overall population, patients on the capivasertib arm (n = 355) experienced a median PFS of 7.2 months (95% CI, 5.5-7.4) vs 3.6 months (95% CI, 2.8-3.7) for those on placebo plus fulvestrant (n = 353; hazard ratio, 0.60; 95% CI, 0.51-0.71; P < .001).¹

Patients with PIK3CA/AKT1/PTEN alterations experienced a median PFS of 7.3 months (95% CI, 5.5-9.0) with capivasertib and fulvestrant vs 3.1 months (95% CI, 2.0-3.7) with placebo and fulvestrant (n = 134; hazard ratio 0.50; 95% CI, 0.38, 0.65; P < .0001).¹

Although the PFS benefit was observed across prespecified subgroups, an exploratory analysis of patients without PIK3CA/AKT1/PTEN alterations demonstrated a numerical but not statistically significant increase in PFS (HR, 0.79; 95% CI, 0.61, 1.02) with capivasertib plus fulvestrant. ¹

Based on these data, the FDA approved capivasertib plus fulvestrant on November 16, 2023 for the treatment of this patient population harboring 1 or more PIK3CA, AKT1, or PTEN alteration following progression on at least 1 endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.²

“This [approval] is exciting because it offers a new opportunity for treatment in patients with an [AKT] pathway alteration who have progressed on upfront endocrine-based treatment,” said Tolaney, who is the chief of the Division of Breast Oncology at Susan F. Smith Center for Women’s Cancers, the associate director of the Susan F. Smith Center for Women’s Cancers, a senior physician at Dana-Farber Cancer Institute, and an associate professor of medicine at Harvard Medical School, in Boston, Massachusetts.

In an interview with OncLive®, Tolaney discussed the significance of the FDA approval of capivasertib and fulvestrant in this patient population, highlighted the efficacy and notable toxicities seen in the CAPItello-291 trial, and touched on key considerations when selecting between this and other standard regimens following CDK4/6 inhibitor progression.

OncLive: Please discuss the significance of the FDA approval of capivasertib plus fulvestrant in HR-positive, HER2-negative breast cancer.

Tolaney: I was excited to see the approval for capivasertib in patients with metastatic HR-positive disease. Right now, one area of unmet need is [determining how to treat] a patient who experienced progression on endocrine therapy and a CDK4/6 inhibitor. We have been trying to improve how we [approach treatment] in this setting because we know that endocrine monotherapy has limited activity following CDK4/6 inhibition. In CAPItello-291, patients who experienced disease progression on prior endocrine treatment and were randomly assigned to receive fulvestrant with capivasertib [vs without achieved] a significant improvement in PFS. [This was] particularly [evident] in those patients who had an alteration in PIK3CA, PTEN, or AKT1. Their PFS was substantially longer with a combination of fulvestrant plus capivasertib relative to fulvestrant alone.

Could you expand on these efficacy data from CAPItello-291?

In CAPItello-291, the addition of capivasertib to fulvestrant improved PFS in the overall population. It increased from 3.6 months to 7.2 months, with a hazard ratio of 0.6. However, when you looked at the biomarker-altered group, which was about 40% of patients, the benefit was even larger. It increased from 3.1 months to 7.3 months with a hazard ratio of 0.5. When we looked at the unaltered group of patients, the hazard ratio was closer to 0.8. This suggests that the majority of the benefit with capivasertib is being driven by the biomarker-altered group. That's likely what led to the FDA limiting the approval to the biomarker-altered population, because this group derived the largest benefit from the addition of capivasertib to fulvestrant.

What should be known about the safety profile of this combination?

Capivasertib is an AKT inhibitor and the [its safety profile] does involve increased gastrointestinal toxicity. Approximately 80% of patients in the trial did experience some level of diarrhea. That's probably the most prevalent toxicity with capivasertib. [Another AE to] be aware of is a risk of rash. It's important to note that patients did not receive prophylaxis, such as an antihistamine agent, in this trial to prevent rash uniformly. We saw 38% of people having a rash. [Of these,] 12% were high grade. We don't know what that [rate] would have been if people had been receiving antihistamine prophylaxis. We also [saw] some hyperglycemia in approximately 16% of patients, but rates of high-grade hyperglycemia were low at [approximately] 2%.

[Notably, researchers] were more liberal with patient eligibility [criteria]. Patients could have a history of diabetes and a hemoglobin A1C up to 8 and be eligible for this trial. This is different, for example, than what was utilized in [the phase 3] SOLAR-1 [NCT02437318] in which alpelisib [Piqray] was administered to patients with a PIK3CAmutation. [In this trial,] they limited hemoglobin A1C to 6.5. This was a broader population of patients, and yet the rate of hyperglycemia was lower.

We're still going to have to learn how to ultimately manage these AEs. What's the optimal way to manage diarrhea? Right now, most of us would use loperamide as needed. For the rash, most of us would probably consider using antihistamine prophylaxis. Given that rates of high-grade hyperglycemia [with the combination] are low at this time, we likely will not be using things like metformin as prophylactic therapy. Rather, [we may] just monitor for hyperglycemia and initiate metformin as needed.

How do you envision this combination fitting into the treatment paradigm for this population?

Someone with metastatic HR-positive disease will typically receive endocrine therapy and CDK4/6 inhibition as a first-line standard treatment. After disease progression, most of us [will request a] genomic assay. I typically get a circulating tumor DNA assay, and I'm looking to see if they have an ESR1 mutation or if they have PIK3CA-, PTEN-, or AKT1-altered [tumor] to help make this decision. If they do have an alteration in that PI3K/PTEN/AKT pathway, it would make [me more strongly consider] fulvestrant and capivasertib. For patients without an alteration, I'm using things like fulvestrant and everolimus (Afinitor). We also have elacestrant (Orserdu) available for patients who have ESR1 mutations in this setting. Getting that genomic information following CDK 4/6 inhibition is critical to determining which treatment choice to use in that setting.

References

1. 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
2. FDA approves capivasertib with fulvestrant for breast cancer. News release. FDA. November 16, 2023. Accessed December 19, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer