How Do Final CAPItello-291 OS Data Shape Capivasertib Use in Breast Cancer?

In a recent CancerNetwork® Between the Lines program, a panel of breast oncology experts read between the lines of the final overall survival (OS) analysis from the phase 3 CAPItello-291 trial (NCT04305496), which evaluated capivasertib (Truqap) plus fulvestrant (Faslodex) in hormone receptor (HR)–positive, HER2-negative advanced breast cancer.¹ The combination originally established itself on a strong progression-free survival (PFS) benefit that supported its FDA approval; with mature survival data now available, the panel considered what the results mean for sequencing therapy in the post-CDK4/6 inhibitor setting.

The panel was led by Erica L. Mayer, MD, MPH, director of Breast Cancer Clinical Research in the Breast Oncology Center at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School. She was joined by Seth A. Wander, MD, PhD, director of translational research for the Breast Oncology Program and director of precision medicine in the Termeer Center for Targeted Therapies at Massachusetts General Hospital, and Sarah Sammons, MD, co-leader of breast oncology at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center in Baltimore.

A Crowded Post-CDK4/6 Landscape

Mayer opened by asking Sammons how the treatment landscape has evolved in the post-CDK4/6 inhibitor setting. “It is evolving rapidly, and it continues to change a couple times a year. This space is just so active,” Sammons said. “We now have several novel endocrine therapy agents approved for patients with ESR1 mutations: elacestrant [Orserdu], imlunestrant [Inluriyo], and vepdegestrant [Veppanu]. We also have a multitude of PIK3CA or AKT inhibitors. We’ve had alpelisib [Piqray] and fulvestrant [Faslodex] for patients with PIK3CA mutations, and now we have a second option in capivasertib. Capivasertib can also be offered to patients with PTEN or AKT alterations. [There are] lots of new data and lots of choices.”

Wander added that clinicians must now layer molecular and genomic data on top of traditional disease and patient factors. “We now have multiple new FDA approvals just in the last couple of years that are based on specific molecular genomic targets,” he said. “We have 3 FDA-approved medications based on the presence of ESR1 mutations, several based in the PI3K/AKT pathway, and now gedatolisib [Revtorpyk], the first PI3K/AKT/mTOR inhibitor, regardless of PIK3CA status. We have to look at what the genomics are and then try to look across our toolbox.”

Pathway Biology and Biomarker Testing

Alterations in the PI3K/AKT pathway arise in roughly half of patients with HR-positive, HER2-negative advanced breast cancer and represent a common mechanism of endocrine resistance, particularly after a CDK4/6 inhibitor.^2,3 “In about 40% of patients with ER-positive metastatic disease, we see activating mutations in PIK3CA,” Wander explained. “Another 5% to 10% will have activation downstream, either through turning on AKT or turning off the tumor suppressor PTEN. Think of it like a ladder moving down inside the cell: PI3K turns on AKT, AKT turns on mTOR, and mTOR turns on effector molecules important for cell survival, growth, and metastasis.”

On testing, Sammons said she sends tissue testing at diagnosis for every patient with metastatic HR-positive disease and follows with circulating tumor DNA (ctDNA) testing at progression. “I always send new ctDNA at the time of progression on a patient’s CDK4/6 inhibitor because we know we’re going to see emergence of ESR1 mutations over the course of first-line therapy,” she said. “The vast majority of PIK3CA, PTEN, or AKT alterations will be picked up by ctDNA. However, in the phase 3 SOLAR-1 analysis [NCT02437318], some patients whose ctDNA was negative had positivity on tissue, so it’s comprehensive to send tissue testing up front.”⁴

Trial Design and the Original PFS Benefit

CAPItello-291 randomly assigned 708 patients with HR-positive, HER2-negative advanced breast cancer 1:1 to capivasertib plus fulvestrant or placebo plus fulvestrant after progression on prior endocrine therapy, with at least 51% of patients having received a prior CDK4/6 inhibitor.⁵ Capivasertib was dosed at 400 mg twice daily on an intermittent 4-days-on, 3-days-off schedule, which Wander tied to the drug’s toxicity profile. “It’s related to trying to avoid the continuous pressure on the pathway, which results in higher rates of hyperglycemia, mucositis, and GI toxicity,” he said. “It may be a little challenging for patients with a lot of polypharmacy, but the trade-off is a much better therapeutic index.”

Sammons noted that the fulvestrant-only control arm, appropriate when the trial was designed, now reads as somewhat outdated. At the original primary analysis, capivasertib plus fulvestrant significantly improved PFS in both the altered population (7.3 vs 3.1 months; HR, 0.50; 95% CI, 0.38-0.65; P <.001) and the overall population (7.2 vs 3.6 months; HR, 0.60; 95% CI, 0.51-0.71; P <.001), a benefit seen regardless of ESR1 status or prior CDK4/6 inhibitor exposure.^6,7 “The hazard ratio is certainly better in the altered population, and that is where we have FDA approval,” Sammons said. “I do think the [adverse] effect profile is more favorable than alpelisib, and everything will change when gedatolisib is an option.”

[Editor’s note: This filming occurred prior to the July 14, 2026, FDA approval of gedatolisib.]

What the Final Overall Survival Data Show

At final analysis (data cutoff, June 16, 2025), the OS hazard ratio in the PIK3CA/AKT1/PTEN-altered population was 0.83 (95% CI, 0.63-1.10; P = .201), with median OS of 28.5 vs 30.4 months.⁵ Because of the trial’s hierarchical design, OS in the overall population was not formally tested; the observed hazard ratio was 1.00 (95% CI, 0.83-1.19), with a median OS of 29.4 vs 28.6 months.⁴

“It’s hard to show OS in the first couple of lines of therapy for estrogen receptor [ER]–positive metastatic disease,” Wander said. “There are many different roads patients can take after they progress. To me, and this is just my own editorial opinion, this is a very important regimen that’s been durable for a number of years in the second line. The fact that the OS didn’t reach statistical significance doesn’t deter my enthusiasm for using it.”

Sammons described her decision-making as “very much a gestalt.” “Right now, we don’t have a drug in the second-line post-CDK space in [patients with] PIK3CA-altered [disease] that does prolong survival, but if we do see a well-powered study where OS is improved, it could ultimately be a detriment that there was not [an OS benefit here],” she said. “Today, does it bother me? No, because of the alternatives. This is less toxic, it clearly prolongs PFS compared with single-agent fulvestrant, and it has a more favorable toxicity profile than alpelisib.” A prespecified exploratory analysis in patients with prior CDK4/6 inhibitor exposure showed a numerically larger OS benefit in the altered population, extending median OS by roughly 7 months (28.1 vs 21.2 months; HR, 0.78; 95% CI, 0.57-1.07), though the panel cautioned that the confidence interval crosses 1.⁵

Post-Progression End Points and Managing Toxicity

Sammons pointed to post-progression therapy imbalance as a key confounder of OS interpretation, citing a real-world example from triple-negative breast cancer in which 2 similar trials of TROP2 antibody-drug conjugates diverged on OS depending on whether crossover was allowed. “Everyone would love to say we should offer crossover in every trial, but it’s simply not feasible,” she said. “We have such heterogeneous patient populations in HR-positive, HER2-negative breast cancer that it’s very hard to offer in many settings.”

Against that backdrop, capivasertib plus fulvestrant showed sustained benefit on secondary and exploratory end points. Median PFS2 was 15.9 months vs 11.1 months in the altered population (HR, 0.68; 95% CI, 0.53-0.88), compared with 15.4 months vs 12.7 months in the overall population (HR, 0.85; 95% CI, 0.72-100). The median time to first subsequent chemotherapy was 11.0 months vs 6.0 months (HR, 0.62; 95% CI, 0.48-0.80) in the altered population and 11.0 months vs 7.0 months (HR, 0.74; 95% CI, 0.63-0.87) in the overall population.⁵ “Time to subsequent chemotherapy is a little easier for us to wrap our heads around; that’s a concrete measure,” Wander said. “We’re unfortunately not curing this disease at the moment, and if we can’t cure it, quality of life, in addition to length of life, is critically important.”

Updated safety data were consistent with the primary analysis, with diarrhea in about 77% of patients in the capivasertib arm, rash in 41%, and hyperglycemia in 17% across the altered population.⁵ Wander described a team-based approach to patient education involving nursing, pharmacy, and advanced practice providers, with an emphasis on setting expectations early to avoid patients “getting behind the wave” of emerging symptoms. Sammons shared her own practical strategies: “I tell patients that they get a 3-day weekend off, so I recommend Monday through Thursday dosing. I also prescribe prophylactic cetirizine [Zyrtec], not based on CAPItello-291, but based on data from the SOLAR-1 trial showing that a prophylactic antihistamine dramatically lowers rates of high-grade rash. In terms of glucose monitoring, I tell patients to watch their sugars and cut out sugary drinks, and patients appreciate being proactive about that.”

Where Capivasertib Fits Amid Emerging Options

The panel closed by weighing how 2 newer regimens, gedatolisib (Revtorpyk) plus fulvestrant and giredestrant plus everolimus (Afinitor), may reshape sequencing after a CDK4/6 inhibitor. Gedatolisib was recently approved based on the phase 3 VIKTORIA-1 trial (NCT05501886), and giredestrant plus everolimus improved PFS in the phase 3 evERA trial (NCT05306340).^8,9 “We may, in the future, have a label for gedatolisib that includes the PIK3CA mutations, meaning it’s overlapping directly with capivasertib. This is a hard discussion to have,” Wander said. “It’s going to come down to patient preference and clinician preference as we get more experience with these drugs. evERA is a little more straightforward; that’s an all-oral regimen that patients may be excited to use, particularly for the ESR1-mutant, PIK3CA wild-type population, where you might not have other great options outside of endocrine monotherapy.”

Mayer closed by tying the trial back to the broader challenge of interpreting survival end points in a disease with a long natural history. “The final OS analysis that we looked at from CAPItello-291 not only tells us more about that specific trial, but helps us think about how we use survival end points when we’re taking care of HR-positive breast cancer, which we know has a very long course and many different events that happen for patients,” she said.

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. Millis SZ, Ikeda S, Reddy S, Gatalica Z, Kurzrock R. Landscape of phosphatidylinositol-3-kinase pathway alterations across 19784 diverse solid tumors. JAMA Oncol. 2016;2(12):1565-1573. doi:10.1001/jamaoncol.2016.0891
3. Stanciu IM, Parosanu AI, Orlov-Slavu CM, et al. Mechanisms of resistance to CDK4/6 inhibitors and predictive biomarkers of response in HR+/HER2-metastatic breast cancer—a review of the literature. Diagnostics (Basel). 2023;13(5):987. doi:10.3390/diagnostics13050987
4. Andre F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. doi:10.1056/NEJMoa1813904
5. Rugo HS, Oliveira M, Howell SJ, et al. Capivasertib (C) and fulvestrant (F) for patients (pts) with HR+/HER2- advanced breast cancer (ABC): final overall survival (OS) results from the phase 3 CAPItello-291 trial. ESMO Open. 2026;11(suppl 4):107440. doi:10.1016/j.esmoop.2026.107440
6. Rugo HS, Turner NC, Finn RS, et al. Capivasertib and fulvestrant for patients with HR-positive/HER2-negative advanced breast cancer: primary results of the phase 3 CAPItello-291 trial. ESMO Open. 2024;9(9):103697. doi:10.1016/j.esmoop.2024.103697
7. Turner NC, Oliveira M,, Howell SJ, et al. Capivasertib plus fulvestrant in hormone receptor-positive (HR+) advanced breast cancer (ABC): exploratory ctDNA analyses from the Phase 3 CAPItello-291 trial. Presented at: San Antonio Breast Cancer Symposium 2025; December 9-13, 2025; San Antonio, TX. Abstract RF7-05.
8. FDA approves gedatolisib with fulvestrant, with or without palbociclib, for HR-positive, HER2-negative locally advanced or metastatic breast cancer. News release. FDA. July 14, 2026. Accessed August 21, 2026. https://tinyurl.com/yck3eabf
9. Mayer E, Tolaney SM, Martin M, et al. Giredestrant (GIRE), an oral selective oestrogen receptor (ER) antagonist and degrader, + everolimus (E) in patients (pts) with ER-positive, HER2-negative advanced breast cancer (ER+, HER2– aBC) previously treated with a CDK4/6 inhibitor (i): Primary results of the phase III evERA BC trial. Ann Oncol. 2025;36(suppl 2):S1561-S1562. doi:10.1016/j.annonc.2025.09.026