Capivasertib Plus Paclitaxel Misses OS End Points in Advanced Triple-Negative Breast Cancer

The addition of capivasertib (Truqap) to paclitaxel did not produce a statistically significant improvement in overall survival (OS) vs placebo plus paclitaxel as frontline therapy in patients with locally advanced inoperable or metastatic triple-negative breast cancer (TNBC) or those with PIK3CA, AKT1, or PTEN alterations, missing both primary end points of the phase 3 CAPItello-290 trial (NCT03997123).¹

The safety profile of capivasertib plus paclitaxel in CAPItello-290 was largely consistent with the established safety profile of each agent with no new reported safety signals. Findings from the trial will be shared some time in the future.

“Despite modest advances, triple-negative breast cancer remains one of the most challenging forms of disease to treat due to the lack of known actionable biomarker targets, and chemotherapy-based regimens continue to be the mainstay of treatment. While the CAPItello-290 trial results have not shown what we hoped, they provide important information to further understand this aggressive form of breast cancer where patients are in urgent need of new treatments,” Peter Schmid, FRCP, MD, PhD, professor of cancer medicine, centre lead of the Centre of Experimental Cancer Medicine, and the director of the Barts Breast Cancer Centre, at Barts Cancer Institute, in London, England, and principal investigator for the trial stated in a press release.

Previously in the phase 2 PAKT trial (NCT02423603) the combination of capivasertib and paclitaxel demonstrated prolonged progression-free survival (PFS) and OS vs placebo plus paclitaxel as frontline therapy in patients with advanced TNBC, including those with PIK3CA/AKT1/PTEN-altered tumors (n = 138). The median PFS was 5.9 months (95% CI, 3.8-7.5) in the combination arm vs 4.2 months (95% CI, 3.5-5.2) in the placebo arm (HR, 0.74; 95% CI, 0.50-1.08; one-sided P =.06). The median OS in the combination and placebo arms was 19.1 months (95% CI, 10.9-20.9) vs 12.6 months (95% CI, 10.4-16.9), respectively (HR, 0.61; 95% CI, 0.37-0.99; one-sided P =.02).²

Among the subgroup of patients with PIK3CA/AKT1/PTEN-altered tumors (n = 28) the median PFS was 9.3 months (95% CI, 3.7-17.7) with the combination vs 3.7 months (95% CI, 1.9-5.9) with placebo (HR, 0.30; 95% CI, 0.11-0.79; P =.01). The median OS in the combination and placebo was not available (NA; 95% CI, 10.2-NA) compared with 10.4 months (95% CI, 4.0-NA), respectively (HR, 0.37; 95% CI, 0.12-1.12; P =.07).²

CAPItello-290 was designed as a global, double-blind, randomized trial to further evaluate the efficacy and safety of capivasertib plus paclitaxel vs placebo plus paclitaxel as frontline treatment in 923 patients with locally advanced inoperable or metastatic TNBC.¹

To be eligible for enrollment patients had to have histologically confirmed locally recurrent or metastatic TNBC; an ECOG or World Health Organization performance status of 0 or 1; measurable disease according to RECIST 1.1 and/or lytics or mixed bone lesions that could be evaluated by CT or MRI in the absence of measurable disease; and formalin-fixed paraffin-embedded tumor sample from the primary or recurrent tumor.³

In the investigational arm patients received 3 weekly intravenous infusions of paclitaxel at a dose of 80 mg/m2 on day 1 of weeks 1, 2, and 3, plus 400 mg of capivasertib oral tablets administered twice daily on days 2 to 5 of weeks 1, 2, and 3 in 28-day cycles. In the control arm capivasertib was replaced with placebo tablets.

The dual primary end points were OS in the overall patient population and in a subset of patients with tumor alterations in the PI3K/AKT pathway.¹ Secondary end points included investigator-assessed progression-free survival and time to progression or death, overall response rate, duration of response, clinical benefit rate, safety and tolerability characterized by adverse effects (AEs) and serious AEs, quality of life, and pharmacokinetic parameters.³

“We are committed to advancing science for patients in some of the most challenging cancers, including this heterogeneous subtype of breast cancer. While we are disappointed in the CAPItello-290 outcome, these results will further our understanding of the role of the PI3K/AKT pathway in breast cancer as we continue our clinical research across the [capivasertib] clinical development programme and across our pipeline,” Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca, said in the press release.¹

Capivasertib is also being evaluated in the phase 3 CAPItello-292 trial (NCT04862663) in patients with breast cancer as well as the phase 3 CAPItello-280 (NCT05348577) and CAPItello-281 (NCT04493853) trials in patients with prostate cancer. The agent is also currently indicated for use in combination with fulvestrant (Faslodex) for the treatment of patients with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer with 1 or more PIK3CA/AKT1/PTEN alterations, as detected by an FDA-approved test, following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.⁴

References

1. Update on the CAPItello-290 phase III trial for truqap plus chemotherapy in advanced or metastatic triple-negative breast cancer. News release. AstraZeneca. June 18, 2024. Accessed June 18, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/update-on-capitello-290-phase-iii-trial.html
2. Schmid P, Abraham J, Chan S, et al. AZD5363 plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (PAKT): a randomised, double-blind, placebo-controlled, phase II trial. J Clin Oncol. 2018;36(suppl 15):1007. doi:10.1200/JCO.2018.36.15_suppl.1007
3. Capivasertib+paclitaxel as first line treatment for patients with locally advanced or metastatic TNBC (CAPItello-290). ClinicalTrials.gov. Updated January 17, 2024. Accessed June 18, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT03997123
4. FDA approves capivasertib with fulvestrant for breast cancer. FDA. November 16, 2023. Accessed June 18, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer