Capivasertib Plus Fulvestrant Provides Consistent PFS Benefit in HR+ Advanced Breast Cancer, Across Key Subgroups

Capivasertib plus fulvestrant (Faslodex) provided a clinically meaningful improvement in progression-free survival (PFS) over fulvestrant alone in patients with hormone receptor–positive advanced breast cancer, including those who previously received a CDK4/6 inhibitor, chemotherapy in the advanced setting, or had baseline liver metastases.¹

Data from an exploratory analysis of PFS in key subgroups from the phase 3 CAPItello-291 trial (NCT04305496), which had a data cutoff date of August 15, 2022, were presented at the 2023 ESMO Breast Cancer Annual Congress.

In the overall population, those who had prior CDK4/6 exposure and received the doublet (n = 248) experienced a median PFS of 5.5 months (95% CI, 3.9-6.8) vs 2.6 months (95% CI, 2.0-3.5) with the monotherapy (n = 248; adjusted HR, 0.59; 95% CI, 0.48-0.72). In patients who did not have prior exposure and received capivasertib and fulvestrant (n = 107) or fulvestrant alone (n = 105), the median PFS was 10.9 months (95% CI, 7.4-13.0) and 7.2 months (95%, 4.8-7.9), respectively (adjusted HR, 0.64; 95% CI, 0.45-0.90).

Moreover, those who previously received chemotherapy for advanced disease and then went on to receive the combination (n = 65) experienced a longer median PFS than those who received fulvestrant alone (n = 64), at 3.8 months (95% CI, 3.0-7.3) and 2.1 months (95% CI, 1.9-3.6), respectively (adjusted HR, 0.55; 95% CI, 0.36-0.82). In those who did not receive prior chemotherapy, capivasertib plus fulvestrant (n = 290) still resulted prolonged PFS vs fulvestrant alone (n = 289), at a median of 7.3 months (95% CI, 5.6-8.2) and 3.7 months (95% CI, 3.4-5.1), respectively (adjusted HR, 0.62; 95% CI, 0.51-0.75).

Lastly, capivasertib plus fulvestrant also provided a clinically meaningful PFS benefit over fulvestrant alone in patients who did and did not have liver metastases at baseline. In those with baseline metastases who received the doublet (n = 156), the median PFS was 3.8 months (95% CI, 3.5-5.5) vs 1.9 months (95% CI, 1.8-1.9) in those given the monotherapy (n = 150; adjusted HR, 0.61; 95% CI, 0.48-0.78). In those without metastases who received the combination (n = 199) or the monotherapy (n = 203), the median PFS was 9.2 months (95% CI, 7.4-11.1) and 5.5 months (95% CI, 3.9-5.8), respectively (adjusted HR, 0.60; 95% CI, 0.48-0.76).

“Capivasertib plus fulvestrant has the potential to be a future treatment option for patients with hormone receptor–positive advanced breast cancer who have progressed on or after an endocrine-based regimen, with or without a CDK4/6 inhibitor,” said study author Nicholas Turner, MD, MRCP, FRCP, PhD, of the Institute of Cancer Research, The Royal Marsden Hospital in Chelsea, London, United Kingdom, in a presentation of the data.

The randomized, double-blind, placebo-controlled trial enrolled men and pre/postmenopausal women with hormone receptor–positive/HER2-negative advanced breast cancer who recurred or progressed on or within 12 months from the end of adjuvant treatment with aromatase inhibitors (AIs) or progressed while on previous AI for advanced disease. Patients must have received up to 2 lines of previous endocrine therapy and up 1 line of chemotherapy for advanced disease. They were allowed to have prior CDK4/6 inhibitors, but they could not have previously received SERDs, mTOR inhibitors, PI3K inhibitors, or AKT inhibitors.

A total of 708 study participants were randomly assigned 1:1 to receive capivasertib at a twice-daily dose of 400 mg on a 4-days-on/3-days-off schedule plus fulvestrant at 500 mg on days 1 and 15 of cycle and then every 4 weeks thereafter vs placebo plus fulvestrant at the same dose and schedule.

Patients were stratified by liver metastases (yes vs no), previous CDK4/6 exposure (yes vs no), and region (Region 1: United States, Canada, Western Europe, Australia, and Israel vs Region 2: Latin America, Eastern Europe, and Russia vs Region 3: Asia).

Investigator-assessed PFS in the overall population and in those with AKT pathway–altered tumors served as the trial’s co-primary end points.

Data presented at the 2022 San Antonio Breast Cancer Symposium showed that in the overall population, the median PFS for those who received the doublet (n = 355) was 7.2 months (95% CI, 5.5-7.4) vs 3.6 months (95% CI, 2.8-3.7) for those who received the monotherapy (n = 293; adjusted HR, 0.60; 95% CI, 0.51-0.71).2 In the AKT pathway–altered population, those in the combination arm (n = 155) had a median PFS of 7.3 months (95% CI, 5.5-9.0) vs 3.1 months (95% CI, 2.0-3.7) in the monotherapy arm (adjusted HR, 0.50; 95% CI, 0.38-0.65).

Overall survival data remain immature but there is a positive trend in favor of capivasertib plus fulvestrant vs fulvestrant alone in the overall population (HR, 0.74; 95% CI, 0.56-0.98) and in the AKT pathway–altered population (HR, 0.69; 95% CI, 0.45-1.05).

Baseline characteristics were reported to be generally well balanced between the treatment arms in the overall population and the AKT pathway–altered population. The median age ranged from 58 years to 60 years, and most patients were female and postmenopausal. Approximately half of patients were White and from region 1. More than half of patients had secondary endocrine resistance.

Previous treatments were also noted to be well balanced between the arms in both populations. Most patients received 1 prior endocrine therapy for advanced disease, 1 prior CDK4/6 inhibitor, and prior adjuvant or neoadjuvant chemotherapy.

Additional data presented during the 2023 ESMO Breast Cancer Annual Congress indicated that capivasertib plus fulvestrant demonstrated consistent clinically meaningful benefit across relevant subgroups in the AKT pathway–altered population, as well.

Within this population, those who previously received a CDK4/6 inhibitor and were in the investigative and control arms experienced a median PFS of 5.5 months and 2.0 months, respectively; for those who did not receive a prior CDK4/6 inhibitor, the median PFS was 11.0 months and 7.4 months, respectively.

Among those who previously received chemotherapy for advanced disease and later received the doublet or the monotherapy, the median PFS was 4.0 months and 2.0 months, respectively; for those who did not receive prior chemotherapy, the median PFS was 7.4 months and 3.5 months, respectively.

In those who had liver metastases at baseline and received capivasertib, the median PFS was 5.5 months vs 1.8 months in those who received fulvestrant monotherapy; in those who did not have these metastases, the median PFS was 9.1 months and 3.7 months, respectively.

Turner also pointed out that in the overall population, the fulvestrant control arm performance was substantially different between patients who did and did not previously receive a CDK4/6 inhibitor, at 2.6 months (95% CI, 2.0-3.5; adjusted HR, 0.59; 95% CI, 0.48-0.72) and 7.2 months (95% CI, 4.8-7.9; adjusted HR, 0.64; 95% CI, 0.45-0.90), respectively.

Moreover, results from a post-hoc exploratory analysis showed that the PFS benefit provided by the addition of capivasertib to fulvestrant over fulvestrant alone was observed in the overall population irrespective of the duration of prior CDK4/6 inhibitor received in the advanced setting.

Specifically, for those in the doublet arm who received a prior CDK4/6 inhibitor for less than 12 months (n = 93), the median PFS was 4.9 months (95% CI, 3.5-7.7) vs 2.0 months (95% CI, 1.9-3.4) for those in the monotherapy arm (n = 98). Those who received capivasertib plus fulvestrant and a prior CDK4/6 inhibitor for 12 months or longer (n = 152) experienced a median PFS of 5.5 months (95% CI, 3.9-7.2) vs 2.8 months (95% CI, 2.0-3.6) in those who received fulvestrant alone (n = 146).

“Efficacy of fulvestrant single agent (plus placebo) was low, highlighting the unmet need post CDK4/6 inhibitor,” Turner concluded.

Editor’s Note: Dr Turner disclosed that the following relationships exist related to the presentation: a consulting or advisory role for Arvinas, AstraZeneca, Bristol Meyers Squibb, GlaxoSmithKline, Inivata, Ely Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Repare Therapeutics, Roche/Genentech, and Zentalis Pharmaceuticals; and contracted research for AstraZeneca, BioRad, Guardant Health, Inivata, Invitae, Merck Sharp & Dohme, Natera, Personalis, Pfizer, and Roche/Genentech.

References

1. Oliveira M, Rugo HS, Howell SJ, et al. Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant HR+/HER2– advanced breast cancer: subgroup analyses from the phase 3 CAPItello-291 trial. Presented at: 2023 ESMO Breast Cancer Annual Congress; May 11-13, 2023; Berlin, Germany. Abstract 187O.
2. Turner N, Oliveria M, Howell SJ, et al. Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the Phase III CAPItello-291 trial. Presented at the 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS3-04.