Capivasertib + fulvestrant boosts PFS in AI-resistant HR+/HER2– advanced breast cancer

The AKT inhibitor capivasertib, when added to fulvestrant, doubled progression-free survival (PFS) in patients with aromatase inhibitor (AI)-resistant hormone receptor-positive (HR+)/HER2*-negative (HER2–) advanced breast cancer (ABC), results of the phase III CAPItello-291 trial showed.

“Capivasertib + fulvestrant provides a statistically significant and clinically meaningful improvement in PFS in the overall and the AKT pathway-altered population,” remarked Professor Nicholas Turner from The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, UK, at SABCS 2022.

“[The combination] has the potential to be a future treatment option for patients with HR+ ABC who have progressed on an endocrine-based regimen,” he added.

The population comprised 708 men and pre-/postmenopausal women with AI-resistant, HR+/HER2– ABC who had experienced disease progression or recurrence while on or <12 months after completion of AI treatment and were exposed to ≤2 prior lines of endocrine therapy and ≤1 prior line of chemotherapy. The patients were randomized 1:1 to receive capivasertib (400 mg BID on a 4-days-on, 3-days-off schedule) + fulvestrant (500 mg on days 1 and 15 during cycle 1, followed by Q4W) or fulvestrant + placebo.

Prior exposure to CDK**4/6 inhibitors was allowed (69 percent had been exposed) but those with exposure to SERD, mTOR inhibitors, PI3K inhibitors, or AKT inhibitors were excluded. Forty-one percent of patients had AKT pathway-altered tumours.

In the overall population, investigator-assessed PFS was significantly improved in the capivasertib-fulvestrant compared with the fulvestrant-placebo arm (median 7.2 vs 3.6 months; adjusted hazard ratio [adjHR], 0.60, 95 percent confidence interval [CI], 0.51–0.71; p<0.001). [SABCS 2022, abstract GS3-04]

The PFS results were consistent in the AKT pathway-altered population*** (median 7.3 vs 3.1 months; adjHR, 0.50, 95 percent CI, 0.38–0.65; p<0.001), as well as in the non-altered population (median 7.2 vs 3.7 months; HR, 0.70, 95 percent CI, 0.56–0.88), and in those with or without liver metastases (HRs, 0.61 and 0.62, respectively), and with or without prior exposure to CDK4/6 inhibitors (HRs, 0.62 and 0.65, respectively).

Among patients with measurable disease, objective response rate was higher in the capivasertib-fulvestrant vs fulvestrant-placebo arm, both in the overall population (22.9 percent vs 12.2 percent) and AKT pathway-altered population (28.8 percent vs 9.7 percent).

There was a trend toward an improvement in overall survival with the capivasertib-fulvestrant combination vs fulvestrant-placebo, both in the overall population (HR, 0.74, 95 percent CI, 0.56–0.98) and AKT pathway-altered population (HR, 0.69, 95 percent CI, 0.45–1.05), but the results were immature and follow-up continues.

The most common grade ≥3 adverse events (AEs) among capivasertib-fulvestrant recipients were diarrhoea (9.3 percent) and maculopapular rash (6.2 percent). AEs led to discontinuation of capivasertib and placebo in 13.0 and 2.3 percent of patients, respectively.

“Capivasertib + fulvestrant safety profile appears consistent with that previously reported, with a relatively low discontinuation rate due to AEs,” said Turner.

Professor Nicholas Turner (Photo by © MedMeetingImages/Scott Morgan 2022)

A dire need for new therapies

“AKT pathway activation has been implicated in the development of endocrine therapy resistance in HR+/HER2– ABC,” said Turner and co-authors.

“After progression on CDK4/6 inhibitors, further endocrine therapies given alone have relatively low efficacy. We need new treatment options for these patients,” said Turner.

“The improvement in PFS with relatively well-tolerated side effects is extremely encouraging. We are hopeful that capivasertib will become a new treatment option for patients whose cancer has progressed on a regimen containing an endocrine therapy,” he concluded.