First-line use of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors plus endocrine therapy does not provide progression-free survival (PFS) benefit vs second-line use in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, according to findings from a primary analysis of the SONIA trial presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

The phase 3 SONIA trial is evaluating the efficacy, safety, and cost-effectiveness of CDK4/6 inhibitors added to endocrine therapy in the first- or second-line treatment of patients with HR-positive, HER2-negative advanced breast cancer.

“The addition of CDK4/6 inhibitors to [endocrine therapy] improves PFS and overall survival (OS) in HR-positive, HER2-negative [advanced breast cancer], as initial treatment and after prior endocrine monotherapy. Most international guidelines advise first-line use, despite prolonged toxicity and a steep increase in costs compared to use in second-line,” explained Dr Sonke and colleagues.

The SONIA trial enrolled 1050 pre- and postmenopausal women who received no prior therapy for the advanced breast cancer, had measurable or evaluable disease and a World Health Organization (WHO) performance status of 0 to 2. 

Patients were randomized in a 1:1 ratio to receive first-line treatment with a non-steroidal aromatase inhibitor (NSAI) plus a CDK4/6 inhibitor, followed on progression by fulvestrant (first-line strategy) or first-line treatment with an NSAI, followed on progression by fulvestrant plus a CDK4/6 inhibitor (second-line strategy). The treating physician chose between the available CDK4/6 inhibitors: abemaciclib, palbociclib, and ribociclib and CDK4/6 inhibitor choice was a stratification factor.

The primary trial end point is time from randomization to second objective disease progression, as assessed by local investigators, or death. Secondary end points include OS, safety, quality of life, and cost-effectiveness.

At the data cut-off date of December 1, 2022, the median follow-up was 37.7 months. The median time to death was 31 months with the first-line strategy vs 27.8 months with the second-line strategy (hazard ratio, 0.89; 95% confidence interval, 0.75 to 1.04; P = .14). Median time on CDK4/6 inhibitors was 24.7 months vs 8.3 months, respectively.

The safety profile was predictable for endocrine therapy plus CDK4/6 inhibitors. The number of grade ≥3 adverse events was 2778 for the first-line strategy vs 1620 for the second-line strategy. 

“First-line use of CDK4/6 [inhibitors plus endocrine therapy] does not provide statistically significant, nor clinically meaningful PFS benefit compared to second-line use in women with HR-positive, HER2-negative [advanced breast cancer]. Use in first-line prolongs the time on CDK4/6i by 16.4 months and increases toxicity and costs,” wrote Dr Sonke and colleagues.

“Second-line use may thus be a preferred option for the majority of patients,” they concluded.

Source:

Sonke GS, Van Ommen-Nijhof A,  Wortelboer N, et al. Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Presented at 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract LBA1000