Two studies presented at the 2023 ASCO Annual Meeting challenge the use of CDK4/6 inhibitors as part of upfront treatment of advanced hormone receptor–positive, HER2-negative breast cancer. The first, the SONIA trial, found that first-line treatment with CDK4/6 inhibitors led to greater toxicity and higher cost, with no improvement in outcomes over endocrine therapy alone.¹ The second, the PALMIRA trial, showed that maintenance palbociclib therapy did not improve outcomes after disease progression on first-line treatment with palbociclib in advanced hormone receptor–positive, HER2-negative breast cancer.²

“SONIA challenges the need for first-line use of CDK4/6 inhibitors. Endocrine therapy remains an excellent choice, especially in the first line [for hormone receptor–positive, HER2-negative advanced breast cancer].”

— Gabe S. Sonke, MD, PhD

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“In first line compared with second line, CDK4/6 inhibitors do not improve progression-free survival, overall survival, or quality of life. First-line use of CDK4/6 inhibitors extends the time on treatment by 16.5 months. It increases the drug expenditure by $200,000 per patient, and there were 42% more grade 3 or higher adverse events when they are used in the first line,” stated Gabe S. Sonke, MD, PhD, of the Netherlands Cancer Institute. “SONIA challenges the need for first-line use of CDK4/6 inhibitors. Endocrine therapy remains an excellent choice, especially in the first line. However, most guidelines advise first-line use of a CDK4/6 inhibitor [in this setting] despite a lack of comparative efficacy data,” Dr. Sonke told listeners.

SONIA Trial Details and Results

The phase III SONIA trial included 1,050 premenopausal and postmenopausal women with no prior treatment of advanced hormone receptor–positive, HER2-negative breast cancer. Patients were randomly assigned 1:1 to receive a nonsteroidal aromatase inhibitor plus a CDK4/6 inhibitor followed by fulvestrant at disease progression or first-line treatment with a nonsteroidal aromatase inhibitor followed by fulvestrant plus a CDK4/6 inhibitor at disease progression. The CDK4/6 inhibitor used was according to physician’s choice.

About 87% of participants were postmenopausal, 35% were newly diagnosed, about 40% had prior chemotherapy, and about 48% had prior endocrine therapy (all in the neoadjuvant or adjuvant setting). A total of 17% had bone-only metastasis, and 56% had visceral disease.

Patients were evenly split between first- and second-line treatments: 524 and 526, respectively. At a median follow-up of 37.3 months, the median time to second objective disease progression was 31 months for patients given first-line treatment with a CKD4/6 inhibitor and 26.8 months for those who received a CDK4/6 inhibitor after first disease progression—with no statistically significant difference between the two treatment arms (hazard ratio [HR] = 0.87; 95% confidence interval [CI] = 0.74–1.03; P = .10).

Median overall survival for first-and second-line treatments were 45.9 months and 53.5 months, respectively (HR = 0.98; P = .83). There was no difference in quality of life according to Functional Assessment of Cancer Therapy–Breast scores.

The median duration of CDK4/6 inhibitor treatment was longer when used in the first line, at 24.7 months, vs 8.3 months in those treated with this agent at disease progression.

Clinical Considerations

“If you were a patient, would you consider a treatment that offers no improvement in quality of life and does not improve overall survival? As a doctor or nurse, do you recommend to your patient such a treatment that nearly doubles the incidence of side effects? If you were responsible for covering the cost of this treatment, whether as an individual or health-care insurer, would you consider it worth $200,000?” Dr. Sonke asked the audience.

During the question-and-answer session, several audience members agreed with Dr. Sonke’s conclusions that not every patient needs a CDK4/6 inhibitor upfront. Dr. Sonke said the results of SONIA shift the question to which patients do need this treatment, as opposed to which patients can do without it.

“The baseline is that all of us should consider endocrine therapy alone as first-line treatment,” he concluded.

PALMIRA Trial Details and Results

PALMIRA, a smaller phase II trial, showed that maintenance therapy with a CDK4/6 inhibitor (in this case, palbociclib) plus second-line endocrine therapy did not lead to significant improvement in progression-free survival compared with second-line endocrine therapy alone in 198 patients with advanced hormone receptor–positive, HER2-negative breast cancer. The results were similar in all prespecified subgroups.

All patients enrolled in the trial had experienced disease progression on first-line treatment with palbociclib plus endocrine therapy as adjuvant therapy. They were randomly assigned 2:1 to receive palbociclib plus second-line endocrine therapy (fulvestrant or letrozole) or the same endocrine therapy alone.

The study enrolled both premenopausal (about 10%) and postmenopausal women (about 90%). Median follow-up was 13.2 months.

Investigator-assessed progression-free survival did not significantly differ between the two groups: median of 4.9 months for the experimental arm vs 3.6 months with endocrine therapy alone. The difference in progression-free survival was not significant in favor of a CDK4/6 inhibitor for either visceral involvement or no visceral involvement or for the duration of prior palbociclib. Overall survival was almost identical: median of 28.3 months vs 28.8 months, respectively.

Antonio Llombart-Cussac, MD, PhD

There were more grade 3 or 4 adverse events in patients treated with palbociclib plus endocrine therapy compared with endocrine therapy alone at 45.2% and 8.3%, respectively. No new safety signs emerged, and no treatment-related deaths were reported.

Lead author Antonio Llombart-Cussac, MD, PhD, of the University Hospital Arnau de Villanova, Valencia, Spain, said there was a suggestion that a subset of patients may benefit from palbociclib maintenance and “a vast biomarker study is underway to identify such patients.” 

DISCLOSURE: Dr. Sonke has served as an advisor to Biovica, Novartis, and Seagen; and has received research funding from Agendia, AstraZeneca/Merck, Merck Sharp & Dohme, Novartis, Roche, and Seagen. Dr. Llombart-Cussac has stock and other ownership interests in Initia-Research and MedSIR; has served as a consultant or advisor to Eli Lilly, Novartis, Pfizer, and Roche; has served on the speakers bureau of AstraZeneca, Eli Lilly, and Merck Sharp & Dohme; has received research funding from Agendia, Daiichi Sankyo, Gilead Sciences, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, and Roche; and has received reimbursement for travel and accommodations expenses from AstraZeneca, Pfizer, and Roche.

REFERENCES

1. 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, HER2-negative advanced breast cancer. 2023 ASCO Annual Meeting. Abstract LBA1000. Presented June 5, 2023.

2. Llombart-Cussac A, Harper-Wynne C, Perello A, et al: Second-line endocrine therapy with or without palbociclib maintenance in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: PALMIRA trial. 2023 ASCO Annual Meeting. Abstract 1001. Presented June 2, 2023.