Addition of palbociclib to fulvestrant extends OS among certain women with advanced breast cancer

MUNICH — The addition of palbociclib to fulvestrant appeared associated with a clinically meaningful improvement in OS among women with hormone receptor-positive, HER2-negative breast cancer whose disease relapsed or progressed on hormonal therapy, according to study results presented at European Society for Medical Oncology Congress.

Women with sensitivity to prior endocrine therapy and those with nonvisceral disease derived the greatest benefit.

“These findings confirm the use of palbociclib plus fulvestrant as a standard of care [for] patients with previously treated hormone receptor-positive, HER2-negative advanced breast cancer,” Massimo Cristofanilli, MD, professor of medicine at Robert H. Lurie Comprehensive Cancer Center at Northwestern University, said during a press conference.

The majority of patients with hormone receptor-positive breast cancer develop resistance to hormonal therapies. Inhibition of cyclin dependent kinase (CDK) 4/6 has emerged as a target to overcome or delay hormonal therapy resistance among patients with advanced hormone receptor-positive, HER2-negative breast cancer.

The prospective, randomized phase 3 PALOMA-3 study assessed the addition of the CDK 4/6 inhibitor palbociclib (Ibrance, Pfizer) to fulvestrant for women with hormone receptor-positive, HER2-negative advanced breast cancer who relapsed or progressed on prior endocrine therapy.

The analysis included 521 patients who had undergone a median three prior therapies; some patients had received as many as 10 prior therapies.

Researchers randomly assigned patients 2:1 to fulvestrant plus palbociclib (125 mg daily in a 3-weeks-on/1-week-off schedule) or fulvestrant plus placebo.

Investigator-assessed PFS served as the primary endpoint. OS served as a key secondary endpoint.

Previously published results showed the palbociclib-fulvestrant combination significantly improved median PFS (11.2 months vs. 4.6 months; HR = 0.5; 95% CI, 0.4-0.62).

At ESMO, Cristofanilli presented the final OS analysis based on median follow-up of 44.8 months.

Results showed the palbociclib regimen extended median OS by an absolutely difference of 6.9 months (34.9 months vs. 28 months; stratified HR = 0.81; 95% CI, 0.64-1.02; unstratified HR = 0.79; 95% CI, 0.62-0.99).

Researchers observed even greater OS benefits among women with endocrine-sensitive disease (median, 39.7 months vs. 29.7 months; HR = 0.72; 95% CI, 0.55-0.94) and those with nonvisceral disease (median, 46.9 months vs. 35.4 months; HR = 0.69; 95% CI, 0.46-1.04).

“This is the first report demonstrating that the absolute gain in survival is similar to the absolute gain in progression-free survival in the whole population,” Cristofanilli said in a press release. “Moreover, this prolongation of life is of a large magnitude in patients with prior sensitivity to endocrine therapy.

“This is very important for patients, as it shows that the improvement in PFS observed in previous studies may have a positive impact on overall survival, an ultimate goal of treatment, therefore improving the chance for a long-term life in spite of advanced disease,” he added. “The demonstration of a positive impact on OS also provides additional confidence to clinicians and patients as to the benefits of this combination as an appropriate and effective treatment approach.”

No new safety signals emerged during longer follow-up, Cristofanilli said.

Median time on subsequent therapy was comparable between treatment groups. Patients assigned the palbociclib regimen had longer time to the end of next-line treatment (18.8 months vs. 14.1 months; HR = 0.68; 95% CI, 0.56-0.84), as well as longer median time to chemotherapy (17.5 months vs. 8.8 months; HR = 0.58; P < .000001).

The study did not allow crossover. However, approximately 15% patients received a CDK 4/6 inhibitor in later treatment lines per physician’s choice. This may have reduced the magnitude of the OS benefit observed, Cristofanilli said.

Two large randomized trials — PENELOPE-B and PALLAS — are underway to assess palbociclib as adjuvant treatment for early-stage breast cancer.

“The significant impact of CDK 4/6 inhibitors on disease-free and overall survival in metastatic disease lead us to be excited about the potential of this class of agents in early-stage breast cancer, where our goal is to improve the cure rate,” Cristofanilli said. – Mark Leiser

Reference:

Cristofanilli M, et al. Abstract LBA2_PR. Presented at: European Society for Medical Oncology Congress; Oct. 19-23, 2018; Munich.

Disclosures: Pfizer provided funding for this study. Cristofanilli reports personal fees from Merus, Novartis and Pfizer. Please see the abstract for all other authors’ relevant financial disclosures.