Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo, irrespective of the degree of endocrine resistance, hormone-receptor expression level, and PIK3CA mutational status.— Massimo Cristofanilli, MD, and colleagues
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As reported in The Lancet Oncology by Massimo Cristofanilli, MD, of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, and colleagues, the final results of the phase III PALOMA-3 trial showed that the addition of the CDK4/CDK6 inhibitor palbociclib (Ibrance) to fulvestrant (Faslodex) improved progression-free survival in women with hormone receptor–positive, HER2-negative breast cancer progressing on endocrine therapy.1 Benefit was observed regardless of the hormone receptor–expression level, degree of endocrine resistance, or PIK3CA mutation status.
Findings in PALOMA-3 supported the recent U.S. Food and Drug Administration (FDA) approval of palbociclib plus fulvestrant for treatment of hormone receptor–positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. The previously reported interim results of the trial showed improved progression-free survival for palbociclib plus fulvestrant irrespective of menopausal status and line of therapy.2
In the double-blind trial, 521 patients from 144 sites in 17 countries were randomized 2:1 between October 2013 and August 2014 to receive oral palbociclib (125 mg daily for 3 weeks followed by a week off in 28-day cycles) plus intramuscular fulvestrant (500 mg on days 1 and 15 of cycle 1 and then on day 1 of subsequent cycles; n = 347) or placebo plus fulvestrant (n = 174). Patients could have any menopausal status and had to have disease relapse or progression after previous endocrine therapy for advanced disease during treatment or within 12 months of completion of adjuvant therapy.
The primary endpoint was investigator-assessed progression-free survival in the intent-to-treat population. Effects of endocrine therapy resistance assessed by clinical parameters, quantitative hormone receptor expression, and tumor PIK3CA mutation status in circulating DNA at baseline were also investigated.
After a median follow-up of 8.9 months (as of March 2015), median progression-free survival was 9.5 months (95% confidence interval [CI] = 9.2–11.0 months) in the palbociclib/fulvestrant group vs 4.6 months (95% CI = 3.5–5.6 months) in the fulvestrant group (hazard ratio [HR] = 0.46, P < .0001), including median progression-free survival of 9.5 vs 5.4 months (HR = 0.55, P = .02) among 114 patients who had received neoadjuvant or adjuvant therapy but no previous systemic therapy for metastatic disease and 9.9 vs 4.2 months (HR = 0.43, P < .0001) among 407 who had received at least one prior systemic treatment for metastatic disease.
Follow-up for overall survival is ongoing.
No association with progression-free survival treatment effect was observed for levels of estrogen receptor expression (subpremium HR P = .32) or levels of progesterone receptor expression (subpremium HR P = .54). Median progression-free survival was 10.2 vs 4.2 months (HR = 0.42, 95% CI = 0.32–0.56) among 410 patients with sensitivity to prior hormonal therapy and 7.4 vs 5.4 months (HR = 0.64, 95% CI = 0.39–1.07) among 111 patients without sensitivity to prior therapy (P = .13 for interaction). Among 395 patients with mutation data available, median progression-free survival was 9.9 vs 4.6 months (HR = 0.45, P < .0001) among 266 with wild-type PIK3CA and 9.5 vs 3.6 months (HR = 0.48, P = .002) among 129 with PIK3CA mutation.
Grade 3 or 4 adverse events occurred in 73% of patients in the palbociclib/fulvestrant group vs 22% of the fulvestrant group. The most common grade 3 or 4 adverse events were neutropenia (65% vs 1%), leukopenia (28% vs 2%), anemia (3% vs 2%), thrombocytopenia (3% vs 0%), and increased aspartate transaminase (3% vs 2%). Serious adverse events occurred in 13% vs 17%.
The investigators concluded: “Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo, irrespective of the degree of endocrine resistance, hormone-receptor expression level, and PIK3CA mutational status. The combination could be considered as a therapeutic option for patients with recurrent hormone-receptor-positive, HER2-negative metastatic breast cancer that has progressed on previous endocrine therapy.” ■
Disclosure: The study was funded by Pfizer. For full disclosures of the study authors, visit www.thelancet.com.
1. Cristofanilli M, Turner NC, Bondarenko I, et al: Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): Final analysis. Lancet Oncol. March 2, 2016 (early release online).
A biomarker that could identify patients with estrogen receptor–positive breast cancer who do just as well with endocrine therapy alone and may not benefit from the addition of a second agent would be useful, sparing women both the expense and additional side effects of the combination. ...!-->!-->