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ASCO 2021: Addition of Palbociclib to Fulvestrant Attains Overall Survival Benefit in Advanced Breast Cancer With Update of PALOMA-3
Greatest benefits were observed in those with endocrine sensitive disease and those who had not received prior chemotherapy

June 5, 2021—An overall survival (OS) benefit was attained with the addition of palbociclib to fulvestrant after 6 years of follow-up in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer, according to an updated analysis of PALOMA-3, presented at the annual meeting of the American Society of Clinical Oncology, which took place online from June 4 to 8.
“Palbociclib is the first-in-class, orally active cyclin-dependent kinase (CDK) 4/6-selective inhibitor that is approved for the treatment of patients with HR-positive advanced breast cancer,” said lead author Massimo Cristofanilli, MD, of Northwestern University Feinberg School of Medicine in Chicago, during his presentation of the data. Previously reported results of PALOMA-3 revealed improved progression-free survival (PFS) and a nonsignificant trend toward improved OS after a median follow-up of 44.8 months with the addition of palbociclib to fulvestrant in this patient population. The protocol-specified median OS was 34.9 months versus 28.0 months (hazard ratio 0.81, 95% confidence interval 0.64–1.03, P = .0429).
Dr. Cristofanilli presented the final OS analysis with 393 events among the 75% of the total study population who had a median follow-up of 73.3 months. The data cut-off period was August 17, 2020.
For the double-blind, international, phase III PALOMA-3 trial, 521 women with HR-positive, HER2-negative advanced breast cancer were randomized 2:1 to either 125 mg oral palbociclib once daily for 3 weeks on and 1 week off (n = 347) or placebo (n = 174). Both arms also received 500 mg fulvestrant injected intramuscularly on days 1, 15, and 29, followed by 1 monthly doses. All women were pre-/peri- or postmenopausal, had progressed on or after endocrine therapy in the adjuvant or metastatic setting, and had received up to one prior chemotherapy regimen for advanced cancer. Patients were stratified based on documented sensitivity to prior hormonal therapy, menopausal status at study entry, and presence of visceral metastases.
After a median follow-up of 73.3 months, median OS was maintained at 34.8 months for the palbociclib arm, compared with 28.0 months in the placebo arm (stratified hazard ratio 0.81, 95% confidence interval 0.65–0.99, P = .0221). The 5-year OS rate was 23.3% with palbociclib (95% confidence interval 18.7–28.2) and 16.8% with placebo (95% confidence interval 11.2–23.3). Benefits in OS were observed for multiple subgroups, including the stratified and unstratified intent-to-treat population, those who were sensitive to previous hormonal therapy, who did not receive prior chemotherapy, had nonvisceral sites of metastatic disease, were postmenopausal at study entry, and whose disease-free interval was more than 24 months. Notably, OS benefit was not observed in patients who received prior chemotherapy for advanced breast cancer or in those who were not sensitive to prior hormone therapy.
Circulating tumor DNA data were available for 331 patients at day 1 of treatment and 195 patients at the end of treatment. Mutations in ESR1 were detected in 29.3% of the patients. Patients without ESR1 mutations had a longer OS than those with mutations (30.7 months vs 25.4 months, hazard ratio 1.58, 95% confidence interval 1.22–2.06), but palbociclib provided OS benefit regardless of ESR1 mutation status, with a 41% reduction in risk of death with mutations and 19% reduction without. The most prevalent ESR1 mutation variants were D538G, Y537S, E380Q, and Y537N.
PIK3CA mutations were identified in 21.5% of patients and were again associated with a shorter median OS (30.0 months without mutations versus 24.0 months with, hazard ratio 1.44, 95% confidence interval 1.08–1.92). Again, palbociclib provided OS benefit regardless of PIK3CA mutation status, with a 22% reduction in risk of death in patients without mutations and 27% in those with mutations.
A similar trend was observed for the 17.2% of patients with TP53 mutations. Median OS was 31.8 months without mutations and 19.9 months with (hazard ratio 2.19, 95% confidence interval 1.61–2.99). Once again, palbociclib provided an OS benefit in both groups, with a 24% reduced risk of death in unmutated patients and a 17% reduced risk in those with mutations.
The safety profile of palbociclib was consistent with previous reports. The most common any-grade treatment-emergent adverse events were neutropenia (84%), leukopenia (60%), infections (55%), fatigue (44%), nausea (36%), anemia (32%), and stomatitis (31%). Grade 3 neutropenia occurred in 58% and grade 4 in 12%. In the placebo arm, the most common treatment-emergent adverse events were infections (36%), fatigue (32%), and nausea (30%). No grade 4 adverse events were reported in the placebo arm.
“An improvement in OS with palbociclib plus fulvestrant continues to be observed with more than 6 years of median follow-up in patients with HR-positive advanced breast cancer [who] progressed on prior endocrine therapy,” concluded Dr. Cristofanilli. “This prolonged OS benefit is particularly evident in patients with endocrine sensitive disease and those without prior exposure to chemotherapy in the advanced setting, and this is the only study [demonstrating this pattern of outcomes]. … These findings support the continued use of palbociclib plus fulvestrant as standard of care for patients with HR-positive, HER2-negative advanced breast cancer.”
The PALOMA-3 trial was funded by Pfizer Inc.