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Clinical Trial
. 2022 Aug 15;28(16):3433-3442.
doi: 10.1158/1078-0432.CCR-22-0305.

Overall Survival with Palbociclib and Fulvestrant in Women with HR+/HER2- ABC: Updated Exploratory Analyses of PALOMA-3, a Double-blind, Phase III Randomized Study

Massimo Cristofanilli  1 , Hope S Rugo  2 , Seock-Ah Im  3 , Dennis J Slamon  4 , Nadia Harbeck  5 , Igor Bondarenko  6 , Norikazu Masuda  7 , Marco Colleoni  8 , Angela DeMichele  9 , Sherene Loi  10 , Hiroji Iwata  11 , Ben O'Leary  12 , Fabrice André  13 , Sibylle Loibl  14 , Eustratios Bananis  15 , Yuan Liu  16 , Xin Huang  16 , Sindy Kim  16 , Maria Jose Lechuga Frean  16 , Nicholas C Turner  12
Affiliations
Clinical Trial

Overall Survival with Palbociclib and Fulvestrant in Women with HR+/HER2- ABC: Updated Exploratory Analyses of PALOMA-3, a Double-blind, Phase III Randomized Study

Massimo Cristofanilli et al. Clin Cancer Res. .

Abstract

Purpose: To conduct an updated exploratory analysis of overall survival (OS) with a longer median follow-up of 73.3 months and evaluate the prognostic value of molecular analysis by circulating tumor DNA (ctDNA).

Patients and methods: Patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) were randomized 2:1 to receive palbociclib (125 mg orally/day; 3/1 week schedule) and fulvestrant (500 mg intramuscularly) or placebo and fulvestrant. This OS analysis was performed when 75% of enrolled patients died (393 events in 521 randomized patients). ctDNA analysis was performed among patients who provided consent.

Results: At the data cutoff (August 17, 2020), 258 and 135 deaths occurred in the palbociclib and placebo groups, respectively. The median OS [95% confidence interval (CI)] was 34.8 months (28.8-39.9) in the palbociclib group and 28.0 months (23.5-33.8) in the placebo group (stratified hazard ratio, 0.81; 95% CI, 0.65-0.99). The 6-year OS rate (95% CI) was 19.1% (14.9-23.7) and 12.9% (8.0-19.1) in the palbociclib and placebo groups, respectively. Favorable OS with palbociclib plus fulvestrant compared with placebo plus fulvestrant was observed in most subgroups, particularly in patients with endocrine-sensitive disease, no prior chemotherapy for ABC and low circulating tumor fraction and regardless of ESR1, PIK3CA, or TP53 mutation status. No new safety signals were identified.

Conclusions: The clinically meaningful improvement in OS associated with palbociclib plus fulvestrant was maintained with >6 years of follow-up in patients with HR+/HER2- ABC, supporting palbociclib plus fulvestrant as a standard of care in these patients.

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Figures

Figure 1. Kaplan–Meier curves of OS in all patients in the intent-to-treat population. FUL = fulvestrant; HR = hazard ratio; OS = overall survival; PAL = palbociclib; PBO = placebo.
Figure 1.
Kaplan–Meier curves of OS in all patients in the intent-to-treat population. FUL, fulvestrant; HR, hazard ratio; OS, overall survival; PAL, palbociclib; PBO, placebo.
Figure 2. OS by subgroup. P value determined from a one-sided unstratified log-rank test; one-sided P value from log-rank test reflects the sign of the test statistic (z-Score). ABC = advanced breast cancer; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FUL = fulvestrant; ITT = intent-to-treat; PAL = palbociclib; PBO = placebo.
Figure 2.
OS by subgroup. P value determined from a one-sided unstratified log-rank test; one-sided P value from log-rank test reflects the sign of the test statistic (z-Score). ABC, advanced breast cancer; ECOG, Eastern Cooperative Oncology Group; EOT, end of treatment; FUL, fulvestrant; ITT, intent-to-treat; PAL, palbociclib; PBO, placebo.
Figure 3. Outcomes by ESR1 mutation status in ctDNA at day 1 or end of treatment. PFS by treatment (A), OS regardless of treatment (B), and OS by treatment (C). ctDNA = circulating tumor DNA; ESR1 = estrogen receptor 1; FUL = fulvestrant; HR = hazard ratio; mut = mutation; OS = overall survival; PAL = palbociclib; PBO = placebo; PFS = progression-free survival; WT = wild type.
Figure 3.
Outcomes by ESR1 mutation status in ctDNA at day 1 or end of treatment. PFS by treatment (A), OS regardless of treatment (B), and OS by treatment (C). ctDNA, circulating tumor DNA; ESR1, estrogen receptor 1; FUL, fulvestrant; HR, hazard ratio; mut, mutation; OS, overall survival; PAL, palbociclib; PBO, placebo; PFS, progression-free survival; WT, wild type.
Figure 4. Outcomes by PIK3CA mutation status in ctDNA at day 1 or end of treatment. PFS by treatment (A), OS regardless of treatment (B), and OS by treatment (C). ctDNA = circulating tumor DNA; FUL = fulvestrant; HR = hazard ratio; mut = mutation; OS = overall survival; PAL = palbociclib; PBO = placebo; PFS = progression-free survival; PIK3CA = phosphatidylinositol 3-kinase catalytic alpha polypeptide; WT = wild type.
Figure 4.
Outcomes by PIK3CA mutation status in ctDNA at day 1 or end of treatment. PFS by treatment (A), OS regardless of treatment (B), and OS by treatment (C). ctDNA, circulating tumor DNA; FUL, fulvestrant; HR, hazard ratio; mut, mutation; OS, overall survival; PAL, palbociclib; PBO, placebo; PFS, progression-free survival; PIK3CA, phosphatidylinositol 3-kinase catalytic alpha polypeptide; WT, wild type.
Figure 5. Outcomes by TP53 mutation status in ctDNA at day 1 or end of treatment. PFS by treatment (A), OS regardless of treatment (B), and OS by treatment (C). ctDNA = circulating tumor DNA; FUL = fulvestrant; HR = hazard ratio; mut = mutation; OS = overall survival; PAL = palbociclib; PBO = placebo; PFS = progression-free survival; TP53 = tumor protein 53; WT = wild type.
Figure 5.
Outcomes by TP53 mutation status in ctDNA at day 1 or end of treatment. PFS by treatment (A), OS regardless of treatment (B), and OS by treatment (C). ctDNA, circulating tumor DNA; FUL, fulvestrant; HR, hazard ratio; mut, mutation; OS, overall survival; PAL, palbociclib; PBO, placebo; PFS, progression-free survival; TP53, tumor protein 53; WT, wild type.
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References

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