Fulvestrant/Palbociclib Doubles PFS in ESR1+ Advanced Breast Cancer

Fulvestrant plus palbociclib improved outcomes following an aromatase inhibitor plus palbociclib for patients with estrogen receptor–positive, HER2-negative advanced breast cancer with rising ESR1 mutation, according to updated findings from the phase 3 PADA-1 trial.

Fulvestrant (Faslodex) plus palbociclib (Ibrance) improved outcomes following an aromatase inhibitor (AI) plus palbociclib for patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer with rising ESR1 mutation, according to updated findings from the phase 3 PADA-1 trial (NCT03079011).1

In the randomized, open-label trial that was conducted at 83 hospitals in France, results showed that the median progression-free survival (PFS) for patients who switched to fulvestrant/palbociclib was 11.9 months (95% CI, 9.1-13.6) vs 5.7 months (95% CI, 3.9-7.5) for patients who continued with AI/palbociclib in the second-line setting (HR, 0.61; 95% CI, 0.43-0.86; P = .004). The median chemotherapy-free survival was 14.6 months (95% CI, 11.8-17.0) in the experimental arm compared with 13.1 months (95% CI, 10.8-17.6) for the control arm (HR, 0.91; 95% CI, 0.62-1.33; P = .60).

At the July 31, 2021 database lock, the median follow-up was 35.3 months (interquartile range [IQR], 29.2-41.4) from inclusion and 26.0 months (IQR, 13.8-34.3) from random assignment.

Investigators recruited 1017 adult women with ER-positive, HER2-negative advanced breast cancer and an ECOG performance status of 0 to 2 and monitored them for rising ESR1 mutation. In the first step, patients received first-line treatment with once-daily, continuous letrozole at 2.5 mg, 1 mg of anastrozole, or 25 mg of exemestane and 125 mg oral palbociclib on days 1 to 21 of a 28-day cycle. Those with newly present or increased ESR1 mutation in circulating tumor DNA and no synchronous disease progression were randomly assigned to continue with the same therapy (n = 84) or to switch to 500 mg intramuscular fulvestrant on day 1 of each 28-day cycle and day 15 of cycle 1 plus palbociclib on the same dosing schedule (n = 88).

In previous findings presented at the 2021 San Antonio Breast Cancer Symposium, the median PFS was 11.9 months (95% CI, 9.1-13.6) in patients who switched to fulvestrant vs 5.7 months (95% CI, 3.9-7.5) in patients who remained on an AI (HR, 0.63; 95% CI, 0.45-0.88; P = .007). The median follow-up was 26 months (IQR, 0-36).2

In the updated results, the median PFS among all 1017 patients in study was 26.8 months (95% CI, 24.8-28.6).

ESR1 mutations restore an estradiol-independent activity of Erα.1 Although these mutations retain sensitivity to selective estrogen receptor degraders, they are known drivers of resistance to AI-based therapy in patients with hormone receptor–positive, HER2-negative metastatic breast cancer.

The clinical actionability of ESR1 mutations remains unknown; however, they are detectable in the blood by cell-free circulating DNA analysis. These mutations are detected in less than 5% of patients at metastatic relapse but are identified in 30% to 40% of patients at progression following first-line AI-based therapy.

The PADA-1 trial is a randomized, UCBG-GINECO, precision endocrine therapy study evaluating a novel “1.5th-line” treatment for patients with hormone receptor–positive metastatic breast cancer with the goal of delaying tumor progression in patients receiving the first-line combination of an AI and palbociclib.

In step 1 of the trial, patients with hormone receptor–positive, HER2-negative, AI-sensitive metastatic breast cancer received AI-based therapy plus palbociclib in the frontline setting. Patients provided blood samples for ESR1 mutation screening at inclusion, then every month, then every 2 months until progression.

In step 2 of the trial, patients with rising ESR1 mutations and no synchronous progressive disease were randomized to continue with AI/palbociclib or switch to fulvestrant/palbociclib until progression.

The co-primary end points of the study were investigator-assessed PFS per RECIST version 1.1 criteria in step 2 and safety (grade 3 or higher hematologic adverse events [AEs]). Secondary end points included investigator-assessed second PFS after crossover, grade 3 or greater nonhematologic AEs, and serious AEs. Other secondary end points included overall survival, PFS from inclusion in step 1, time to strategy failure, chemotherapy-free survival, and patient-reported outcomes.

Randomization was stratified based on time from inclusion to rising ESR1 mutation detection (less than or at least 12 months) and presence of visceral metastases (yes or no).

The co-primary endpoints were PFS in the second step, defined as the time from random assignment to disease progression according to investigator assessment or death, whichever occurs first in all randomly assigned patients and the rate of grade 3 or higher hematological toxicities in all included patients. Secondary end points include second-line PFS in the crossover cohort, time to strategy failure, chemotherapy-free survival, and PFS measured from the time of inclusion in the first step of PADA-1 to the time of investigator-assessed tumor progression or death, whichever occurs first, in all patients including those who switched to fulvestrant.

Sixty-nine (62.8%) patients assigned to AI/palbociclib had disease progression during the second step. Forty-seven (68.1%) of those patients crossed over to fulvestrant/palbociclib in second line. At a median follow-up of 14.7 months (IQR, 9.7-17.3), the median second PFS was 3.5 months (95% CI, 2.7-5.1).

The median time to strategy failure, including patients who crossed over, was 11.9 months (IQR, 9.1-13.6) in the fulvestrant /palbociclib group vs 10.6 months (IQR, 8.0-13.4) in the AI/ palbociclib group (HR, 1.02; 95% CI, 0.71-1.45).

Sixty-nine (40.1%) patients in the experimental arm were receiving a reduced dose of palbociclib at the time of random assignment compared with 36 (42.9%) in the control arm. During the second step, 7 (8.0%) patients in the fulvestrant group and 6 (7.1%) in the AI group required dose reductions. One patient in the AI group discontinued palbociclib because of hematological toxicity. Two (4.2%) patients in the crossover group required palbociclib dose reductions.

Investigators recorded grade 3 or greater AEs in 44.3% of patients in the fulvestrant arm, 41.7% of the AI arm, and 34.0% of the crossover arm. The most common grade 3 or worse hematological adverse events were neutropenia (41.7% in the AI arm vs 44.3% in the fulvestrant arm) and lymphopenia (3.6% vs 4.5%, retrospectively). The most common grade 3 or worse AE in the crossover cohort was neutropenia (34%.0).

For serious AEs, 1 (1.2%) patient in the AI/palbociclib group experienced grade 4 neutropenia and 1 (1.2%) experienced grade 3 fatigue. One (1.1%) patient in the fulvestrant/palbociclib group experienced grade 4 neutropenia.


  1. Bidard FC, Hardy-Bessard AC, Dalenc F, et al. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. Published online September 29, 2022. doi:10.1016/S1470-2045(22)00555-1
  2. Bidard FC, Hardy-Bessard AC, Bachelot T, et al. Fulvestrant-palbociclib vs continuing AI-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- mBC patients: results of PADA-1, a UCBG-GINECO randomized phase 3 trial. Cancer Research. 2022;82(4_Supplement):GS3-05-GS3-04. doi:10.1158/1538-7445.SABCS21-GS3-05