HR+/HER2- metastatic breast cancer patients with ESR1 mutations benefit from early switch to fulvestrant plus palbociclib

The phase III PADA-1 study is the first trial to demonstrate that resistance-associated mutations in the oestrogen receptor gene can be detected and targeted before tumour progression. In fact, patients with HR⁺ breast cancer treated with an aromatase inhibitor plus palbociclib who displayed a rising ESR1 mutation in their blood before disease progression were able to double their median progression-free survival by switching to fulvestrant plus palbociclib.

The phase III PADA-1 study is a precision endocrine therapy trial exploring a new treatment strategy. First of all, the study aims to detect ESR1 mutations in the blood of patients who started first-line therapy with a combination of an aromatase inhibitor (AI) plus palbociclib as soon as they appear (for example before disease progression and at the start of second-line treatment). Of note, these mutations are rarely detected (<5%) at metastatic relapse but are frequent (30-40%) at progression under first-line AI-based treatment. In PADA-1, these mutations will be targeted by a switch of the endocrine therapy from AI to fulvestrant, while maintaining CDK4/6 inhibition. With this novel strategy, the aim of the study was to delay tumour progression in patients receiving first-line AI-palbociclib therapy.

PADA-1 study design

The PADA-1 trial recruited 1,017 metastatic breast cancer (mBC) patients with ERα-positive/HER2-negative breast cancer treated in a first-line setting with an AI and palbociclib. Patients were required to have an ECOG performance status of 0-2, no relapse in the last 12 months and no prior systemic therapy for mBC. All patients provided blood samples for ESR1 mutation screening at inclusion, at one month and subsequently once every two months until progression or end of study. Blood ESR1 mutation screening was performed by digital droplet PCR. Only the patients with an identified ESR1 mutation who did not experience concurrent disease progression entered the randomisation stage of the trial. These patients were randomly allocated (1:1) to continuing an AI plus palbociclib or switching to fulvestrant plus palbociclib. Patients who progressed after continuing AI treatment were given the option to cross over to the fulvestrant arm (cross-over cohort).

Results

Of the recruited patients, 407 (40.0%) experienced disease progression in the absence of an ESR1 mutation, while 279 patients had a mutation that was detected prior to (N=219) or concurrent with (N=60) disease progression. In total, 172 patients were randomised in the second step of the trial: 84 patients to the standard arm (AI + palbociclib) and 88 patients to the experimental arm (fulvestrant + palbociclib). The median time spent in step 1 of the trial, before the onset of ESR1 mutations, was 18 months. After a median follow-up of 26 months, the median progression-free survival (PFS) of patients who switched to fulvestrant more than doubled compared to that of patients who remained on an AI (11.9 versus 5.7 months, stratified HR [95%CI]: 0.61 [0.43-0.86]; p=0.005). No significant interactions with patient characteristics were observed and no new safety signals were reported.

In total, 69 patients had disease progression in the AI + palbociclib arm. Of them, 47 participated in the optional second-line cross-over cohort. After a median follow-up of 14.7 months, the median PFS in this cohort was only 3.5 months. As such, this supports previous studies showing a relatively short benefit of fulvestrant when used as a second-line therapy and emphasised the importance of early detection.

Conclusion

PADA-1 is the first clinical trial to demonstrate the clinical utility of blood ESR1 mutation monitoring. This monitoring allows the optimisation of the endocrine therapy partner of CDK4/6 inhibitors. Upon detection of ESR1 mutations, the median PFS was doubled by a switch from AI + palbociclib to fulvestrant + palbociclib. The observed clinical benefit might be underpinned by a low burden of ESR1 mutated tumour cells at fulvestrant initiation and might not be catched up by standard fulvestrant-based second-line therapy. These results justify the implementation of the PADA-1 treatment strategy as a valid option in routine care. Finally, the monitoring of the rise of resistance-associated mutations also opens up new opportunities in other clinical settings, beyond ESR1 mutations.

Reference

Bidard F, et al. Fulvestrant-palbociclib vs continuing aromatase inhibitor-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2-metastatic breast cancer patients: Results of PADA-1, a UCBG-GINECO randomized phase 3 trial. Presented at SABCS 2021; abstract GS3-05.