Novel Drug Combo Doubles Progression-Free Survival in HER2-Negative Metastatic Breast Cancer

Average progression-free survival (PFS), which is the time a patient survives before their disease gets worse, was doubled in patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer with rising ESR1 mutations who were treated with an aromatase inhibitor plus Ibrance (palbociclib) and then switched to Faslodex (fulvestrant) plus Ibrance before their disease progressed, according to findings from the phase 3 PADA-1 trial.

Findings, which were presented at the 2021 San Antonio Breast Cancer Symposium, showed that at an average follow-up of 26 months, the median PFS was 11.9 months in patients who switched to Faslodex compared to 5.7 months in patients who remained on treatment with an aromatase inhibitor.

Notably, no new side effect concerns emerged, and approximately 35% of patients in each group experienced severe (grade 3 or 4) neutropenia, a condition where there is a decrease in neutrophils, which are a type of white blood cell.

“PADA-1 is the first trial to demonstrate that, in most patients, resistance-associated mutations in the estrogen receptor (ER) gene can be detected and targeted before tumor progression,” said lead study author Dr. François-Clément Bidard, a professor of medical oncology and co-coordinator of breast cancer research at the Institut Curie and Paris-Saclay University in Paris. “The trial suggests a statistically and clinically significant benefit when fulvestrant is used during this very new window of opportunity.”

ESR1 mutations are known to cause resistance to aromatase inhibitor-based therapy in patients with HR-positive, HER2-negative metastatic breast cancer. While the mutation is only found in less than 5% of patients at metastatic relapse, about 30% to 40% of patients present with ESR1 mutations after they progress on first-line aromatase inhibitor-based treatment.

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

In the first part of the trial, patients with HR–positive, HER2-negative, aromatase inhibitor-sensitive metastatic breast cancer received aromatase inhibitor-based therapy plus Ibrance in the frontline setting. Patients provided blood samples for ESR1 mutation screening at inclusion, then every month, then every two months until progression.

In the second phase of the trial, patients with rising ESR1 mutations and no synchronous progressive disease were randomized to continue with aromatase inhibitor/Ibrance or switch to Faslodex/Ibrance until progression.

An optional third step of the study made it possible for patients who were randomized to and progressed on aromatase inhibitor therapy/Ibrance to cross over and receive Faslodex/Ibrance.

The main goals of the study were investigator-assessed PFS in the second phase and safety (grade 3 or higher hematologic side effects). Additional outcomes included investigator-assessed second PFS after crossover and serious or severe (grade 3 or greater) nonhematologic side effects. Other goals included measuring overall survival, PFS from inclusion in the first portion, 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).

Overall, 1,017 patients with ER-positive, HER2-negative breast cancer were enrolled to the first portion of the PADA-1 trial. At a cut-off date of July 31, 2021, 407 patients (40%) had an ESR1 mutation–negative PFS event. Of the 279 patients (27.4%) who had detectable rising ESR1 mutations, 219 had no synchronous progressive disease and 172 were randomized in the second portion. Of these patients, 84 received an aromatase inhibitor plus Ibrance (standard treatment group) and 88 received Faslodex plus Ibrance.

In the standard treatment group, patients were a median age of 60 years and 63% (53 patients) did not receive prior adjuvant aromatase inhibitor-based therapy. In the experimental treatment group, patients were a median age of 62 years and 66% did not receive prior adjuvant aromatase inhibitor-based therapy.

Across both groups, most patients had visceral sites of metastasis (occurring in the soft internal organs) and at least 12 months of time to rising ESR1 mutations.

Notably, the results did not show any significant interactions with patient subgroups.

As of July 31, 2021, 69 patients who received an aromatase inhibitor plus Ibrance developed progressive disease and 47 patients crossed over to the Faslodex plus Ibrance treatment group.

In the cross-over cohort, and with a median follow-up of 14.7 months, the average PFS was 3.5 months in the third portion.

Bidard noted that the observed clinical benefit may be underpinned by a lower burden of ESR1 mutation tumor cells at initiation of Faslodex. The benefit may also not be equalized with standard second-line Faslodex-based therapy.

“This targeted approach, after the start of the first-line endocrine therapy but before the second line, yields a statistically and clinically significant gain in PFS,” Bidard said. “That benefit might not catchup when you wait, which might justify the adoption of the PADA-1 treatment strategy as a valid option in routine care.”

Moreover, monitoring the rise of resistance-associated mutations opens new opportunities for patients with metastatic breast cancer with novel agents, such as oral SERDs, as well as in other clinical settings beyond ESR1-mutant disease.

Additionally, the phase 2 INTERACT and phase 3 SERENA-6 trials are ongoing to further evaluate the efficacy of switching therapy after detection of an ESR1 mutation.

A version of this article originally appeared on OncLive as, “Fulvestrant/Palbociclib Following AI/Palbociclib Doubles PFS in HR+/HER2- Metastatic Breast Cancer.”

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