AI and Palbociclib Followed By Fulvestrant Plus Palbociclib Doubled PFS for Hormone Receptor+, HER2- Metastatic Breast Cancer

When switching to fulvestrant (Faslodex) plus palbociclib (Ibrance) before disease progression, progression-free survival (PFS) doubled for patients with hormone receptor–positive, HER2-negative metastatic breast cancer with rising ESR1 mutations who were previously treated with an aromatase inhibitor (AI) plus palbociclib, according to findings from the phase 3 PADA-1 trial (NCT03079011) that were presented during the 2021 San Antonio Breast Cancer Symposium.¹

At a median follow-up of 26 months (range, 0-36), 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; stratified HR, 0.61; 95% CI, 0.43-0.86; P = .005).

Notably, no new safety signals were observed; approximately 35% of patients in each arm experienced grade 3 or 4 neutropenia.

“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 François-Clément Bidard, MD, PhD, a professor of medical oncology and co-coordinator of breast cancer research at the Institut Curie and Paris-Saclay University in Paris, France. “The trial suggests a statistically and clinically significant benefit when fulvestrant is used during this very new window of opportunity.”

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

Moreover, 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.

An optional third step of the study made it possible for patients who were randomized to and progressed on AI/palbociclib to cross over and receive fulvestrant/palbociclib.

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 effects [AEs]). Secondary end points included investigator-assessed second PFS after crossover and 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).

Overall, 1017 patients with Erα-positive, HER2-negative breast cancer were enrolled to step 1 of the PADA-1 trial. At a cut-off date of July 31, 2021, 40% of patients (n = 407) had an ESR1 mutation–negative PFS event. Of the 27.4% of patients (n = 279) who had detectable rising ESR1 mutations, 219 had no synchronous progressive disease and 172 were randomized in step 2. Of these patients, 84 received an AI plus palbociclib (standard arm) and 88 received fulvestrant plus palbociclib.

In the standard arm, patients were a median age of 60 years (range, 30-80) and 63% (n = 53) did not receive prior adjuvant AI-based therapy. In the experimental arm, patients were a median age of 62 years (range, 23-88) and 66% (n = 58) did not receive prior adjuvant AI-based therapy.

Across both arms, most patients had visceral sites of metastasis 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 AI plus palbociclib developed progressive disease and 47 patients crossed over to the fulvestrant plus palbociclib arm.

In the cross-over cohort, and with a median follow-up of 14.7 months, the median PFS was 3.5 months (95% CI, 2.7-5.1) in step 3.

Bidard noted that the observed clinical benefit may be underpinned by a lower burden of ESR1 mutation tumor cells at initiation of fulvestrant. The benefit may also not be equalized with standard second-line fulvestrant-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.² “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 (NCT04256941) and phase 3 SERENA-6 (NCT04964934) trials are ongoing to further evaluate the efficacy of switching therapy after detection of an ESR1 mutation.²

References

1. 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. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; virtual. Abstract GS3-05.
2. Breast cancer patients with estrogen receptor mutations may benefit from early switch to fulvestrant/palbociclib. News release. SABCS. December 7, 2021. Accessed December 7, 2021. https://bit.ly/3ImyIhI