Early Switch to Fulvestrant, Palbocilib Combination Therapy May Provide Benefit to Certain Patients With Breast Cancer

Patients with hormone receptor-positive breast cancer treated with an aromatase inhibitor plus palbociclib who displayed a rising ESR1 mutation detected in their blood before disease progression doubled their median progression-free survival (PFS) following a switch to fulvestrant plus palbociclib, according to results from the phase 3 PADA-1 clinical trial, presented at the San Antonio Breast Cancer Symposium.

“PADA-1 is the first trial to demonstrate that, in most patients, resistance-associated mutations in the estrogen receptor gene can be detected and targeted before tumor progression,” said presenter François-Clément Bidard, MD, PhD, professor of medical oncology at Institut Curieand Paris-Saclay University in France, in a press release. “The trial suggests a statistically and clinically significant benefit when fulvestrant is used during this very new window of opportunity.”

Patients with breast tumors that express estrogen receptor alpha (ERα) are frequently treated with aromatase inhibitors, which block the body’s production of estradiol. Recent studies have shown that these patients could derive more benefit from concurrent treatment with cell cycle inhibitors, such as palbociclib.

Tumors can become resistant to aromatase inhibitors by mutating ESR1, the gene that encodes ERα, so that it no longer requires estradiol to function. The PADA-1 trial demonstrates that some patients with this mutation can benefit by switching to a drug that degrades the estrogen receptor while maintaining palbociclib.

“Fulvestrant remains effective against receptors with these mutations, but it provides a limited progression-free survival benefit when used as a second-line therapy,” Bidard said in the release. “Our goal was to track the emergence of ESR1 mutations in patients’ blood during first-line therapy and act on them as soon as they appeared, before they led to an actual clinical progression of the disease.”

To conduct the study, researchers enrolled 1017 patients with ERα-positive breast cancer that had no overexpression of human epidermal growth factor receptor 2, who were being treated in a first-line setting with an aromatase inhibitor plus palbociclib. Participants provided blood samples every 2 months for ESR1 mutation screening.

Among all recruited patients, 407 experienced disease progression in the absence of an ESR1 mutation, and a mutation was detected in 279 patients prior to or concurrent with disease progression. Patients with an identified mutation who did not experience concurrent disease progression were randomly assigned either to continuing an aromatase inhibitor plus palbociclib (84 patients) or switched to fulvestrant plus palbociclib (88 patients).

The median PFS of patients switched to fulvestrant was 11.9 months at a median follow-up of 26 months, compared to 5.7 months among those who remained on an aromatase inhibitor. Patients who progressed in the aromatase arm were offered the option of switching to the fulvestrant arm of the study. This crossover population had a median PFS of 3.5 months, which the investigators said emphasized the importance of early detection and demonstrated the relatively short benefit of fulvestrant as a second-line 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 progression-free survival,” Bidard said in the release. “That benefit might not catch up when you wait, which might justify the adoption of the PADA-1 treatment strategy as a valid option in routine care.”

REFERENCE

Breast cancer patients with estrogen receptor mutations may benefit from early switch to fulvestrant/palbociclib [news release]. SABCS; December 7, 2021. Accessed December 14, 2021. https://aacr.ent.box.com/s/tdrl0yleow572a6sze15uhfzl6hbytg9