In a double-blind, phase III study that enrolled both pre- and postmenopausal women, the addition of palbociclib to fulvestrant conferred significant benefit for women with hormone-positive (HR+), HER-negative (HER-) advanced breast cancer for whom prior endocrine therapy had failed.
The results of the PALOMA3 study were presented by Nicholas C. Turner, MBBS, PhD, of the Royal Marsden Hospital, United Kingdom, during the Breast Cancer—HER2/ER Oral Abstract Session on Monday, June 1 (Abstract LBA502).
“Palbociclib and fulvestrant improved progression-free survival compared with placebo and fulvestrant in women with hormone-positive and HER2-negative advanced breast cancer whose disease had progressed on prior endocrine therapy,” Dr. Turner said.
Palbociclib is an orally active selective inhibitor of CDK 4/6. The pathway is important, he said, because the growth of HR+ breast cancer relies on cyclin-D1—a direct transcriptional target of the estrogen receptor—which, in turn, activates the CDK 4/6 that allows tumor cells to transition from the G1 to S phase of the cell cycle. Previous cell-line studies, he said, have demonstrated that endocrine resistance is heavily dependent on cyclin-D1 and CDK 4/6.
To test the activity of the drug, investigators enrolled 521 patients and randomly assigned them 2:1 to receive either palbociclib (125 mg every day; 3 weeks on/1 week off) and fulvestrant (500 mg every 4 weeks; 347 patients) or placebo (3 weeks on/1 week off) and fulvestrant (500 mg every 4 weeks; 174 patients).
Importantly, Dr. Turner said, the study enrolled women who were both pre- and postmenopausal, although all premenopausal women were prescribed goserelin for ovarian function suppression. Postmenopausal patients had to have disease that had progressed on prior aromatase inhibitor therapy, he said.
The study met its primary endpoint of improvement in progression-free survival (PFS) by investigator assessment. Median PFS was improved by 5.4 months in the palbociclib and fulvestrant group compared with the placebo plus fulvestrant group.
An independent audit of the study results accorded with the findings of the investigators, Dr. Turner said.
The results were consistent among a number of preplanned subgroups; of note, Dr. Turner said, was that menopausal status at the time of enrollment did not affect the outcome. The median PFS in pre- and perimenopausal women was 5.6 and 9.5 months in the placebo plus fulvestrant and palbociclib plus fulvestrant groups, respectively; these values were 3.7 and 9.2 months among postmenopausal women.
Active treatment also demonstrated a benefit in secondary outcomes, including objective response and clinical benefit ratio, Dr. Turner said.
Overall, palbociclib was well tolerated, although there was significantly more neutropenia, leukopenia, anemia, and thrombocytopenia noted in the palbociclib plus fulvestrant treatment group. Additionally, 54%, 41%, and 32% of patients in the palbociclib plus fulvestrant treatment group required dose interruption because of treatment-related adverse events (AEs), cycle delays resulting from AEs, and dose reductions, respectively. These values were 4%, 9%, and 2% in the placebo plus fulvestrant treatment group.
Joseph A. Sparano, MD, of Montefiore Medical Center, offered a perspective on the study during a panel discussion.
“These findings confirm the strong signal observed in the phase II PALOMA1 trial, and there was no subgroup that did not derive benefit, with the possible exception of patients who had a short disease-free interval,” Dr. Sparano said.
He noted that there are a number of CDK inhibitors currently in phase III trials, which could be a benefit for the treatment of women with HR+/HER- breast cancer.
“CDK4/6 inhibitors represent an important advance in ER-positive metastatic breast cancer,” Dr. Sparano said. “This represents an entirely new treatment modality, and we are just beginning to understand how to appropriately use these agents.”
Watch the session: Visit the ASCO Virtual Meeting website.