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CHICAGO – A drug that targets cyclin-dependent kinases (CDKs) may delay the need for chemotherapy in women with hormone receptor–positive, HER2-negative metastatic breast cancer that is showing resistance to endocrine therapy, suggests the randomized PALOMA-3 trial (PALbociclib: Ongoing trials in the Management of breast cAncer).
In the phase III trial, palbociclib—a first-in-class oral inhibitor of CDKs 4 and 6 that prevents cell cycle progression—prolonged median progression-free survival by about 5 months compared with placebo when added to standard endocrine therapy, according to interim data reported at the annual meeting of the American Society of Clinical Oncology. These efficacy findings led to early stopping of the trial.
Susan London/Frontline Medical NewsDr. Nicholas C. Turner
“This study confirms that as breast cancers become resistant to endocrine therapy, CDK 4/6 is still a target and palbociclib is still very active,” lead study author Dr. Nicholas C. Turner, a consultant medical oncologist at The Royal Marsden and a team leader at The Institute of Cancer Research, London, said in a press briefing.
Earlier this year, the Food and Drug Administration approved palbociclib in combination with letrozole as first-line therapy for estrogen receptor–positive, HER2-negative metastatic breast cancer in postmenopausal women. But that is a different patient population, still having endocrine-sensitive disease, he noted.
The investigators opted to study palbociclib in combination with a different hormonal therapy, fulvestrant, in the trial for several reasons. “Fulvestrant is likely the most active hormone therapy when the first hormone therapy has stopped working,” Dr. Turner explained. Additionally, “there is quite significant data looking at cell line models that you get synergy between the two [drugs] in models of endocrine resistance.”
“I think the PALOMA-3 trial results are incredibly important for women with hormone receptor–positive advanced or metastatic breast cancer, and it represents a new standard of care option after progression of disease on prior endocrine therapy,” commented Dr. Don S. Dizon, an ASCO spokesperson and moderator of the press briefing, as well as clinical co-director of Gynecologic Oncology at the Massachusetts General Hospital, Boston.
“For women with advanced breast cancer, it’s remarkable to be able to stall disease progression and stave off the need for chemotherapy for months with a simple pill. In one of the most common forms of advanced breast cancer, palbociclib works in both older and younger women,” he said.
Susan London/Frontline Medical NewsDr. Don S. Dizon
The 521 women in the Pfizer-funded trial had hormone receptor–positive, HER2-negative metastatic breast cancer and had experienced a failure of prior endocrine therapy. They were randomized in 2:1 ratio to palbociclib (Ibrance) or placebo, each in addition to fulvestrant (Faslodex). Of note, 21% were premenopausal, and this group additionally received goserelin (Zoladex).
Results of the preplanned interim analysis showed that median progression-free survival, the trial’s primary endpoint, was 9.2 months with palbociclib versus 3.8 months with placebo (hazard ratio, 0.42; P less than .000001). “The curves separate early and then continue to separate with ongoing follow-up,” Dr. Turner noted.
“Benefit from palbociclib was demonstrated across all prespecified subgroups, including in both pre- and post-menopausal women,” he further reported. Overall survival results are not yet mature, and quality of life data will be reported separately.
Combination therapy was generally well tolerated, Dr. Turner said.
The most common any-grade adverse events seen with the drug versus placebo were hematologic, with sharply higher rates of neutropenia (79% vs. 3%) and leukopenia (46% vs 4%); however, the rate of febrile neutropenia was low and identical, at 0.6% in each group. Additionally, only 2.6% of patients in the palbociclib group had to stop treatment because of adverse events.
The efficacy of the initial palbociclib-letrozole combination is being further assessed in the ongoing PALOMA-2 trial, according to Dr. Turner. In addition, the investigators may evaluate palbociclib-containing combinations in early-stage breast cancer.