For younger women with metastatic hormone receptor-positive breast cancer, CDK4/6 inhibition plus ovarian suppression prolonged progression-free survival (PFS) compared with single-agent chemotherapy, a randomized trial indicated.
Among nearly 200 patients in the Korean study, the group randomized to palbociclib (Ibrance) plus endocrine therapy had a median PFS of 20.1 months compared with 14.4 months for those treated with capecitabine (HR 0.66, 95% CI 0.44-0.99), reported Yeon Hee Park, MD, of Samsung Medical Center in Seoul, South Korea, and colleagues.
“The debate about chemotherapy versus endocrine therapy for patients with hormone receptor-positive metastatic breast cancer is ongoing, especially for those with a higher tumor burden who have a recurrence of disease within 24 months of adjuvant endocrine therapy, who are in particularly high need of a rapid response to further treatment” they wrote in the Lancet Oncology.
Roughly 50% of the women in each arm of the phase II study were receiving treatment as their initial therapy for metastatic disease. Objective response rates were similar between the two groups, at 37% for those treated with palbociclib plus exemestane (Aromasin) and 34% with capecitabine, as were rates of disease control (97% vs 91%, respectively) and clinical benefit (80% vs 67%).
Post-hoc subgroup analyses found significant PFS benefit for several subsets of women — those age >35 and with worse performance status (ECOG 1-2), and those without visceral metastases or exposure to chemotherapy in the metastatic setting — though Park’s group cautioned against reading too much into the findings due to the small patient numbers.
Median times to best response among the 65% of patients with measurable disease were 2.9 months in the chemotherapy group versus 4.3 months in the palbociclib group (P=0.111).
“Despite the later response in the palbociclib plus endocrine therapy group, the median progression-free survival was significantly longer than that in the capecitabine group,” the authors wrote. “This paradoxical finding might suggest that the response to palbociclib should be carefully assessed to achieve the best response.”
Whether to use chemotherapy or endocrine therapy upfront for patients with bulkier symptomatic disease has been a question, said Daphne Stewart, MD, of City of Hope in Duarte, California, in discussing the trial when it was first presented at the 2019 American Society of Clinical Oncology (ASCO) annual meeting.
“There was a superior progression-free survival in premenopausal patients treated with upfront endocrine therapy, including a CDK4/6 inhibitor, rather than a standard chemotherapy option in a frontline setting,” she told MedPage Today. “This perhaps isn’t earth shattering, but it is reassuring because we actually do have a trial comparing the two options.”
Guidelines recommend endocrine therapy for first-line treatment in women with hormone receptor-positive breast cancer (including those with visceral disease), yet anywhere from 35% to 60% of women in North America and Europe receive chemotherapy, wrote Marie Robert, MD, and Nicholas Turner, MD, PhD, both of the Royal Marsden Hospital in London, in a linked comment.
“Although this is the first prospective randomized trial to directly compare treatment with endocrine therapy plus a CDK4/6 inhibitor and chemotherapy, and to demonstrate improved outcome with endocrine-based therapy, these findings should be interpreted in the context of the study design,” they wrote, noting the small size of the trial, the open-label design, absence of blinded imaging review, and the fact that 78% of patients didn’t hit their expected palbociclib dose (likely due to a high rate of high-grade neutropenia).
Robert and Turner said the current study, combined with the overall survival benefit seen with CDK4/6 inhibitors in the MONALEESA-7, MONARCH 2, and MONALEESA-3 trials, confirm that these agents “in combination with endocrine therapy should now be the standard of care in first-line treatment for estrogen receptor-positive, HER2-negative breast cancers, even in young women and in patients with visceral disease for whom evidence from real-world clinical practice has suggested a reluctance by some physicians to follow endocrine-based strategies.”
One outstanding question, the editorialists said, is what to do for patients with visceral crisis. “Should these patients receive chemotherapy followed by CDK4/6 inhibitors plus endocrine therapy in maintenance, or should chemotherapy be continued until disease progression, or could endocrine and CDK4/6 inhibitor combinations also supplant chemotherapy for these patients?”
From 2016 to 2018, the KCSG-BR15-10 trial randomized 184 eligible hormone receptor-positive, HER2-negative metastatic breast cancer patients to treatment with either palbociclib plus exemestane versus capecitabine. Median age was 44, half of the patients had visceral disease, and roughly 75% had received no prior chemotherapy for their metastatic disease.
Treatment-related grade 3/4 neutropenia was more common in the palbociclib-exemestane arm (75%) than in the capecitabine arm (16%). Serious treatment-related adverse events occurred in 2% vs 17%, respectively. Twelve patients died, all due to disease progression, with seven in the palbociclib group and five in the chemotherapy group.
The study was funded by Pfizer, Shinpoong, Daewoong Korea, and Takeda.
Park disclosed support from Pfizer, AstraZeneca, Eisai, Novartis, Merck, and Roche. Co-authors disclosed multiple relevant relationships with industry including Pfizer.
Robert disclosed relevant relationships with Amgen, Roche, and Novartis. Turner disclosed relevant relationships with AstraZeneca, Bio-Rad, Bristol-Myers Squibb, Clovis, Guardant Health, Lilly, Merck, Novartis, Pfizer, Roche/Genentech, Tesaro, Bicycle Therapeutics, and Taiho.