Women with metastatic hormone-sensitive breast cancer lived nearly 8 months longer with the addition of fulvestrant (Faslodex) to first-line anastrozole (Arimidex), long-term results of a phase III trial showed.
In the study of nearly 700 patients, overall survival (OS) in the combination arm was 49.8 months versus 42.0 months with anastrozole alone at 7 years median follow-up (HR 0.82, 95% CI 0.69-0.98, P=0.03), Rita S. Mehta, MD, of the University of California, Irvine, and colleagues reported.
At 5 years, 42% of patients in the combination arm were still alive compared with 33% in the anastrozole arm, despite nearly half the women in the control arm crossing over to fulvestrant, a selective estrogen-receptor down-regulator, after disease progression, they wrote in the New England Journal of Medicine.
Mehta told MedPage Today that until now, first-line metastatic breast cancer trials have shown improvements in progression-free survival (PFS) but not OS.
“If we don’t see a survival benefit with newer agents compared to old agents, then we haven’t really moved the needle,” she said. “Ultimately patients want to see if they can live longer or not.”
Early findings from SWOG S0226 were first reported by Mehta in 2011, at a median 3 years follow-up, and showed a significant PFS benefit with the combination (15.0 vs 13.5 months) and a trend toward improved OS.
“Some physicians changed their practice back then — some were not convinced,” Mehta said. “But now they should be convinced, because now we have one of the longest follow-ups and one of the largest studies.”
Certain subgroups appeared to drive this survival advantage. Among the 60% of patients naive to adjuvant tamoxifen, median OS was 52.2 months in the fulvestrant-anastrozole arm versus 40.3 months with anastrozole alone (HR 0.73, 95% CI 0.58-0.92). In contrast, those with prior tamoxifen had a non-significant OS advantage with the combination (48.2 vs 43.5 months).
Post-hoc subgroup analyses also revealed that women who were disease free for at least 10 years (29.8%) from the time of their initial diagnosis had a median OS of 65.4 months with fulvestrant-anastrozole versus 49.7 months with anastrozole alone (HR 0.69, 95% CI 0.49-0.98).
“The combination therapy in this trial provides another option for patients with estrogen receptor-positive, metastatic breast cancer, and I think also demonstrates that survival is improving for these patients as we gain more options for treatment,” Jennifer Litton, MD, of MD Anderson Cancer Center in Houston, told MedPage Today.
“Clinically, when considering first-line therapy, an endocrine agent plus CDK inhibitor still will likely be the preferred first choice given the very prolonged median PFS,” she said, but added that fulvestrant-anastrozole does provide an option, especially for patients unable to receive CDK4/6 inhibitors in first line.
In the phase III PALOMA-2 trial, for example, median PFS was 24.8 months with first-line letrozole plus the CDK 4/6 inhibitor palbociclib (Ibrance) versus 14.5 months with letrozole alone (HR 0.58, 95% CI 0.46-0.72, P<0.001). OS data are still immature.
Mehta pointed to the randomized phase II PALOMA-1 study, however, which did report OS data — 37.5 months with letrozole-palbociclib versus 35.5 with letrozole alone, a non-significant advantage in favor of the combination.
“Median survival was just 3 years, which was even worse than the control arm we had,” she said.
The current study, SWOG Cancer Research Network S0226, examined outcomes of 694 women randomized 1:1 to standard-dose anastrozole or the combination of anastrozole plus intramuscular fulvestrant. Patients were stratified by prior use of tamoxifen. All patients had hormone receptor-positive disease.
Further subgroup analyses for OS in the updated findings showed no benefit for the combination among those whose disease progressed from 5 to 10 years from their initial breast cancer diagnosis (HR 1.01, 95% CI 0.69-1.48) and in patients not sensitive to endocrine therapy (HR 1.08, 95% CI 0.64-1.80).
Mehta noted that with the longer follow-up, there were no additional grade 4/5 adverse events (AEs) on the combination arm. “In fact, if there was any additional grade 4 toxicity it was on the anastrozole arm,” she said.
Previous grade 4 AEs in the combination arm included arthralgia, dyspnea, thrombosis or embolism, and thrombocytopenia, each occurring in one patient, and there were three treatment-related deaths in the combination arm — all previously reported.
Grade 3 toxicities were similar between the two arms, at 15% of patients on the combination and 13% of those on anastrozole-alone (P=0.47). The most common grade 3 AEs (ranging from 1% to 4%) were fatigue, GI symptoms, hot flashes, mood alterations, and musculoskeletal pain. Treatment discontinuation due to AEs were rare — 12 patients on the combination and five on anastrozole alone.
The study was funded by the National Cancer Institute and AstraZeneca.
Mehta disclosed non-financial support from AstraZeneca during the conduct of the study, and grants from AstraZeneca, Pfizer, OBI Pharma, and Novartis unrelated to the current study.
Co-authors disclosed relevant relationships with Agendia, AstraZeneca, Cellworks, Cepheid, CVS/Caremark, Eli Lilly, Freenome, Genentech/Roche, Genomic Health, Immunomedics, Inbiomotion, Janssen, Menarini Silicon Biosystems, Merck, Merrimack, Myriad, Novartis, Oncimmune, Pfizer, Puma, and Sandoz.