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MUNICH -- Median survival in advanced hormone receptor-positive (HR+) improved by as much as 10 months in patients who received the cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib (Ibrance) in addition to hormonal therapy, a randomized trial showed.

In the overall study population, median survival increased from 28.0 months with the hormonal agent fulvestrant (Faslodex) alone to 34.9 months with the combination. However, the difference did not achieve statistical significance.

On the other hand, the subgroup of patients who responded to prior hormonal therapy did show a statistically significant 10-month improvement in median survival with the palbociclib regimen, increasing to 11 months in patients without visceral metastases.

The findings provided a measure of reassurance about CDK 4/6 inhibitors' potential to improve survival, which has been lacking with all three of the approved agents in the class, Massimo Cristofanilli, MD, of the Robert H. Lurie Comprehensive Cancer Center in Chicago, said here at the annual congress.

The study was published simultaneously by the .

"This is the first report demonstrating that the absolute gain in survival is similar to the absolute gain in progression-free survival in the whole population," said Cristofanilli. "Moreover, this prolongation of life is of a large magnitude in patients with prior sensitivity to endocrine therapy."

"We now have solid data to suggest that this treatment should be the new standard of care," he added.

Even though the survival difference did not achieve statistical significance, cancer specialists will probably agree that a survival gain of almost 7 months is clinically meaningful, said Cristofanilli.

Speculation about CDK 4/6 inhibitors' ability to improve survival has been a "hot question," said Carmen Criscitiello, MD, of the European Institute of Oncology in Milan. Although the PALOMA-3 results provided the first evidence of improvement in survival, the study did not entirely resolve the issue.

"The study was underpowered for overall survival, so the data should be cautiously interpreted," she said. "Although the results strongly suggest that the PFS [progression-free survival] benefit may translate into an overall survival benefit, the other trials conducted with CDK 4/6 inhibitors will contribute to confirm the estimate of the survival benefit observed in this study."

The three approved CDK 4/6 inhibitors -- palbociclib, ribociclib (Kisqali), and abemaciclib (Verzenio) -- have become standard of care for patients with advanced, HR+/HER2- breast cancer. In randomized, phase III trials, all three drugs demonstrated statistically significant improvement in progression-free survival (PFS) when added to standard endocrine therapy, as compared with endocrine therapy alone. However, data to show that the drugs improve overall survival were lacking.

Cristofanilli reported findings from an updated analysis of the randomized, phase III , which compared the palbociclib-fulvestrant combination with fulvestrant-placebo in 521 patients whose disease had progressed after initial endocrine therapy. The primary analysis, published in 2016, showed that the combination .

Overall survival was a key secondary endpoint, but at the time the PFS results were announced, survival data were too immature to permit a meaningful analysis. Cristofanilli reported findings from a median follow-up of 44.8 months.

As required by the trial protocol, investigators performed a stratified analysis of the survival data, taking into account patients' prior sensitivity to hormonal therapy, presence or absence of visceral metastases, menopausal status, effect of subsequent treatment after disease progression, and safety. The analysis showed that the 6.9-month difference in survival translated into a 19% reduction in the survival hazard ratio (95% CI 0.64-1.03). An unstratified analysis yielded a 21% reduction in the hazard ratio (95% CI 0.63-1.00).

Investigators performed several subgroup analyses in an effort to identify patients who benefited most from the addition of the CDK 4/6 inhibitor to endocrine therapy. An analysis of 410 patients whose disease was sensitive to prior endocrine therapy, the combination resulted in a median overall survival of 39.7 months versus 29.7 months with fulvestrant alone (HR 0.72 for death, 95% CI 0.55-0.94). Among patients without sensitivity to first-line endocrine therapy (endocrine resistance), the median overall survival was 20.2 months with palbociclib and 26.2 months with fulvestrant alone.

The study population included 201 patients who did not have visceral metastases at enrollment. They had a median survival of 46.9 months with the palbociclib combination versus 35.4 months with fulvestrant alone (HR 0.69 for death, 95% CI 0.46-1.04, P=0.44). Postmenopausal women (N=413) fared better with the combination (34.8 vs 27.1 months) than did premenopausal women (38.0 months in both treatment groups).