In a randomized, Phase III trial led by researchers at The University of Texas MD Anderson Cancer Center, ribociclib, in combination with the aromatase inhibitor letrozole, dramatically improved progression-free survival (PFS) of post-menopausal women with hormone receptor-positive metastatic breast cancer, compared to the hormone therapy alone.

Interim results from the MONALEESA-2 study found a 44 percent improvement in PFS with ribociclib, a CDK4/6 inhibitor, and letrozole as a front line therapy. Gabriel Hortobagyi, M.D., professor of Breast Medical Oncology, presented the findings at ESMO 2016 Congress, and is the corresponding author of the New England Journal of Medicine paper.

"These findings have the potential to impact tens of thousands of women each year," says Hortobagyi, the study's principal investigator. "At some point, all breast cancers become resistant to endocrine therapy, so reversing, preventing or delaying that resistance is a major unmet need in this population.

"Women with metastatic disease will be on some therapy for the rest of their lives, and it's paramount that we delay the progression of their disease for as long as possible," continues Hortobagyi.

The international double-blind study, MONALEESA-2, enrolled 668 post-menopausal women with advanced breast cancer at 223 trial sites in 29 countries. They were randomized to receive either ribociclib and letrozole, or letrozole and placebo. None had been previously treated for their advanced disease.

The study's primary endpoint was PFS; secondary endpoints included overall survival, overall response rate (ORR) and safety. The median follow up of patients was 15.3 months.

The median PFS was not reached in the study arm at data cut-off, compared to 14.7 months in the placebo arm. In those with measurable disease who received ribociclib, the ORR was 52.7 percent, compared to 37.1 percent in those who received letrozole alone.

Serious adverse events occurred in less than five percent of patients overall, but side effects were higher in the ribociclib arm, including neutropenia (59 percent vs., 1 percent) and leukopenia (21 percent vs. 1 percent). Most could be managed through dose interruption and reduction, says Hortobagyi. The discontinuation rate of the investigative drug was 7.5 percent, compared to 2.1 percent in the placebo cohort.

These findings could represent a paradigm shift in the future medical management of this patient population.

"When I started my career at MD Anderson in the 1970s, the median survival for women with metastatic breast cancer was just under two years. Now, with this discovery and other advances in the field, we can increasingly treat this as a chronic disease," says Hortobagyi. "Also, because we are able to delay or avoid chemotherapy, the quality of these women's lives has improved dramatically."

Commenting on the findings, Professor Giuseppe Curigliano, Director of the New Drugs and Early Drug Development for Innovative Therapies Division at the European Institute of Oncology, Milan, Italy, said, "I believe the results of this study are significant because now we have a new CDK4/6 inhibitor for patients with estrogen-receptor positive metastatic breast cancer, in addition to palbociclib and abemaciclib ."

"The addition of ribociclib to letrozole does increase the rate of toxicity, but overall, if we evaluate the magnitude of clinical benefit, there is definitely a benefit to be gained from adding ribociclib."

Curigliano also suggested that further studies of ribociclib should examine the use of cancer biomarkers to better identify patients who would respond to the combination.

As follow-up, adjuvant trials with ribociclib are now being designed, says Hortobagyi. Ribociclib will also be studied in younger, pre-menopausal women with breast cancer.

Ribociclib is developed by Novartis, who also sponsored the trial. Hortobagyi receives research support from Novartis and has served as a consultant.