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COPENHAGEN -- The addition of a targeted agent to endocrine therapy for metastatic breast cancer led to unprecedented improvement in progression-free survival (PFS) that will have a "paradigm changing" effect on clinical management, an investigator said here.

Patients who received the cyclin-dependent kinase (CDK)4/6 inhibitor ribociclib in addition to letrozole (Femara) had a 44% reduction in the PFS hazard compared with patients treated with letrozole alone. The median PFS (primary endpoint) was 14.7 months with letrozole but had yet to be reached with letrozole plus ribociclib, "but it is expected to far exceed what the control arm did," , reported at the (ESMO) conference.

"We did a number of preplanned subset analyses, and the benefit was present in all subsets, regardless of age, performance status, and extent or location of metastases," Hortobagyi, of the University of Texas MD Anderson Cancer Center, said during an ESMO press briefing. "Secondary endpoints, such as response rate and clinical benefit rate, also favored the combination.

The trial, known as , along with the recently reported trial involving the CDK4/6 inhibitor palbociclib (Ibrance), "will be paradigm changing, in the sense that historically there have not been studies in metastatic breast cancer with this magnitude of benefit," he added. Moving forward, the challenge will be to identify biomarkers to determine which patients should receive combination therapy with a CDK4/6 inhibitor.

The results were published online simultaneously in the .

Following presentation of the data at an ESMO Presidential Symposium, invited discussant , of the Royal Marsden Hospital in London, agreed that anti-CDK4/6-endocrine combination therapy will change clinical practice for advanced HR-positive, HER2-negative breast cancer.

"Is this a game changer? I think it will be," said Johnston. "We now have data from two large randomized clinical trials, providing level 1 evidence in support of this strategy."

However, Johnston also ticked off a list of unanswered questions posed by the MONALEESA-2 and PALOMA-2 results: Will endocrine monotherapy retain a role, and if so, which patients? Are other biomarkers available to guide patient seletion or is CDK4/6 ubiquitous for HR-positive metastatic breast cancer? What about affordability? What are the treatment options in the face of resistance to anti-CDK4/6 therapy?

CDK4/6 inhibition has a sound biologic basis as a therapeutic strategy for hormone-receptor breast cancer, as explained by Hortobagyi. CDK 4 and 6, and the associated protein cyclin D1 (a transcriptional target of estrogen-receptor signaling), regulate cell-cycle progression. Overexpression of CDK4/6 and amplification of the gene that encodes for cyclin D1 occur frequently in hormone receptor-positive breast cancer. Increased CDK4/6 activity is associated with resistance to endocrine therapy.

Clinical experience with palbociclib showed that disruption of the signaling pathway that includes cyclin D, CDK4/6, inhibitor of CDK4, and retinoblastoma protein represents an effective therapeutic strategy for HR-positive advanced breast cancer. Beneficial effects were demonstrated in trials of first-line therapy and treatment after progression on initial endocrine therapy.

Ribociclib demonstrated antitumor activity in xenograft models of HR-positive breast cancer, both as a single agent and in combination with letrozole and PI3K inhibitors. Additional evidence of safety and efficacy emerged from preliminary clinical trials involving patients with HR-positive, HER2-negative advanced breast cancer.

MONALEESA-2 involved 668 postmenopausal women with untreated HR-positive, HER2-negative recurrent or metastatic breast cancer. All patients received letrozole and were randomized to ribociclib or matching placebo. Treatment continued until disease progression.

The trial had a primary endpoint of investigator-assessed PFS, and secondary endpoints included overall survival, overall response rate, and safety. The trial ended after the initial preplanned interim analysis revealed a significant advantage in favor of the ribociclib arm.

After a median follow-up of 15.3 months, patients treated with ribociclib had a hazard ratio for disease progression or death of 0.56 compared with the placebo group (95% CI 0.43-0.72, P=0.00000329). Blinded, independent review of PFS resulted in a hazard ratio of 0.59 in favor of ribociclib.

The 18-month PFS was 63.0% with ribociclib and 42.2% with placebo. Data for overall survival remained immature. The ribociclib group had an overall response rate of 52.7% compared with 37.1% in the placebo group (P<0.001).

Patients treated with ribociclib incurred additional toxicity, including more grade 3/4 adverse events. The incidence of grade 3/4 adverse events was 81.2% with ribociclib versus 32.7% with letrozole alone. The most prominent grade 3/4 adverse events in the ribociclib arm included neutropenia (59.5% vs 0.9% with letrozole alone) and leukopenia (21.0% vs 4.5%).

Other adverse events (all grades) that occurred more often with ribociclib were nausea (51.5% vs 28.5%), diarrhea (35.0% vs 22.1%), alopecia (33.2% vs 15.5%), and vomiting (29.3% vs 15.5%).