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BARCELONA -- Maturing clinical trials data indicated that treatment with CDK 4/6 inhibitors offer a survival advantage to women with advanced breast cancer, researchers said here.

In the MONARCH 2 trial, women treated with abemaciclib (Verzenio) plus fulvestrant achieved a median overall survival (OS) of 46.7 months compared with 37.3 months among women treated with placebo and fulvestrant (P=0.0137), reported George Sledge Jr., MD, of Stanford University School of Medicine in California, at the European Society for Medical Oncology (ESMO) annual meeting.

"The addition of abemaciclib to fulvestrant provided a statistically significant overall survival improvement in patients with HR-positive, HER2-negative advance breast cancer who progressed on prior endocrine therapy," Sledge said at an ESMO press conference. "Overall survival benefit was consistent across subgroups including patients with poor prognostic factors such as visceral metastases and primary endocrine therapy resistance."

Treatment with abemaciclib was tied to a longer time to chemotherapy, which was important to patients, Sledge added. Patients taking abemaciclib achieved a median 50.2 months before requiring chemotherapy versus 22.1 months among people taking placebo-fulvestrant alone (P<0.0001), he stated.

In a second study presented at ESMO, a statistically significant OS prolongation was achieved with ribociclib (Kisqali) plus fulvestrant versus placebo plus fulvestrant in women with advanced HR-positive/HER2-negative disease, reported Dennis Slamon, MD, of the University of California Los Angeles. In the MONALEESA-3 trial, patients in the ribociclib-fulvestrant arm had not reached a median survival after a median of 42 months of treatment. Women who received placebo-fulvestrant had a median OS of 40 months (P=0.00455).

"This is certainly good news for the women in this study who are receiving ribociclib," Slamon said at the press conference. "There data demonstrates a consistent, meaningful prolongation of survival with ribociclib with multiple endocrine therapy partners, regardless of menopausal status. This is not only statistically significant, but it is also clinically meaningful."

MONARCH 2

MONARCH 2 was a global, randomized, double-blind phase III trial of abemaciclib-fulvestrant or placebo-fulvestrant in pre- or perimenopausal (with ovarian suppression) and postmenopausal women with advanced, endocrine therapy-resistant HR-positive/HER2-negative advanced disease.

The study enrolled 669 patients who were stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior endocrine therapy (primary versus secondary). They were randomized 2:1 to the abemaciclib (150 mg twice a day and fulvestrant 500 mg in monthly injections) or placebo arm.

The primary objective was investigator-assessed progression-free survival (PFS). OS was a gated secondary endpoint. The boundary P-value for the interim analysis was 0.0208.

Sledge and colleagues reported that PFS was significantly improved (hazard ratio 0.675, 95% CI 0.558, 0.816) in the abemaciclib arm, as was time to chemotherapy (HR 0.622, 95% CI 0.499, 0.775).

The OS benefit was consistent in all stratification factors, although more pronounced effects were observed in subgroups of visceral disease (HR 0.675) and primary resistance to prior endocrine therapy (HR 0.686), they added.

MONALEESA-3

Postmenopausal patients with HR-positive/HER-negative advanced disease were randomized 2:1 to receive ribociclib-fulvestrant or placebo-fulvestrant in the first- and second-line settings.

"This is the 2nd of 3 protocol-specified OS analyses," the authors explained.

At the data cutoff date of June 3, 2019, 153 patients were still on treatment (25% in the ribociclib arm; 13.2% in the placebo arm).

OS was evaluated after 275 deaths (34.5% of patients in the ribociclib arm; 44.6% in the placebo arm). Median follow-up was 39.4 months.

Ribociclib-fulvestrant demonstrated a statistically significant OS prolongation over placebo-fulvestrant (median not reached vs 40.0 months, HR 0.724, 95% CI 0.568-0.924).

The result crossed the prespecified for superior efficacy, the authors noted, so "Per protocol, these OS results will be considered final."

OS benefit with ribociclib versus placebo was consistent across all subgroups:

• First-line: median not reached vs 45.1 months (HR 0.700, 95% CI 0.479-1.021)
• Early-relapse/second-line: median 40.2 vs 32.5 months (HR 0.730, 95% CI 0.530-1.004)

Time to progression on next-line therapy or death was also longer with ribociclib versus placebo (median 39.8 vs 29.4 months, HR 0.670, 95% CI 0.542-0.830).

These data, along with results, confirm ribociclib's benefit with multiple combination partners in pre- and postmenopausal patients, and support the agent as a recommended CDK4/6 inhibitor as first- and second-line treatment in patients with HR-positive/HER2-negative advanced breast cancer, the authors concluded.

'Game-Changer'

ESMO discussant Nadia Harbeck, MD, PhD, of the University of Munich called data from both studies "highly meaningful data."

In MONARCH in particular, the more than 50-month delay to chemotherapy is "a game-changer. In addition, this is the first time we see an overall survival advantage with abemaciclib. [Along] with ribociclib, we now have evidence that the drug is advantageous in both first-line and second-line settings," she said.

"I think these results will make a huge impact on how we treat metastatic breast cancer," Harbeck stated, adding that most European registries indicate OS of about 2 years in metastatic breast cancer, but results from MONARCH AND MONALEESA-3 indicate that extended survival is possible.

"These drugs are going to be the standard of care, and, in my opinion, should be first-line treatment in the metastatic setting because you can never guarantee that a patient will come back for a second-line treatment," Harbeck said. "We should give the best drugs first. I think these drugs will be a similar success as the HER2 story with trastuzumab."