MONARCH 3 final OS data support abemaciclib-NSAI for HR+/HER2- advanced breast cancer

In the final overall survival (OS) analysis of the phase III MONARCH 3 trial, the combination of the CDK 4/6 inhibitor abemaciclib and a nonsteroidal aromatase inhibitor (NSAI) continued to show clinically meaningful signals as first-line (1L) treatment for HR+/HER2- advanced breast cancer.

After a median follow-up of 8.1 years, abemaciclib-NSAI conferred numerically longer median OS compared with NSAI alone in the intention-to-treat (ITT) population (66.8 vs 53.7 months; hazard ratio [HR], 0.804; p=0.0664). However, statistical significance was not reached, noted presenting author Dr Matthew Goetz from the Mayo Clinic, Rochester, Minnesota, US, at SABCS 2023.

A similar trend favouring abemaciclib over placebo was seen in the subgroup of patients with visceral disease (63.7 vs 48.8 months; HR, 0.758; p=0.0757). [SABCS 2023, presentation ID GS01-12]

These findings were supported by the consistent OS effect size seen across different subgroups. “Of note, there were subgroups where the effect was a bit more pronounced [such as those] who had prior AI therapy (HR, 0.565) and those who had progesterone-receptor-negative disease (HR, 0.498),” said Goetz.

“At 8 years of follow-up, when the natural history of metastatic breast cancer starts to substantially impact patient survival, it is highly encouraging to see abemaciclib combined with AI therapy deliver a meaningful survival difference of 13 months in the ITT population and >14 months in women at even higher risk due to visceral disease," said study co-investigator Dr Stephen Johnston from The Royal Marsden NHS Foundation Trust, London, UK, in a press release.

PFS benefit sustained

At the final progression-free survival (PFS) data cut (median follow-up 26.7 months), median PFS was nearly doubled in the abemaciclib vs the placebo arm (28.2 vs 14.8 months; HR, 0.540; p_nominal=0.000002). “This robust PFS benefit ultimately led to the global regulatory approval of abemaciclib [for this indication],” noted Goetz.

In the current analysis, the median PFS benefit with abemaciclib-NSAI was sustained in the ITT cohort, as evidenced by the 14.3-month improvement (29.0 vs 14.8 months; HR, 0.535; p_nominal<0.0001) and continued separation of curves at longer follow-up.

Moreover, there was a marked difference between the abemaciclib and placebo arms in terms of PFS rates at the 6-year mark (23.3 percent vs 4.3 percent).

Other outcomes

Median chemotherapy-free survival (CFS) – defined as time to initiation of subsequent chemo or death from any cause, whichever is earlier – was also better with abemaciclib vs placebo (46.7 vs 30.6 months; HR, 0.693; p_nominal=0.0010). This implies that abemaciclib delayed subsequent receipt of chemotherapy by a median of 16.1 months.

Six-year CFS rates for abemaciclib and placebo were 35.7 percent and 20.5 percent, respectively.

There were no new safety signals with prolonged exposure to abemaciclib. The most frequent grade ≥3 treatment-emergent adverse events with abemaciclib were neutropenia, diarrhoea, and anaemia (28, 10, and 9 percent, respectively).

Clinically relevant data

MONARCH 3 evaluated 493 postmenopausal women with HR+/HER2- advanced (locoregionally recurrent or metastatic) breast cancer who have had no prior systemic treatment for advanced disease. They were randomized 2:1 to receive oral abemaciclib 150 mg or placebo BID, without interruption, given in combination with either anastrozole 1.0 mg or letrozole 2.5 mg QD until disease progression or unacceptable toxicity.

“The clinically meaningful improvement in median OS, combined with the sustained significant improvement in median PFS and substantial extension in median CFS continue to support the use of abemaciclib in combination with NSAI as 1L therapy in HR+/HER2- advanced breast cancer,” said Goetz.

“Despite missing statistical significance, these data are clinically relevant and highly consistent with the overall body of evidence for abemaciclib in advanced or metastatic breast cancer,” Johnston said.