Daphne Stewart, MD

Standard first-line therapy for advanced hormone receptor-positive breast cancer is a CDK 4/6 inhibitor with endocrine therapy. Unfortunately, most patients progress, and optimal second-line therapy remains uncertain.

After progression on first-line therapy, clinicians generally offer a second line of endocrine therapy when we believe patients’ cancer remains sensitive to ER signaling inhibition. Based on trials, we typically use an alternative endocrine therapy: exemestane with everolimus based on the BOLERO II trial, or fulvestrant — a selective estrogen receptor degrader — alone or in combination with everolimus based on the phase 2 PrECOG 0102 trial.

However, given the significant benefit with CDK 4/6 inhibitor therapy and the slightly different mechanisms of action of CDK 4/6 inhibitors, there is interest in additional CDK 4/6 inhibitor given its highly effective clinical response and tolerable safety profiles.

There have been three phase 2 trials evaluating ongoing use of a CDK 4/6 inhibitor in the second line after progression on first-line CDK 4/6 inhibitor therapy. Two of those trials — PACE and PALMIRA — continued palbociclib after progression on palbociclib, and both showed no benefit. The MAINTAIN trial studied ribociclib after most patients progressed on palbociclib, and researchers reported a statistical benefit in the primary endpoint.

The postMONARCH trial is the first phase 3 trial of a CDK 4/6 inhibitor therapy after progression to be presented. Researchers randomly assigned patients after progression on first-line CDK 4/6 inhibitor and endocrine therapy to fulvestrant plus abemaciclib or placebo. The patients most likely to benefit were those who had responded to first-line therapy for more than 12 months, and those who had no visceral disease.

The postMONARCH study included patients with driver mutations, and the treatment benefit of abemaciclib was seen across genomic subgroups, including those with ESR1 and PIK3CA mutations.

I believe the results of this study will affect general practice, particularly for patients who remain endocrine sensitive, without rapidly progressing visceral metastatic disease, and who have no identified driver mutations (ESR1, PIK3CA, PTEN, AKT) or who have not had access to genomic sequencing to identify such mutations.

The data from other trials support the use of mutation-directed therapies in the second-line setting. Elacestrant (Orserdu, Stemline Therapeutics) in ESR1-mutated breast cancer is associated with improved PFS, capivasertib (Truqap, AstraZeneca) is approved in the second line in combination with fulvestrant for patients with PIK3CA/PTEN/AKT mutations, and alpelisib (Vijoice, Novartis) with fulvestrant is associated with improved PFS for patients with PIK3CA mutations.

The postMONARCH results address a need for patients who progress and may not have actionable mutations or may not tolerate mutation-directed therapies due to underlying diabetes or other comorbidities. Unfortunately, the postMONARCH results do not provide a durable response compared with first-line therapy, and importantly they do not address the need for patients with hormone-positive breast cancer who progress with visceral metastases after front-line therapy, a group that represents the majority of patients with metastatic disease.