For patients who have metastatic hormone receptor positive, HER2 negative breast cancer first-line therapy tends to be endocrine therapy with CDK4/6 inhibitor. Eventually, however, patients progress and disease is resistant. So there’s an unmet need to identify best treatment strategies for patients who progress on CDK4/6 inhibitors.

Giredestrant is an oral SERD, so that’s a selective estrogen receptor degrader, and it is a pure estrogen receptor antagonist and degrader with great potency. Everolimus is an oral mTOR inhibitor. Both of these agents target pathways that help to support the resistance in cancer cells, thus providing a rationale to evaluate this as a combination therapy post-CDK4/6 inhibitor.

evERA is a phase IIII randomised study that enrolled patients with metastatic hormone receptor positive, HER2 negative breast cancer who had had up to two prior lines of endocrine therapy for metastatic disease and all patients had prior CDK4/6 inhibitor. No patients had prior chemotherapy for metastatic disease; all patients had measurable or evaluable disease. Patients were randomised 1:1 to receive giredestrant with everolimus, that’s the treatment arm, or in the control arm provider choice standard of care endocrine therapy which could be exemestane, fulvestrant or tamoxifen with everolimus. Importantly, prophylactic dexamethasone mouthwash was strongly recommended.

The study was designed to enrich for patients with ESR1 mutation with a target of 55% and the study has co-primary endpoints evaluating progression free survival in the ESR1 mutant population and progression free survival in the ITT population. Key secondary endpoints include overall survival, response rate and duration of response.

The patient population that was accrued, 373 patients, is very representative of modern practice. There is the 55% ESR1 mutation enrichment, about 30% of patients had a PI3 kinase mutation in their cancer, three quarters of patients were receiving therapy in the second line setting and almost half the patients had prior fulvestrant exposure. So a very modern patient population. What we saw in the primary endpoint was that patients who received the giredestrant-based regimen had a statistically significant and very clinically meaningful prolongation in progression free survival – a 62% improvement at 9.99 months, compared to about 5.5 months in the standard of care endocrine therapy arm. So this was statistically significant and clinically meaningful. We also noted that the benefit of giredestrant was consistent whether the patient in the standard of care arm was receiving exemestane or fulvestrant.

Similarly, for the co-primary endpoint of PFS in the ITT population, there was a very similar improvement, statistically significant, in progression free survival with also a substantial improvement compared to standard of care therapy. Interim overall survival is immature, yet the curves are separating in a very favourable way with supportive hazard ratios.

The toxicity profile of the regimen was quite balanced between the two arms and reflects the individual components that were used in the trial. Notably, endocrine-related toxicity, because evERA is focussing on an endocrine agent, giredestrant, was not substantially different between the arms and was fairly low. The primary toxicities seen, including things like mucositis or nausea or diarrhoea, were related to everolimus and those were balanced between the arms.

So, overall, these exciting results from evERA show us that the combination of an oral SERD and an mTOR inhibitor, which is an all-oral combination, post CDK4/6 inhibitor provides substantial benefit compared to a standard of care combination regimen with endocrine therapy and everolimus. This may represent a new treatment option for patients who have metastatic hormone receptor positive, HER2 negative disease post-CDK4/6 inhibitor.