Giredestrant plus palbociclib shows limited benefit in ER-positive, HER2-negative metastatic breast cancer

Published: 10 Jun 2026

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Dr Mabel Mardones - Rocky Mountain Cancer Centers, Denver, USA

Dr Mabel Mardones speaks to ecancer about the primary analysis of the phase III persevERA BC trial.
In first-line treatment of ER-positive, HER2-negative locally advanced or metastatic breast cancer (LA/mBC), CDK4/6 inhibitors combined with endocrine therapy remain the standard of care.

Giredestrant, a next-generation oral selective oestrogen receptor degrader, has shown promising efficacy in earlier settings, prompting evaluation in combination with palbociclib versus letrozole plus palbociclib in the phase 3 persevERA BC trial.

Results showed a numerical improvement in progression-free survival with giredestrant plus palbociclib compared to letrozole plus palbociclib, with a median benefit of 4.9 months. However, this difference did not reach statistical significance.

The safety profile was consistent with known effects of CDK4/6 inhibition, with haematologic toxicities being the most common high-grade adverse events. Treatment discontinuation rates due to adverse events were low and similar between groups.

Dr Mardones says that overall, while giredestrant demonstrated modest clinical activity, it did not significantly improve outcomes over standard endocrine therapy in this setting.

The persevERA study is looking a novel SERD, giredestrant, which is a potent next-generation SERD with full ER antagonist activity, in combination with CDK4/6 inhibitors compared to CDK and endocrine therapy in the front-line setting in metastatic breast cancer patients.

What was the study design?

The study design of persevERA, this was a phase III, randomised, double-blind placebo-controlled multicentre trial in the frontline, locally advanced or metastatic disease setting. It included patients who were ER-positive with no prior endocrine therapy, no prior oral SERD in the adjuvant setting. They could have had disease recurrence for greater than a year or less than a year, de novo breast cancer patients were capped at 20% and they included 992 patients randomised to receive giredestrant and palbociclib versus letrozole and palbociclib in this study. The primary endpoint was investigator assessed progression free survival.

They did have a statistical significant boundary of efficacy defined in the study as a hazard ratio of 0.85 and the demographics of the study included a medium population, average age of these women was around 63. Around 60% of these patients were Caucasian, 28% were Asian. About 80% were postmenopausal and 70% of these patients had had a treatment-free interval of greater than a year. About 60% of these patients had visceral metastases and this truly represents the type of patients we see in our clinics today.

What were the results of this study?

The primary endpoint was investigator assessed progression free survival and what they noted were in the combination of giredestrant and palbociclib there was a numerical improvement of 33 months versus 28 months in the patients who received letrozole and palbociclib with a delta of five months. However, the hazard ratio here did not meet the prespecified statistical significance boundary, as the hazard ratio in this study was 0.89.

The median duration of response was numerically longer in the giredestrant/palbociclib, 38 months versus 30 months in the other one.

What is the clinical significance of these results?

There are a variety of different clinically significant elements. We do learn from both negative and positive trials and all of us were very, very eagerly awaiting the first trial that showed that SERDs in the frontline setting may not actually over-perform with the current standard which is an AI and CDK4/6 inhibitor. This was an unselected group of patients and what we’re hoping to learn with more data is is there a different group of patients who truly do merit the addition of oral SERDs.

This landscape is very complex, we have the pionERA study which is looking at the same agent, giredestrant, and fulvestrant now, instead of an aromatase inhibitor in endocrine-resistant groups. So these are patients who have progressed on adjuvant endocrine therapy or within 12 months or have had less than a year from their treatment-free interval. Maybe that group could merit consideration for oral SERDs. We also await the SERENA-4 trial looking at a different oral SERD, camizestrant, in the frontline setting. This is a larger study and we hope to see results at San Antonio this year and this might explain also potentially a group for which SERDs are of benefit.

The other clinical aspect of this is that we know that both in the adjuvant and in the metastatic setting aromatase inhibitors can be challenging from a musculoskeletal perspective. In this trial, like others, they did not or were not able to tease out a group that really had a whole lot less musculoskeletal events. They were similar in the persevERA study. Hepatotoxicity was about the same but what we know about all these agents is that they have different side effect profiles. So to reference the persevERA study, when it came to AEs, one specific one that is bradycardia was noted, an all-grade toxicity of 11% versus 1.8% in the comparator arm. But it’s important to note that all of these patients, in fact the vast majority, were grade 1 events.

So it will be interesting to have options for our patients and we also await the approval of this same agent, giredestrant, in the adjuvant setting as well in a high-risk population.