Camizestrant is an oral SERD and a complete ER antagonist that's designed to inhibit and degrade mutant and wild-type estrogen receptors. The main purpose of this abstract presented at ASCO was to report PFS-2 results for SERENA-6. In SERENA-6, patients that were on first-line CDK4/6 plus AI were screened for emergent ESR1 mutations at molecular progression via Guardant ctDNA testing—so this was different than our traditional radiographic testing that we would do to check for progression. If an ESR1 mutation was seen in these patients, they were transitioned to either camizestrant with continuation of their CDK4/6 inhibitor or they continued on the control arm, which was AI with their CDK4/6 inhibitor.

Results showed improvement in PFS-2 by 6.6 months. And prior to this abstract, we also have data with SERENA-6 that showed improvement in PFS of 7.6 months as well as a substantially higher rate of total ctDNA clearance on camizestrant, with 51% vs 2% on the control arm.

Of note, there was debate at ASCO amongst clinicians about the true value of PFS-2 and whether this should be factored into FDA approval for a variety of types of oncolytic treatments, including this one. Several limitations and weaknesses to this trial were highlighted, including incorporation of a new disease assessment strategy, molecular vs anatomical progression, and also the practicality of regularly screening our patients for ESR1 and the study design.

Regardless, it is clear that camizestrant does provide benefit for ER-positive patients with ESR1 mutations developing endocrine resistance. So switching to camizestrant at the time of ESR1 emergence will help extend time on endocrine therapy for our ER-positive metastatic breast cancer patients, which we know can improve their quality of life by extending their time before switching to a chemo or an ADC option. More cytotoxic agents like chemo and ADCs can lead to deterioration in overall patient condition and reduce daily functioning. Deterioration events favor the camizestrant arm on quality-of-life questionnaires for patient-reported outcomes for this trial.

So, what are some special considerations for APPs based on this abstract? Camizestrant could be an upcoming treatment option for our patients with emerging ESR1 mutations on first-line CDK4/6 and AI. More to come on this potential approval. If it is approved, we will need to consider regularly testing our patients with liquid biopsy on first-line therapy to detect these mutations to consider a switch.

In SERENA-6, patients were screened every 2 to 3 months and approximately 20% of the patients had an ESR1 mutation incidence at 2 years. SERENA-4 is also an ongoing phase III trial, which is evaluating camizestrant in the first-line setting with palbociclib.

AEs with camizestrant tend to show neutropenia. This is about 10% higher grade three or greater neutropenia events than the AI arm on this trial, but similar rates of overall neutropenia. Photopsia was seen, and we've seen this with other oral SERDs that we have in clinical trials. Photopsia is flashes of light; sometimes this is in the peripheral vision, sparks of light and shimmering light in the visual field, and this was seen in about 21% of patients. So a little bit of a unique AE than we've seen with some of our other approved agents for this population. Other AEs we need to look for are similar to those with a CDK4/6 and AI, including arthralgias, fatigue, and anemia.