John Robertson, MB chB BSc, MD, FRCS, University of Nottingham, United Kingdom, shared results from the SERENA-3 trial, investigating the effect multiple doses of camizestrant at different treatment durations has on ER, ki-67, and PgR expression in  endocrine receptor-positive, HER2-negative breast cancer.

Dr Robertson stated “the optimal dose of camizestrant is 75 mg, and that's the dose that is being used already in the advanced breast cancer setting. It's also the dose that's now going to be taken forward in the adjuvant setting trials— two of those have already started to recruit, CAMBRIA-1 and CAMBRIA-2.”

Transcript:

I'm professor John Robertson and I'm a professor of surgery at University of Nottingham in the UK and a Consultant Surgeon at the University Hospitals of Derby and Burton. I presented today on the SERENA-3 trial. SERENA-3 is a randomized presurgical study looking at dose and duration of an oral cell called camizestrant in hormone-sensitive primary breast cancer.

Camizestrant is an oral served and an estrogen-receptor antagonist, it follows on from SERENA-1 and SERENA-2. SERENA-1 was a phase 1 study looking at the safety, tolerability, and efficacy of multiple doses of camizestrant. SERENA-2 was a phase 2 randomized trial comparing camizestrant at two doses: 75 and 150 mg and comparing it to fulvestrant, which is the first cell developed, an IM injection. What it showed— SERENA-2 was that it was safe, but also superior efficacy at both the 2 doses: 75 and 150 compared to fulvestrant.

SERENA-3 is a presurgical study which looks at the biological effects of camizestrant on primary breast tumors and looked at 3 doses: 75, 150, and 300 mg. We recruited patients who were ER-positive, HER2-negative, post-menopausal, and the primary end point was a change in ERH score by immunohistochemistry. The secondary end points included ki-67, which is the biomarker we were reporting on, in addition to ER today in the presentation.

The study was an adaptive design study, so we started off looking at the 2 doses—75 and 150 and randomized 24 patients and biopsied the tumors between 5 to 7 days. That initial data gave a hint that there might be a dose effect, so for that reason stage 2 was to look at more patients to try and give a statistical purity as to whether there was a difference or not. We also added in a 300 mg dose because that would give us a chance to establish was there any dose curve in this, and that data showed that for ER down regulation, there was there was no difference across all the doses, they all gave the same ER down regulation. There still was a slight question about ki-67 so that moved us on to a third stage where we looked at 75 and 150 again, but this time letting the biopsy occur at 12 to 15 days. These biopsies were core cut biopsies, the same as the pretreatment biopsies, and they were flagged in each side by PK data, so good [pharmacokinetic]PK and [pharmacodynamic] PD data. What they showed, and this is the primary end point first of all, was that there was no difference between the doses, 75, 150, and 300, in the downregulation of ER—no difference by dose or by time of biopsy, whether it was 5 to 7 days or whether it was 12 to 15 days.

As I mentioned, in stage 1 and 2, there still was still some questions about ki-67 and that's why we moved to the stage 3 where we biopsied the patients later. When you look at the ki-67 data, what you see in stage 1 and 2 was at 5 to 7 days the 75 mg dose gave less of a decrease in ki-67 compared to the 150 and 300 but when you looked at the stage 3 where we biopsied the 2 months later, the ki-67 reduction was the same in 75 and 150. I think what that shows is that while you get PK, a steady state early, the biomarkers may be slightly different in terms of timing to get the right time to biopsy them. For estrogen receptor it seemed it didn't matter whether it was 5 to 7 or 12 to 15 days, you got the maximum effect early on but when it came to ki-67, it looked as though you needed to wait a bit longer to see the effect on that biomarker in terms of PD.

Overall, the 3 stages of the study showed that 75 mg give as good downregulation of ER and as good decrease in Ki-67 as the higher doses 115 and 300, so the optimal dose of camizestrant is 75 mg, and that's the dose that is being is being used already in the advanced breast cancer setting. It's also the dose that's now going to be taken forward in the adjuvant setting trials— two of those have already started to recruit, CAMBRIA-1 and CAMBRIA-2, so that's what we showed.

I think in addition to the specific data about camizestrant, the study also showed that this was a very specific study, which looked at dose and duration, I think it tells us that we have to be very careful in future presurgical studies that we choose the right time for the biopsies to make sure that we get the right results in terms of the biological effects of drugs.

Source:

Robertson J, Gogitidze T, Katashvili Z, et al. SERENA-3: A randomized pre-surgical window of opportunity study assessing dose and duration of camizestrant treatment in post-menopausal women with ER-positive, HER2-negative primary breast cancer. Presented at the 2023 San Antonio Breast Cancer Symposium; December 5-9; San Antonio, Texas. Abstract RF01-01