SABCS 2021 | RV-471: novel PROTAC® estrogen receptor degrader, in ER+ breast cancer

This was a poster spotlight. It was ARV-471, which is an oral PROTAC, so a different twist on an estrogen degrader. And specifically we reported data on 60 patients dosed from about 30 up to 700 milligrams and what we saw is that the drug was pretty well tolerated. Any grade nausea was only 30% with only one patient having grade 3. There was less than 20% any grade fatigue, and there were no dose-limiting toxicities. So we’re very encouraged about this. And as far as the activity, the clinical benefit rate in the conservative definition, so complete responses plus partial responses plus stable disease, at least for 24 weeks, was 40% in the 47 evaluable patients. That include three confirmed PRs and 14 patients that are still ongoing at study at this time.

We also had some correlative data in this abstract. So we saw robust degradation of ER, up to 89%. And in median across all the dose level study, it was 67%. And so this compound is being explored further. It’s currently being looked at in the VERITAC expansion, which is looking at both the 200 as well as the 500 milligram dose. It’s current being looked at in a Phase Ib expansion in combination with palbociclib, and then Phase III studies are underway as well.

I think the particularly meaningful part of this abstract is really how pretreated the patients were. 100% of them had seen prior CDK4/6 inhibitor, 80% had seen prior fulvestrant, and 78% prior chemotherapy. So really to be getting a clinical benefit rate of 40% with minimal toxicities is very encouraging as it moves forward. There’s multiple places that this could fit, the large clinical need right now is in the post AI CDK4/6 setting, so in the second line metastatic setting. That’s where we’ve seen fulvestrant not do as well as we have historically felt that it should after CDK4/6 inhibitors. So in the Veronica trial, the progression free survival of fulvestrant was only 1.8 months. We also saw results of the first Phase III SERD trial at San Antonio, the EMERALD trial with elacestrant and fulvestrant only performed at 1.8 months there as well. And so we’re really looking for more effective agents in that second line setting, as well as we certainly could combine with CDK4/6 in the first line, or even see it go earlier into the adjuvant setting.