Comprehensive insight on novel treatment approaches in the setting of relapsed/refractory HR+/HER2- breast cancer, including oral SERDs, SERMs, and ER PROTAC degraders.
Hope S. Rugo, MD, FASCO: Let’s move on and talk about the next wave of endocrine therapy. Where are we going now? Patients who have progressed now on their first-line setting, first-line treatment, or maybe we’re going to be moving some of those more effective therapies even earlier. There have been a lot of oral SERDs [selective estrogen receptor downregulators] out in the meeting areas where we’ve seen a lot of phase 1 and phase 2 studies, one phase 3 trial, and some subgroup analyses. Tell us a little bit about where we are at ASCO [American Society of Clinical Oncology] 2022 with the oral SERDs.
Komal Jhaveri, MD, FACP: We have a lot of data with a lot of oral SERDs. There are about 10 that we know of in clinical development, and this is just the oral SERDs. We have other novel endocrine agents such as the novel SERMs [selective estrogen receptor modulator]. We have Circas [ph], the covalent antagonists. We have Celans [ph], which are complete ER [estrogen receptor] antagonists, and then we have PROTACs [proteolysis targeting chimeras]—a lot of effort with a common goal to see how we can find an optimal endocrine therapy agent that can overcome our current issues with the currently approved endocrine therapies. It may be the toxicity profile or it may be the pharmacological liabilities that we face with these drugs. Certainly, we have seen a lot of data; we’ve seen the majority of these data in patients who are pretreated who progressed on prior CDK4/6 inhibitors, have had fulvestrant in some proportion of patients. We’ve seen activity regardless of ESR1 mutation, regardless of CDK [cyclin-dependent kinase], and regardless of fulvestrant. Dr Bardia, who’s with us today—we’ve heard results from the EMERALD trial, the phase 3 trial, the randomized study of elacestrant vs physician choice endocrine therapy. We did see that there was a 30% reduction in the risk of progression or death with elacestrant compared to physician choice endocrine therapy in all comers and about a 45% reduction in those patients whose tumors have the mutant ESR1 mutations. I think what we’re trying to now figure out is can we do better? Is there a patient population, or a way of identifying ER-dependent tumors, who can potentially derive the maximum or optimal benefit from a single-agent oral SERD? At this meeting we presented data for another oral SERD, the imlunestrant SERD. This was data from a phase 1 study, monotherapy data from about 114 breast cancer patients, and the recommended phase 2 dose of 400. We saw modest overall response rates, which are 12%, but the clinical benefit rate, again, was 55%. Interestingly in the pure second-line post-CDK4/6 granted in a small subset of patients, about 50 or so, we did see a median progression-free survival of 6.5 months. Now we’re looking forward to the next step, a registrational phase 3 study, the EMBER-3 trial. This study is looking at patients who have not had chemotherapy post CDK, not had fulvestrant, and would get imlunestrant vs SERD. There are many attempts looking at combinations with CDK4/6 either in the first line or combinations with PI3/KAKT/MTOR inhibitors post CDK, so we’d really look forward to seeing how these data will impact our current care.
Hope S. Rugo, MD, FASCO: Can you comment a little bit about the toxicity of these drugs? Is that an issue for us?
Komal Jhaveri, MD, FACP: Yes, that’s another great question. I think predominantly overall if we had to make a broad comment about this class, the most common toxicity that we see is gastrointestinal [GI] toxicities, usually nausea or diarrhea. They’re usually low-grade toxicities. We have seen reports of fatigue as we see with other anti-cancer therapies. We’ve also seen some hot flashes and arthralgias reported with some of these agents. Then some of these agents do have reports of bradycardia and visual disturbances, which is very interesting because we really don’t understand the true pathophysiology of these [adverse] effects. There are some nuances in the [adverse] effect profile for a given agent but overall, they’re well tolerated or generally well tolerated with low-grade GI toxicities.
Hope S. Rugo, MD, FASCO: That’s really interesting. You mentioned about the proteolysis-targeting chimera, PROTAC. The pictures for this, the diagrams are just very complex. The drug which has been studied most is ARV471, now also being codeveloped with Arvinas [ph] and Pfizer. Erica Hamilton has reported some interesting work with this agent both alone and in combination with palbociclib. What’s your take on that?
Komal Jhaveri, MD, FACP: That seems to be a very interesting molecule and a very interesting mechanism of action as well. This is the first in class for a PROTAC and I’m sure we’ll see more and more generations of PROTACs. We have a PROTAC for AR [androgen receptor] as well; this one is obviously for ER. As you said, Erica Hamilton did present monotherapy data with this. In about 47 patients, the clinical benefit rate was about 40%. The drug was very well tolerated; there was very low-grade nausea or GI [adverse] effects that we saw. I think there is an ongoing phase 1/2 trial that is now evaluating a combination with palbociclib and this PROTAC. This is because it’s a phase 1/2 study; it is even allowing more than 1 prior line of endocrine therapy, no more than 2 lines of chemotherapy. It’d be interesting to see how this combination plays out and what the next steps in the phase 3 trials would look like, including in the first-line with palbociclib or post CDK4/6.
Hope S. Rugo, MD, FASCO: Yes, and they’re really moving ahead very quickly with all of these trials. There also was another interesting agent presented here, lasofoxifene. Go back to selective estrogen receptor modulators, a SERM. ELAINE 1 looked at lasofoxifene alone vs endocrine therapy, a physician choice that hasn’t been presented yet, a larger randomized trial. What they did present was ELAINE 2, which is an open-label phase 2 trial just looking at the safety of lasofoxifene and abemaciclib. There were only 29 patients. But lasofoxifene is very well tolerated and the [adverse] effects seem to be all [abemaciclib]-related. Some people dose-reduced. But the PFS [progression-free survival] was 13.9 months in 72% of patients that had prior fulvestrant and all but 1 had had a prior CDK4/6 inhibitor. It’s quite tiny numbers, but quite intriguing. I look forward to seeing ELAINE 2 and of course they have a number of other studies in combination with CDK4/6 inhibitors. Then there’s a selective androgen receptor modulator, a novo SERM that’s also being studied in a randomized trial, that I think is another intriguing agent.
Transcript edited for clarity.