SABCS 2024: Combination of Elacestrant and Abemaciclib Shows Promising Progression-Free Survival in ER+/HER2- Advanced Breast Cancer

In an interview with Pharmacy Times®, Hope Rugo, MD, professor of medicine at the University of California San Francisco (UCSF), shared that the combination of the oral selective estrogen receptor degrader (SERD) elacestrant and the CDK4/6 inhibitor abemaciclib, demonstrated encouraging progression-free survival of nearly 9 months in patients with ER+, HER2- advanced or metastatic breast cancer. This included patients with estrogen receptor 1 (ESR1) mutations, which are a common resistance mechanism seen with prior endocrine therapies. Rugo noted that the combination was well-tolerated, with no new safety signals, suggesting this may be an effective treatment approach to overcome resistance in this patient population.

Pharmacy Times

What are the potential benefits of combining elacestrant plus abemaciclib in patients with estrogen receptor-positive ER+, HER2- advanced or metastatic breast cancer?

Hope Rugo, MD

We have a world of expanding endocrine therapies that are being tested in the treatment of hormone receptor positive, HER2 negative breast cancer and in the metastatic setting, in particular, where the drugs are first being studied. Although there's a whole host of studies in both the metastatic and early-stage settings with a lot of different designs. The question is, why is this important and how are these new hormone therapies working to counteract resistance? Hormone receptor positive, HER2 negative disease is the most common subset of breast cancer, which is the most common cancer in women worldwide. So, it is a huge number of patients, and we know that although we're curing more and more women with early-stage breast cancer, that we still have a large group of patients with metastatic disease where HR+, HER2- disease predominates.

We really struggle in breast oncology, and I think in all the field of oncology, in identifying resistance mechanisms, but in particular in identifying ways to overcome these resistant mechanisms. What we know is that under the pressure of treatment, that breast cancer is about 40% developed mutations in the estrogen receptor, and they're called ESR1-mutations. There are many different ones that can be seen and are really caused by the treatment that you give. We see, for example, an untreated metastatic disease that ESR1-mutations are in the 4% or less range, but it goes up to 40% under the pressure of treatment. So, the treatment we give improves progression free survival, but it also generates this mechanism of resistance. We also know that fulvestrant — prior endocrine standard after aromatase inhibitors, does work, but it doesn't work very well in patients who have ESR1-mutations. Actually, it doesn't turn out to work all that well in the majority of patients — unless they have exquisitely endocrine sensitive disease, also it's an injection which patients don't really like, 2 injections every month.

So, this whole field of developing selective estrogen receptor down regulators and degraders that are oral has really exploded. Elacestrant is our only approved oral SERD at the moment. This drug actually has already been shown to improve progression free survival in the ESR1-mutant population compared to standard endocrine therapy in the second or greater line setting. So, that's already very encouraging. These drugs are very well tolerated in general, and elacestrant is very well tolerated in the clinical setting.

We're really interested now in moving forward with combining endocrine therapy with targeted agents. Even at this meeting, at SABCS 2024, we saw data that giving a CDK4/6 inhibitor after progression on a CDK4/6 inhibitor may improve progression free survival over giving an endocrine therapy alone. In order to address that interest as practitioners, we want to give single agent endocrine therapy — we want combinations. We wanted to understand how we could optimize the approach, maintain the benefit of using an oral SERD, elacestrant in the ESR1 mutant population, and then add a targeted agent.

The first thing we did to understand that was to combine all these different targeted agents with elacestrant and we have completed the dose expansion now with abemaciclib and elacestrant, but we have many more subsets, including our most recent subset with capivasertib and a subset where we're still looking for a randomized phase 2 dose with ribociclib. But overall, the combinations were very well tolerated. Interestingly, although preclinical data suggests some drug interactions, we didn't see any. The pharmacokinetics were all very favorable, and the toxicity profile just looked like you were giving the targeted agent with our standard endocrine therapies.

We were able to actually look at progression free survival in 38 patients who had received the RP2D or the randomized phase 2, so called dose — that we used to call MTD, but the full dose of abemaciclib and the full dose of elacestrant. We saw very impressive progression free survival in this patient group of just under 9 months — 8.7 months. When we looked at the patients who had ESR1-mutations, we saw it was still 8.7 months, a little bit shorter, but less than a month difference in the wild type population. That was really encouraging. Then we looked at the subset, again, very small numbers of patients who actually had CDK4/6 inhibitors for more than a year, where we know that subsequent endocrine therapy and elacestrant is likely to be more effective, because these are patients with very endocrine sensitive disease. There the median PFS was 16.6 months. Again, small numbers, but very encouraging. With no new toxicity signals at all. It just looked like you were giving abemaciclib with any of our other endocrine agents.

I think this is really encouraging, and it begs the question of how we should move forward with new oral SERDS and combining them with targeted agents — since we don't want to do a million phase 3 studies, and nobody's going to be willing to not give the targeted agents. I think that we really need to look at getting enough data in patient populations that we can be sure of not just the safety, which we're sure of now, but also the efficacy. We just need a slightly larger patient population. That will be really helpful for us in the future. We're excited about the ability to combine elacestrant with different targeted agents, and now we have efficacy data with abemaciclib. We had a little bit of preliminary efficacy data with everolimus, and we'll have more with the other target agents in the near future.