Novel Agents Under Study for HR+/HER2- MBC


A panel of breast oncologists highlight exciting treatment strategies being explored in clinical trials to help address treatment limitations in HR+/HER2- metastatic breast cancer.

Joyce O’Shaughnessy, MD: Sarah, what are some of the other agents being looked at to help address some of the mechanisms of resistance that may be driving progression on CDK4/6? What are some of the other hypotheses going on?

Sarah Sammons, MD: Endocrine therapy in CDK4/6 inhibitor resistance has been studied extensively at this point. We have the circulating tumor DNA data from PALOMA-3. Those data showed us that emergence of RB1 mutations that lead to functional loss of RB1 may be 1 of the areas implicated in resistance. We’re also seeing some upregulation of CDK2, some upregulation of CDK7. There are some clinical trials with new CDK inhibitors that target CDK2, specifically target CDK7. Those are ongoing. A crowded space right now is the oral SERD [selective estrogen receptor degrader], SERM [selective estrogen receptor modulators], SERCA [sarcoplasmic reticulum calcium-ATPase] area. ESR1 mutations are implicated in endocrine resistance in about 40% of patients. Unlike PI3-kinase mutations, these mutations do evolve over time in patients who are on aromatase inhibitors [AIs] and patients on fulvestrant and CDK4/6 inhibitors.

Fulvestrant, we know from retrospective series, seems to work better than aromatase inhibitors for ESR1 mutations. However, its single-agent efficacy in ESR1-mutant breast cancer is still not great. There are ESR1 mutations, like Y537S, that seem to be resistant to ESR1 mutations. Preclinical data are showing that oral SERDs and SERMs, like lasofoxifene, seem to have much better efficacy in ESR1-mutant breast cancer than fulvestrant and then aromatase inhibitors. There are many oral SERDs out there. Elacestrant, amcenestrant, giredestrant are some of the ones in later-phase clinical trials. We saw the first neoadjuvant study that Sara Hurvitz presented with giredestrant vs AI in a neoadjuvant setting, and it seemed to lead to fairly robust cell cycle arrest, which was exciting. There are many ongoing phase 3 trials going on as well.

Joyce O’Shaughnessy, MD: Thanks a lot. The oral SERDs really are interesting, aren’t they? The SERCAs and the SERMs for the ESR1-mutant patients in particular. It’d be nice to have a better single-agent endocrine therapy to offer patients post-CDK4/6. We can still do it, but as you said, we have limited effectiveness with fulvestrant post–CDK4/6. We saw that in VERONICA, the failed trial of venetoclax with fulvestrant post–CDK4/6. It was just shy of 3 months, or right around 3 months, median PFS [progression-free survival] with fulvestrant as a single agent. We need some improvement, clearly. Hopefully the oral SERDs, SERCAs, and SERMs will do that for patients. Gabe, what other agents, what other novel strategies, are hopefully going to come into the HR [hormone receptor]–positive, HER2 [human epidermal growth factor receptor 2]–negative metastatic space to make the next big advances for patients?

Gabriel Hortobagyi, MD, MACP, FASCO: These are very exciting times and arguably the most exciting times since I’ve been in oncology, which is more than a few weeks. First, an area we haven’t mentioned is that a number of other CDK inhibitors are under development: CDK2, CDK7, CDK9, CDK12. Some of them are in clinical trials. Some of them were developed to address CDK4/6 resistance. There’s hope that some of them will turn out to be of great interest.

We haven’t touched on the area of DNA repair. Of course, some of the hormone receptor–positive breast cancers have BRCA mutations. We have the entire field of PARP inhibitors making progress finally. You were 1 of the early investigators involved in this field, so you have followed that very closely. And there are some exciting things happening. The OLYMPIA trial has shown some advantage in the metastatic setting, and recently it was reported to show that olaparib prolonged relapse-free survival in the primary BRCA-mutated population. That’s very exciting. In the wake of olaparib, there are, of course, other PARP inhibitors. Talazoparib is arguably 1 of the more exciting ones. There are some newer ones, like pamiparib—it’s reported to be about 16-fold more potent than olaparib.

Joyce O’Shaughnessy, MD: Wow.

Gabriel Hortobagyi, MD, MACP, FASCO: We’ll have to see how this field evolves, but it’s very exciting. The area that’s relatively novel, even though it’s relatively very old, is the area of androgen receptor [AR] inhibition. We’ve ignored that to a large extent because we didn’t quite understand what androgens and androgen receptors were supposed to do. But there’s some emerging understanding of that. The Breast Cancer Research Foundation is funding a multiproject program to address this issue, to understand the biology of androgen receptor, and to understand the activity of androgen receptor–active agents. Many of the early clinical trials are based on enzalutamide, but of course there are other AR inhibitors that are of great interest. This is relevant not only to ER+, HER2- breast cancer but also to the triple-negative population.

Finally, the most exciting part for me, and something that was underlined at this ESMO [European Society for Medical Oncology Congress] presentation, is the area of antibody-drug conjugates [ADCs]. While many of the antibody-drug conjugates focus on the HER2+ population and, to a lesser extent, the triple-negative population, some are clearly focused on the HR+, HER2- breast cancer. Sacituzumab govitecan is 1. We already have data that suggest that about a third of the patients with HR+ breast cancer benefit from this drug. Then there’s the low HER2, ER+ population where the trastuzumab deruxtecan data suggest there might be extension of the activity of that ADC beyond the HER2+ data. There are many more, but there’s not enough time to talk about them. This is a very exciting field because the technology gives us the possibility of developing many more of these, having identified many relevant and worthwhile targets.

Joyce O’Shaughnessy, MD: As soon as we get great data in the metastatic setting, we get them right into the curative setting. There’s a superhighway from metastatic to the curative. It’s really good. We have to pat ourselves on the back about how quickly and courageously we bring things from the metastatic into the curative setting.

Transcript edited for clarity.

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