Broad perspectives on various novel mechanisms of action that may address acquired resistance to therapies for HR+/HER2- metastatic breast cancer.
Harold Burstein, MD, PhD: SERDs [selective estrogen receptor degraders] are an interesting class of drug that binds to the estrogen receptor and cause it to be broken down by the cell machinery that breaks down proteins. We use a SERD every day: fulvestrant, which is an effective drug for ER [estrogen receptor]–positive metastatic breast cancer. But there have always been some issues with fulvestrant. One is that it’s a monthly intramuscular injection, which is no fun for patients. It takes awhile to get up to therapeutic doses. You have to give a loading dose, and pharmacologically a once-a-month dose, which means it’s probably not a consistent-dose drug.
There’s been a lot of thought over the past 15 to 20 years, when using fulvestrant, that it would be great to have an oral version of a SERD. Many companies have begun developing oral SERDs, and we’re seeing the first reports of randomized data coming forward. In December 2021, we saw results from the EMERALD study, which was a comparison of the oral SERD fulvestrant vs a physician’s choice of other endocrine therapies, whether it’s an aromatase inhibitor or fulvestrant in second-line treatment of ER+ metastatic breast cancer. In that study, which was just published in the Journal of Clinical Oncology, an interesting observation was made about half the tumors being resistant to both therapies. In the half who don’t immediately progress, there’s a tale that favors the outcome for the elacestrant arm compared with fulvestrant or the dealer’s choice of drugs. That’s a little more pronounced in tumors that have an ESR1 mutation.
This suggests that this class of drugs is going to have activity, and if we can identify the correct patient population by prior therapy and the correct tumor biology, perhaps by looking at those tumors with ESR1 mutations, then we can improve the longer-term outcomes by using 1 of these novel oral SERDs, which is obviously very convenient for patients as opposed to getting the shot.
There have been 2 other trials that have recently reported…looking at SERDs. One was MIRA-3, which was a similar trial looking at anastrozole vs either fulvestrant or an aromatase inhibitor in the second line or beyond therapy of ER+ metastatic breast cancer. The press statements say the study did not meet its progression-free survival end point. Similarly, there was a randomized study with a drug called giredestrant, which is another orally available SERD that had a fundamentally similar design. This was a randomized phase 2 trial, and it also didn’t meet its progression-free survival end point.
In each of these latter trials, we’re still waiting for the full report of the data, and we’re also going to be really interested in how these compared specifically with, say, fulvestrant and perhaps even more narrowly in those tumors with ESR1 mutations. It’s an exciting class of drugs we’re seeing with some early study results coming in. We had 1 positive study, and we’ve had a couple of not-positive studies, so we’re still sorting out where these drugs are going to fit. The question is: are they better than fulvestrant and, if so, in which patients?
Richard Finn, MD: The studies that we’ve looked at in the clinic have identified some alterations, such as cyclin E amplification or gains in cyclin E, which may be a way to bypass the CDK4/6 pathway. In that group of patients, a CDK2 inhibitor might be of interest. That story is being pursued. We know that PI3K mutations occur in breast cancer, and PI3K inhibitors have activity, probably after patients have prior CDK inhibitors. That’s not to say that this alteration is driving that resistance. We commented a little before that patients can have BRCA mutations in ER+ HER2 [human epidermal growth factor receptor 2]–negative breast cancer. The role of PARP inhibitors in this population is also being explored.
As far as novel targets, preclinical data suggest that alterations in the fibroblast growth factor receptor family, which has been pursued for a long time in breast cancer, might be driving resistance. I’m sure we’ll be seeing studies evaluating and targeting this alteration as well. Also, there’s interest in other endocrine partners. My colleagues talked about the SERDs being looked at in this group as well. There has been an interest in BCL2 inhibitors in ER+ disease. A number of avenues are being looked at. However, at this time, no one can say which mechanism is most important. I don’t know that any of these is going to be broadly important vs identifying subgroups that might be dependent on these pathways.
Harold Burstein, MD, PhD: The success of the CDK4/6 inhibitors has made people interested in other cyclin-independent kinases that might regulate cell growth and division in ER+ metastatic breast cancer. There are other enzymes involved in this whole process. There’s CDK2, CDK9, and CDK7. Companies are developing selective inhibitors, like tyrosine kinase inhibitors that go after different components of this cell cycle machinery. One CDK7. It’s an interesting target. There’s been speculation that CDK7 function may accommodate or account for the resistance to CDK4/6 inhibitors. It’s a very rational target based on what’s been reported in the success spaces for CDK4/6 inhibitors and what the preclinical models suggest. Therefore, we’re looking forward to seeing how the data come forward for that class of drugs.
Transcript edited for clarity.